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Weiss-Tessbach M, Dizdarevic AM, Kupis A, Bischof T, Firbas C, Quehenberger P, Derhaschnig U, Frimmel M, Jilma B, Schoergenhofer C. Osmotic laxatives do not alter dabigatran plasma concentration in healthy volunteers - a randomized, controlled, cross-over trial. Front Pharmacol 2025; 16:1579014. [PMID: 40421205 PMCID: PMC12104081 DOI: 10.3389/fphar.2025.1579014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Accepted: 04/28/2025] [Indexed: 05/28/2025] Open
Abstract
Background Laxatives are among the most commonly used pharmacological agents worldwide. Available data indicate a significant potential for clinically relevant drug-drug interactions. We hypothesized that osmotic laxatives may reduce the oral bioavailability of the direct oral anticoagulant dabigatran and thereby its anticoagulant effects. Methods In the first part of this single-centre, randomized, double-blind, crossover trial, 24 healthy volunteers received 150 mg dabigatran with placebo (10 g glucose) or 20 g lactulose. In the second, open label part, eight of these 24 healthy volunteers were randomly assigned to receive dabigatran with either 27.6 g macrogol, 30 g flaxseeds, or to receive 20 g lactulose 4-h after dabigatran intake. We measured dabigatran plasma concentrations using an ecarin-based chromogenic assay and calculated the pharmacokinetic parameters. Statistical analysis was performed using a linear mixed-effects model on log-transformed AUC values. Results The main pharmacokinetic parameters AUC, Cmax, Tmax, or t1/2 did not differ significantly between most treatment periods. A reduction in AUC was observed with flaxseed compared to placebo. Dabigatran's pharmacokinetics remained unaffected by concomitant intake of lactulose or macrogol. There was a high inter- and intra-individual variability in the pharmacokinetics of dabigatran. Conclusion In this study osmotic laxatives such as lactulose, macrogol or flaxseeds did not affect the pharmacokinetics of dabigatran in healthy individuals. These findings support the safe concurrent use of dabigatran with osmotic laxatives.
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Affiliation(s)
| | - Al Medina Dizdarevic
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Vienna, Austria
| | - Alexander Kupis
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Vienna, Austria
| | - Thorsten Bischof
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Vienna, Austria
| | - Christa Firbas
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Vienna, Austria
| | - Peter Quehenberger
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Vienna, Austria
| | - Ulla Derhaschnig
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Vienna, Austria
| | - Max Frimmel
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Vienna, Austria
| | - Bernd Jilma
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Vienna, Austria
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Romański M, Staniszewska M, Myslitska D, Paszkowska J, Banach G, Polak S, Garbacz G, Danielak D. Gastric stress events impact the bioavailability of a poorly soluble weak base dabigatran from pellet-filled capsules: An outcome from pharmacokinetic simulations based on biorelevant dissolution testing, machine learning, and a novel timewise first-order dissolution model. Int J Pharm 2025; 674:125464. [PMID: 40086652 DOI: 10.1016/j.ijpharm.2025.125464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 03/10/2025] [Accepted: 03/11/2025] [Indexed: 03/16/2025]
Abstract
Current physiologically-based biopharmaceutics modeling (PBBM) neglects the effect of gastrointestinal stress events on the disintegration and dissolution of oral solid dosage forms. Biorelevant dissolution testing can simulate the behavior of drug products under physiological agitation but a workload limits variability examination. In this study, we overcame these deficiencies by inputting dissolution profiles generated by machine-learning (ML) into PBBM-based simulations. Our specific aim was to examine how the varied timing of intragastric stress and housekeeping wave (GET) and fasted stomach pH affect dabigatran exposure from the Pradaxa capsule. Twenty experimental dissolution profiles of dabigatran etexilate from the flow-through apparatus PhysioCell and 1,036 ML-derived profiles representing various gastric motility patterns were a basis for single-dose simulations. A novel timewise dissolution model, which estimates the first-order rate constants at consecutive two-point time intervals, provided an excellent fit to the highly irregular and variable dissolution curves (coefficient of determination ≥ 0.9835, median 0.9992). The time between the onset of dissolution (Tlag), either intragastric stress-related or spontaneous, and the housekeeping wave (GET) systematically impacted the bioavailability of dabigatran. Regardless of gastric emptying rate constant and pH, the dabigatran bioavailability was an increasing sigmoid function of the GET - Tlag difference, with the midpoint around 7 min and plateau of 7-8% after 20 min. The plasma concentrations and bioavailability of dabigatran simulated under varied gastric motility well matched clinical data reported for healthy subjects. We expect that the proposed approach will improve the prediction of the in vivo variability of oral formulations.
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Affiliation(s)
- Michał Romański
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 3 Rokietnicka St. 60-806 Poznań, Poland.
| | | | | | | | | | - Sebastian Polak
- Department of Pharmaceutical Technology and Biopharmaceutics, Jagiellonian University Medical College, 9 Medyczna St. 30-688 Cracow, Poland
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Dong J, Jin Z, Li C, Yang J, Jiang Y, Li Z, Chen C, Zhang B, Ye Z, Hu Y, Ma J, Li P, Li Y, Wang D, Ji Z. Machine Learning Models With Prognostic Implications for Predicting Gastrointestinal Bleeding After Coronary Artery Bypass Grafting and Guiding Personalized Medicine: Multicenter Cohort Study. J Med Internet Res 2025; 27:e68509. [PMID: 40053791 PMCID: PMC11926454 DOI: 10.2196/68509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 02/04/2025] [Accepted: 02/13/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND Gastrointestinal bleeding is a serious adverse event of coronary artery bypass grafting and lacks tailored risk assessment tools for personalized prevention. OBJECTIVE This study aims to develop and validate predictive models to assess the risk of gastrointestinal bleeding after coronary artery bypass grafting (GIBCG) and to guide personalized prevention. METHODS Participants were recruited from 4 medical centers, including a prospective cohort and the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. From an initial cohort of 18,938 patients, 16,440 were included in the final analysis after applying the exclusion criteria. Thirty combinations of machine learning algorithms were compared, and the optimal model was selected based on integrated performance metrics, including the area under the receiver operating characteristic curve (AUROC) and the Brier score. This model was then developed into a web-based risk prediction calculator. The Shapley Additive Explanations method was used to provide both global and local explanations for the predictions. RESULTS The model was developed using data from 3 centers and a prospective cohort (n=13,399) and validated on the Drum Tower cohort (n=2745) and the MIMIC cohort (n=296). The optimal model, based on 15 easily accessible admission features, demonstrated an AUROC of 0.8482 (95% CI 0.8328-0.8618) in the derivation cohort. In external validation, the AUROC was 0.8513 (95% CI 0.8221-0.8782) for the Drum Tower cohort and 0.7811 (95% CI 0.7275-0.8343) for the MIMIC cohort. The analysis indicated that high-risk patients identified by the model had a significantly increased mortality risk (odds ratio 2.98, 95% CI 1.784-4.978; P<.001). For these high-risk populations, preoperative use of proton pump inhibitors was an independent protective factor against the occurrence of GIBCG. By contrast, dual antiplatelet therapy and oral anticoagulants were identified as independent risk factors. However, in low-risk populations, the use of proton pump inhibitors (χ21=0.13, P=.72), dual antiplatelet therapy (χ21=0.38, P=.54), and oral anticoagulants (χ21=0.15, P=.69) were not significantly associated with the occurrence of GIBCG. CONCLUSIONS Our machine learning model accurately identified patients at high risk of GIBCG, who had a poor prognosis. This approach can aid in early risk stratification and personalized prevention. TRIAL REGISTRATION Chinese Clinical Registry Center ChiCTR2400086050; http://www.chictr.org.cn/showproj.html?proj=226129.
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Affiliation(s)
- Jiale Dong
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- Department of Acute Abdomen Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing, China
- Department of General Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Zhechuan Jin
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Chengxiang Li
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Jian Yang
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Yi Jiang
- Department of Cardiovascular Surgery, Nanjing Drum Tower Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, China
| | - Zeqian Li
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Cheng Chen
- Department of Cardiovascular Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Beijing, China
| | - Bo Zhang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
- Department of General Surgery, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Zhaofei Ye
- Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Yang Hu
- Department of General Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Jianguo Ma
- School of Instrumentation and Optoelectronic Engineering, Beihang University, Beijing, China
| | - Ping Li
- Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Yulin Li
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Dongjin Wang
- Department of Cardiovascular Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Beijing, China
| | - Zhili Ji
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- Department of Acute Abdomen Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing, China
- Department of General Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
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Bosch A, Olivieri M, Holzhauer S. The Use of DOACs in Pediatrics: Current Therapeutic and Prophylactic Indications, Cardiac Indications, and Real-World Evidence-A Review. Hamostaseologie 2025; 45:89-101. [PMID: 39970905 DOI: 10.1055/a-2486-6735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2025] Open
Abstract
Based on clinical trials that have been conducted and published in the past decade, direct oral anticoagulants (DOACs) are increasingly being used as an antithrombotic treatment in children with venous thrombotic events and to prevent thrombotic events in children at risk. In this review, current indications and standards for the initiation of DOACs in children are summarized for the treatment of venous thrombotic events and for the primary and secondary prevention in children at risk of developing thromboses based on the published randomized controlled trials (RCT). Similarly, indications for DOACs in children with underlying cardiac disease are portrayed based on RCT findings. Lastly, available real-world data are reviewed for the use of DOACs in pediatric patients with a focus on patients at higher risk of both thrombosis and bleeding who were primarily excluded from the RCTs. DOACs contribute largely to the evolving individualization of care of thrombotic events in children, but at-risk patient populations remain underrepresented regarding DOAC experience, such as preterm infants, and children with severe renal or hepatic disease. Real-world data from observational studies and registries will continue to be necessary to establish DOACs' effectiveness and safety in children in everyday clinical use.
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Affiliation(s)
- Alessandra Bosch
- Department of Haematology, University Children's Hospital Zurich - Eleonore Foundation, Zurich, Switzerland
| | - Martin Olivieri
- Paediatric Thrombosis and Haemostasis Unit, Dr. Von Hauner Children's Hospital, LMU Clinic, LMU Munich, Germany
| | - Susanne Holzhauer
- Department of Paediatric Haematology and Oncology, Paediatric Haemostasis Centre, Charité University Medicine, Berlin, Germany
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Park JW, Kim JM, Bang YY, Kim KA, Yu S, Park JY. UGT2B15 single nucleotide polymorphism reduces dabigatran acylglucuronide formation in humans. Front Pharmacol 2025; 15:1507915. [PMID: 39850575 PMCID: PMC11754044 DOI: 10.3389/fphar.2024.1507915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 12/02/2024] [Indexed: 01/25/2025] Open
Abstract
Background Dabigatran etexilate (DABE), a prodrug of dabigatran (DAB), is a direct thrombin inhibitor used to prevent ischemic stroke and thromboembolism during atrial fibrillation. The effect of genetic polymorphisms on its metabolism, particularly UGT2B15, has not been extensively explored in humans. This study aimed to investigate the effects of UGT2B15, ABCB1, and CES1 polymorphisms on the pharmacokinetics of DAB and its acylglucuronide metabolites in healthy subjects. Methods A total of 124 healthy males were genotyped for UGT2B15, ABCB1, and CES1 polymorphisms. After a single 150 mg dose of DABE, plasma concentrations of total and free DAB, as well as dabigatran acylglucuronide (DABG) were measured using LC-MS/MS. Pharmacokinetic parameters were analyzed using non-compartmental methods, and statistical comparisons were conducted between the genotype groups. Results UGT2B15 c.253G>T significantly affected free DAB pharmacokinetics, with a lower Tmax and oral clearance in TT genotype (n = 28, p < 0.05). For DABG, Cmax was significantly higher in GG genotypes (n = 32, 42.3 ± 16.3 ng/mL) compared to that in GT (n = 64, 32.4 ± 20.5 ng/mL) and TT (29.7 ± 17.1 ng/mL) genotypes. Similarly, the AUCall of DABG was highest in GG genotypes (327 ± 148.3 ng h·mL-1), followed by GT (238.7 ± 166.5 ng h·mL-1) and TT (223.3 ± 165.4 ng h·mL-1) genotypes (p < 0.05). The metabolite-to-parent ratios (m/p ratios) for Cmax and AUCall were significantly higher in GG and GT genotypes than that in TT genotype. ABCB1 and CES1 polymorphisms had no significant impact on the pharmacokinetics of DAB or DABG. Conclusion UGT2B15 polymorphisms were associated with difference in DAB glucuronidation and pharmacokinetics in healthy male participants.
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Affiliation(s)
- Jin-Woo Park
- Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
- Department of Neurology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Jong-Min Kim
- Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Young Yoon Bang
- Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Kyoung-Ah Kim
- Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Sungwook Yu
- Department of Neurology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Ji-Young Park
- Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
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Eaton MP, Nadtochiy SM, Stefanos T, Anderson BJ. Dabigatran pharmacokinetic-pharmacodynamic in sheep: Informing dose for anticoagulation during cardiopulmonary bypass. Perfusion 2025; 40:183-191. [PMID: 38171494 PMCID: PMC11715065 DOI: 10.1177/02676591231226291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
BACKGROUND The effect of the anticoagulant, dabigatran, and its antagonist, idarucizumab, on coagulation remains poorly quantified. There are few pharmacokinetic-pharmacodynamic data available to determine dabigatran dose in humans or animals undergoing cardiopulmonary bypass. METHODS Five sheep were given intravenous dabigatran 4 mg/kg. Blood samples were collected for thromboelastometric reaction time (R-time) and drug assay at 5, 15, 30, 60, 120, 240, 480 min, and 24 h. Plasma dabigatran concentrations and R-times were analyzed using an integrated pharmacokinetic-pharmacodynamic model using non-linear mixed effects. The impact of idarucizumab 15 mg/kg administered 120 min after dabigatran 4 mg/kg and its effect on R-time was observed. RESULTS A 2-compartment model described dabigatran pharmacokinetics with a clearance (CL 0.0453 L/min/70 kg), intercompartment clearance (Q 0.268 L/min/70 kg), central volume of distribution (V1 2.94 L/70 kg), peripheral volume of distribution (V2 9.51 L/70 kg). The effect compartment model estimates for a sigmoid EMAX model using Reaction time had an effect site concentration (Ce50 64.2 mg/L) eliciting half of the maximal effect (EMAX 180 min). The plasma-effect compartment equilibration half time (T1/2keo) was 1.04 min. Idarucizumab 15 mg/kg reduced R-time by approximately 5 min. CONCLUSIONS Dabigatran reversibly binds to the active site on the thrombin molecule, preventing activation of coagulation factors. The pharmacologic target concentration strategy uses pharmacokinetic-pharmacodynamic information to inform dose. A loading dose of dabigatran 0.25 mg/kg followed by a maintenance infusion of dabigatran 0.0175 mg/kg/min for 30 min and a subsequent infusion dabigatran 0.0075 mg/kg/min achieves a steady state target concentration of 5 mg/L in a sheep model.
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Affiliation(s)
| | | | | | - Brian J Anderson
- Department Anesthesiology, University of Auckland, Auckland, New Zealand
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Cohen H, Bahash N, Raccah B, Matok I, Ekstein D, Goldstein L, Kalish Y, Eyal S. The level is in the details: Why differences between direct-acting oral anticoagulants should be considered in the treatment of patients with epilepsy. Epilepsia 2024; 65:3474-3483. [PMID: 39460651 DOI: 10.1111/epi.18144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 09/07/2024] [Accepted: 09/26/2024] [Indexed: 10/28/2024]
Affiliation(s)
- Hagar Cohen
- Department of Clinical Pharmacy, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Nahawand Bahash
- Department of Clinical Pharmacy, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Bruria Raccah
- Department of Clinical Pharmacy, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Ilan Matok
- Department of Clinical Pharmacy, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Dana Ekstein
- Department of Neurology, Agnes Ginges Center for Human Neurogenetics, Hadassah Medical Organization, Jerusalem, Israel
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Lee Goldstein
- Internal Medicine C and Clinical Pharmacology Unit, Haemek Medical Center, Afula, Israel; affiliated with the Bruce Rapapport School of Medicine, Technion, Haifa, Israel
| | - Yosef Kalish
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
- Department of Hematology, Hadassah Medical Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Sara Eyal
- Department of Clinical Pharmacy, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
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Yang Z, Qu Y, Sun Y, Pan J, Zhou T, Yu Y. Evaluation of Drug-Drug Interactions Between Clarithromycin and Direct Oral Anticoagulants Using Physiologically Based Pharmacokinetic Models. Pharmaceutics 2024; 16:1449. [PMID: 39598572 PMCID: PMC11597346 DOI: 10.3390/pharmaceutics16111449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 10/31/2024] [Accepted: 11/08/2024] [Indexed: 11/29/2024] Open
Abstract
Objective: This study assessed the pharmacokinetic (PK) interactions between clarithromycin (a P-glycoprotein [P-gp] inhibitor) and four direct oral anticoagulants (DOACs) (P-gp substrates) using physiologically based PK (PBPK) models to elucidate the influence of P-gp in the interaction between them. Methods: PBPK models for clarithromycin, DABE-dabigatran (DAB), rivaroxaban, apixaban, and edoxaban were constructed using GastroPlus™ (version 9.9), based on physicochemical data and PK parameters from the literature. The models were optimized and validated in healthy subjects. We evaluated the predictive performance of the established model and further assessed the impact of P-gp on the PK of the four DOACs. Successfully validated models were then used to evaluate potential drug-drug interactions (DDIs) between clarithromycin and the DOACs. Results: The established PBPK models accurately described the PK of clarithromycin, DABE-DAB, rivaroxaban, apixaban, and edoxaban. The predicted PK parameters (Cmax, Tmax, AUC0-t) were within 0.5-2 times the observed values. A sensitivity analysis of P-gp parameters indicated that an increase in P-gp expression was reduced by in vivo exposure to DOACs. The models demonstrated good predictive ability for DDIs between clarithromycin and the anticoagulants, and the ratio of the predicted values to the observed values of Cmax and the area under the curve (AUC) in the DDI state was within the range of 0.5-2. Conclusions: Comprehensive PBPK models for clarithromycin, DABE-DAB, rivaroxaban, apixaban, and edoxaban were developed, which can effectively predict DDIs mediated by P-gp's function. These models provide theoretical support for clinical dose adjustments and serve as a foundation for future PBPK model development for DOACs under specific pathological conditions.
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Affiliation(s)
- Zhuan Yang
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China; (Z.Y.); (Y.S.); (J.P.)
- College of Pharmaceutical Science, Soochow University, Suzhou 215123, China
| | - Yuchen Qu
- School of Pharmacy, Nanjing Medical University, Nanjing 211166, China;
| | - Yewen Sun
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China; (Z.Y.); (Y.S.); (J.P.)
- College of Pharmaceutical Science, Soochow University, Suzhou 215123, China
| | - Jie Pan
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China; (Z.Y.); (Y.S.); (J.P.)
| | - Tong Zhou
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Yunli Yu
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China; (Z.Y.); (Y.S.); (J.P.)
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Torralba EJV, Short RF, Travers JB, Mathis JM. Pharmacology of spinal interventions: review of agents used in spine pain procedures. FRONTIERS IN PAIN RESEARCH 2024; 5:1408905. [PMID: 39444579 PMCID: PMC11496298 DOI: 10.3389/fpain.2024.1408905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 08/22/2024] [Indexed: 10/25/2024] Open
Abstract
Spine procedures are commonly performed to diagnose and treat various spinal conditions, ranging from degenerative disc disease to vertebral fractures. These procedures often involve the use of pharmaceutical agents to enhance the efficacy of the intervention and improve patient outcomes. This review provides an overview of the pharmaceuticals commonly utilized in spine procedures, including corticosteroids, anesthetics, antibiotics, radiographic contrast, neurolytic agents, and materials used in kyphoplasty and vertebroplasty. This review summarizes the utilization of these pharmaceutical agents in spine procedures in an effort to optimize patient outcomes. Understanding the pharmacological properties and appropriate uses of these pharmaceuticals is essential for interventionalist and healthcare providers involved in the care of patients undergoing spinal interventions.
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Affiliation(s)
- Ericson John V. Torralba
- Department of Interventional Radiology, UCLA Medical Center, UCLA David Geffen School of Medicine, Los Angeles, CA, United States
- Boonshoft School of Medicine, Wright State Univeristy, Dayton, OH, United States
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH, United States
| | - Robert F. Short
- Boonshoft School of Medicine, Wright State Univeristy, Dayton, OH, United States
- Department of Therapeutic and Diagnostic Imaging, Dayton VA Medical Center, Dayton, OH, United States
| | - Jeffrey B. Travers
- Boonshoft School of Medicine, Wright State Univeristy, Dayton, OH, United States
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH, United States
| | - John M. Mathis
- Boonshoft School of Medicine, Wright State Univeristy, Dayton, OH, United States
- Department of Therapeutic and Diagnostic Imaging, Dayton VA Medical Center, Dayton, OH, United States
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Kagawa T, Ishikawa S, Hidaka Y, Colvin HS, Nakanishi A, Ohkawa J, Negishi S, Yasutomi E, Yamauchi K, Okamoto K, Sakakihara I, Izumikawa K, Yamamoto K, Takahashi S, Tanaka S, Matsuura M, Wato M, Hasui T, Inaba T. Risk factors for postgastric endoscopic submucosal dissection bleeding in direct oral anticoagulant users. Dig Endosc 2024; 36:1130-1139. [PMID: 38695106 DOI: 10.1111/den.14806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 03/27/2024] [Indexed: 10/12/2024]
Abstract
OBJECTIVES Bleeding after endoscopic submucosal dissection (ESD) for gastric tumors in patients taking antithrombotic drugs, in particular direct oral anticoagulants (DOACs), remains unresolved; therefore, we evaluated the risk factors for post-ESD bleeding and drug differences in patients taking DOACs. METHODS We included 278 patients taking antithrombotic drugs who underwent gastric ESD between January 2017 and March 2022. Antithrombotic drugs were withdrawn following the 2017 guidelines (Appendix on anticoagulants including DOACs). To further clarify differences in antithrombotic agents' effects, the peri-cancerous mucosa in the resected specimen was pathologically evaluated according to the Updated Sydney System. Multivariate analysis was performed to assess the risk of post-ESD bleeding. RESULTS The incidence of post-ESD bleeding in patients taking DOACs was 19.6% (10/51). Among patients taking antithrombotic drugs, DOACs were identified as a possible factor involved in post-ESD bleeding (odds ratio [OR] 4.92). Among patients taking DOACs, possible factors included resection length diameter ≥30 mm (OR 3.72), presence of neutrophil infiltration (OR 2.71), lesions occurring in the lower third of stomach (OR 2.34), and preoperative antiplatelet use (OR 2.22). Post-ESD bleeding by DOAC type was 25.0% of patients (4/16) receiving apixaban, in 20.0% (3/15) receiving edoxaban, in 21.4% (3/14) receiving rivaroxaban, and in none of those receiving dabigatran. CONCLUSIONS The administration of DOACs was shown to be a possible factor involved in post-ESD bleeding, and risk factors for patients taking DOACs included neutrophil infiltration. The pharmacological differences in the effects of DOACs contributing to bleeding in gastric ulcers suggest comparatively less bleeding with dabigatran after ESD.
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Affiliation(s)
- Tomo Kagawa
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Shigenao Ishikawa
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Yu Hidaka
- Department of Medical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hugh Shunsuke Colvin
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Akira Nakanishi
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Jumpei Ohkawa
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Shin Negishi
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Eriko Yasutomi
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Kenji Yamauchi
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Kunio Okamoto
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
- Department of Medical Oncology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Ichiro Sakakihara
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Koichi Izumikawa
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Kumiko Yamamoto
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Sakuma Takahashi
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Shigetomi Tanaka
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Mihoko Matsuura
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Masaki Wato
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Toshimi Hasui
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Tomoki Inaba
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Kagawa, Japan
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11
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Kim JH, Baek E, Kang HE. The pharmacokinetics of dabigatran in a rat model of hyperlipidaemia induced by poloxamer 407. Xenobiotica 2024; 54:723-729. [PMID: 39264043 DOI: 10.1080/00498254.2024.2404168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/09/2024] [Accepted: 09/10/2024] [Indexed: 09/13/2024]
Abstract
Various pharmacokinetic changes have been reported in experimental hyperlipidemic (HL) animal models. To evaluate whether P-glycoprotein (P-gp) activity was affected in HL rats, we assessed the pharmacokinetics of dabigatran after oral administration of dabigatran etexilate (DABE); this is a dabigatran prodrug and a well-known P-gp substrate.HL and control rats exhibited similar area under the plasma concentration-time curve (AUC), total body clearance (CL), and steady state volume of distribution (Vss) values following intravenous administration of dabigatran (1 mg/kg). This suggested that the distribution and elimination of dabigatran were similar in control and HL rats.The hepatic and intestinal P-gp protein levels did not differ significantly between control and HL rats. The dabigatran AUC and extent of absolute oral bioavailability (F) values were similar in control and HL rats following oral administration of DABE (10 mg/kg as dabigatran). Therefore, there was no apparent change in intestinal P-gp activity in HL rats compared to control rats.This study revealed no significant change in P-gp expression or activity in the intestine or liver of HL rats, and similar pharmacokinetics of dabigatran. Hyperlipidaemia may not directly affect the oral absorption of P-gp substrate drugs.
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Affiliation(s)
- Ji Hyeon Kim
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea
| | - Eugene Baek
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea
| | - Hee Eun Kang
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea
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12
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Zaher A, ElSaygh J, Midani A, Treihaft A, Banerji B, Bouso MF, Mushannen M, Hussein R, Crawford CV. A Closer Look into Gastrointestinal Bleeding in Heart Failure Patients. Curr Probl Cardiol 2024; 49:102739. [PMID: 38972470 DOI: 10.1016/j.cpcardiol.2024.102739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Accepted: 07/04/2024] [Indexed: 07/09/2024]
Abstract
BACKGROUND The frequency and risk factors for gastrointestinal bleed (GIB) in patients with heart failure with reduced ejection fraction (HFrEF) have not been extensively researched. OBJECTIVE We aim to assess the frequency of GIB in this subset of patients and identify potential risk factors for bleeding. This study will evaluate the frequency of commonly used antiplatelet and anticoagulation agents in the HFrEF population, as well as look at some of the endoscopic features of the GIB. METHODS A retrospective cohort analysis of 670 patients admitted between November 2021 to August 2023 to a single urban, tertiary teaching institution with acute HFrEF ICD-10 codes. Upper or lower GIB (hematemesis, coffee ground emesis, melena or hematochezia during admission) was identified on a manual chart review. Patients with GIB were defined as our cases. No GIB was defined as our controls. Sub analysis included comparing the use of anticoagulant and antiplatelet between the cohort. Independent t test assessed statistical differences in the case and control groups RESULTS: Out of the 670 patients, 134 (20%) were identified with GIB. The cases were older than the controls (median age 77 vs. 70 years) (p = 0.001), had a lower hemoglobin (9 g/dL vs. 12 g/dL) (p =<0.05), and had higher BNP levels (7,938 pg/ml vs. 6472 pg/ml) (IQR: 3,239, 23,701) (p =<0.01). Among the anticoagulant users, 64% of cases were on an anticoagulant compared to 42% of the controls (p<0.05). Among the antiplatelet users, 68% of the controls were on one or more antiplatelet agents, compared to 52% in the controls (p = 0.01). When combining AC and AP treatment, there was no statistical difference between cases and controls. Ninety-three (69%) patients from cases had cross-sectional imaging with only 23 (25%) showing abnormal findings which included diverticulosis, colitis, and GI masses. When comparing upper endoscopy findings, the presence of esophageal diseases (esophagitis and esophageal varices) and gastric/duodenal diseases (gastritis, gastric ulcer, duodenal ulcer and AVM) were significantly higher in cases compared to controls (p < 0.05). In addition to the colonoscopy findings, polyps and diverticulosis were more prevalent in the cases compared to the controls (p = 0.01). CONCLUSION Heart failure patients are at risk of developing GIB. Age and high BNP on admission are risk factors for GIB, the higher the BNP levels the higher risk of GIB. Anticoagulant and antiplatelet use are associated with a higher risk of bleeding. However, the addition of dual antiplatelet therapy or concurrent antiplatelet and anticoagulation does not increase the risk of GIB. Some of the most common upper endoscopy findings include esophagitis/gastritis and esophageal/gastric ulcer. In terms of colonoscopy, findings include colonic mass, diverticulosis and hemorrhoids.
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Affiliation(s)
- Anas Zaher
- New York Presbyterian-Brooklyn Methodist Hospital/ Weill Cornell Medicine, 506 6th street, Brooklyn, NY 11215, United States.
| | - Jude ElSaygh
- New York Presbyterian-Brooklyn Methodist Hospital/ Weill Cornell Medicine, 506 6th street, Brooklyn, NY 11215, United States
| | - Akram Midani
- New York Presbyterian-Brooklyn Methodist Hospital/ Weill Cornell Medicine, 506 6th street, Brooklyn, NY 11215, United States
| | - Andrew Treihaft
- New York Presbyterian-Brooklyn Methodist Hospital/ Weill Cornell Medicine, 506 6th street, Brooklyn, NY 11215, United States
| | - Brinda Banerji
- New York Presbyterian-Brooklyn Methodist Hospital/ Weill Cornell Medicine, 506 6th street, Brooklyn, NY 11215, United States
| | - Muhammed Fouad Bouso
- New York Presbyterian-Brooklyn Methodist Hospital/ Weill Cornell Medicine, 506 6th street, Brooklyn, NY 11215, United States
| | - Malik Mushannen
- New York Presbyterian-Brooklyn Methodist Hospital/ Weill Cornell Medicine, 506 6th street, Brooklyn, NY 11215, United States
| | - Rawan Hussein
- New York Presbyterian-Brooklyn Methodist Hospital/ Weill Cornell Medicine, 506 6th street, Brooklyn, NY 11215, United States
| | - Carl V Crawford
- New York Presbyterian-Weill Cornell Medicine, 1300 York Ave, New York, NY 10065, United States
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13
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Muric M, Nikolic M, Todorovic A, Jakovljevic V, Vucicevic K. Comparative Cardioprotective Effectiveness: NOACs vs. Nattokinase-Bridging Basic Research to Clinical Findings. Biomolecules 2024; 14:956. [PMID: 39199344 PMCID: PMC11352257 DOI: 10.3390/biom14080956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/18/2024] [Accepted: 07/19/2024] [Indexed: 09/01/2024] Open
Abstract
The use of non-vitamin K antagonist oral anticoagulants (NOACs) has brought a significant progress in the management of cardiovascular diseases, considered clinically superior to vitamin K antagonists (VKAs) particularly in the prevention and treatment of thromboembolic events. In addition, numerous advantages such as fixed dosing, lack of laboratory monitoring, and fewer food and drug-to-drug interactions make the use of NOACs superior to VKAs. While NOACs are synthetic drugs prescribed for specific conditions, nattokinase (NK) is a natural enzyme derived from food that has potential health benefits. Various experimental and clinical studies reported the positive effects of NK on the circulatory system, including the thinning of blood and the dissolution of blood clots. This enzyme showed not only fibrinolytic activity due to its ability to degrade fibrin, but also an affinity as a substrate for plasmin. Recent studies have shown that NK has additional cardioprotective effects, such as antihypertensive and anti-atherosclerotic effects. In this narrative review, we presented the cardioprotective properties of two different approaches that go beyond anticoagulation: NOACs and NK. By combining evidence from basic research with clinical findings, we aim to elucidate the comparative cardioprotective efficacy of these interventions and highlight their respective roles in modern cardiovascular care.
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Affiliation(s)
- Maja Muric
- Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (M.M.); (V.J.)
- Center of Excellence for Redox Balance Research in Cardiovascular and Metabolic Disorders, 34000 Kragujevac, Serbia;
| | - Marina Nikolic
- Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (M.M.); (V.J.)
- Center of Excellence for Redox Balance Research in Cardiovascular and Metabolic Disorders, 34000 Kragujevac, Serbia;
| | - Andreja Todorovic
- Department of Cardiology, General Hospital Ćuprija, 35230 Ćuprija, Serbia;
| | - Vladimir Jakovljevic
- Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (M.M.); (V.J.)
- Center of Excellence for Redox Balance Research in Cardiovascular and Metabolic Disorders, 34000 Kragujevac, Serbia;
- Department of Human Pathology, First Moscow State Medical, University IM Sechenov, 119991 Moscow, Russia
| | - Ksenija Vucicevic
- Center of Excellence for Redox Balance Research in Cardiovascular and Metabolic Disorders, 34000 Kragujevac, Serbia;
- Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
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14
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Xie Y, Lu Z, Styles IK, Reddiar SB, Phillips ARJ, Windsor JA, Porter CJH, Han S, Trevaskis NL. Lymphatic Uptake of a Highly Lipophilic Protease Inhibitor Prodrug from a Lipid-Based Formulation is Limited by Instability in the Intestine. J Pharm Sci 2024; 113:2342-2351. [PMID: 38582284 DOI: 10.1016/j.xphs.2024.03.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 03/31/2024] [Accepted: 03/31/2024] [Indexed: 04/08/2024]
Abstract
Dabigatran etexilate (DABE) is a lipophilic double alkyl ester prodrug of dabigatran (DAB) which is a serine protease inhibitor used clinically as an anticoagulant. Recently, translocation of serine protease enzymes, including trypsin, from the gut into the mesenteric lymph and then blood has been associated with organ failure in acute and critical illnesses (ACIs). Delivery of DABE into mesenteric lymph may thus be an effective strategy to prevent organ failure in ACIs. Most drugs access the mesenteric lymph in low quantities following oral administration, as they are rapidly transported away from the intestine via the blood. Here, we examine the potential to deliver DABE into the mesenteric lymph by promoting association with lymph lipid transport pathways via co-administration with a lipid-based formulation (LBF). A series of self-emulsifying LBFs were designed and tested in vitro for their potential to form stable DABE loaded emulsions and keep DABE solubilised and stable over time in simulated gastrointestinal conditions. The LBFs were found to form fine emulsions with a droplet size of 214 ± 30 nm and DABE was stable in the formulation. The stability of DABE in vitro in simulated intestinal conditions, plasma and lymph samples was also evaluated to ensure stability in collected samples and to evaluate whether the prodrug is likely to release active DAB. Ultimately, a highly uniform and stable self-emulsifying Type III A LBF of DABE was chosen for progression into in vivo studies in male Sprague Dawley rats to confirm the lymphatic uptake and plasma pharmacokinetics. Both in vitro and in vivo in plasma and lymph, DABE was rapidly converted to an intermediate and DAB. The main species present in vivo in both plasma and lymph was DAB and mass transport of DABE and DAB in lymph was minimal (∼0.5 % of dose). Importantly, the concentration of DABE in lymph was substantially (20-176 fold) higher than in plasma, supporting that if the prodrug were stable and did not convert to DAB in the intestine, it would be lymphatically transported. Future studies will therefore focus on optimizing the design of the prodrug and formulation to improve stability during absorption and further promote lymphatic uptake.
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Affiliation(s)
- Yining Xie
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Zijun Lu
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Ian K Styles
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Sanjeevini Babu Reddiar
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | | | - John A Windsor
- Department of Surgery, The University of Auckland, Auckland, New Zealand
| | - Christopher J H Porter
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Sifei Han
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Natalie L Trevaskis
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
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15
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Pereira Portela C, Gautier LA, Zermatten MG, Fraga M, Moradpour D, Bertaggia Calderara D, Aliotta A, Veuthey L, De Gottardi A, Stirnimann G, Alberio L. Direct oral anticoagulants in cirrhosis: Rationale and current evidence. JHEP Rep 2024; 6:101116. [PMID: 39100819 PMCID: PMC11296254 DOI: 10.1016/j.jhepr.2024.101116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 04/19/2024] [Accepted: 04/30/2024] [Indexed: 08/06/2024] Open
Abstract
Cirrhosis is a major health concern worldwide with a complex pathophysiology affecting various biological systems, including all aspects of haemostasis. Bleeding risk is mainly driven by portal hypertension, but in end-stage liver disease it is further increased by alterations in haemostatic components, including platelet function, coagulation, and fibrinolysis. Concurrently, patients with cirrhosis are prone to venous thromboembolic events (VTE) because of the altered haemostatic balance, in particular an increase in thrombin generation. In patients with cirrhosis, vitamin K antagonists (VKA) and low molecular weight heparins (LMWH) are currently the standard of care for VTE prevention, with VKA also being standard of care for stroke prevention in those with atrial fibrillation. However, direct oral anticoagulants (DOAC) could have specific advantages in this patient population. Clinical experience suggests that DOAC are a safe and possibly more effective alternative to traditional anticoagulants for the treatment of VTE in patients with compensated cirrhosis. In addition, emerging data suggest that primary prophylactic treatment with anticoagulants may improve clinical outcomes in patients with cirrhosis by reducing the risk of hepatic decompensation. The selection of the most appropriate DOAC remains to be clarified. This review focuses on the rationale for the use of DOAC in patients with cirrhosis, the specific effects of the different DOAC (as assessed by in vitro and in vivo pharmacokinetic and pharmacodynamic studies), as well as clinical outcomes in patients with cirrhosis on DOAC.
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Affiliation(s)
- Cindy Pereira Portela
- Hemostasis and Platelet Research Laboratory, Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
| | - Lucas A. Gautier
- Hemostasis and Platelet Research Laboratory, Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
| | - Maxime G. Zermatten
- Hemostasis and Platelet Research Laboratory, Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
| | - Montserrat Fraga
- Division of Gastroenterology and Hepatology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
| | - Darius Moradpour
- Division of Gastroenterology and Hepatology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
| | - Debora Bertaggia Calderara
- Hemostasis and Platelet Research Laboratory, Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
| | - Alessandro Aliotta
- Hemostasis and Platelet Research Laboratory, Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
| | - Lucas Veuthey
- Hemostasis and Platelet Research Laboratory, Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
| | - Andrea De Gottardi
- Luzerner Kantonsspital, Lucerne, Switzerland
- Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Lugano, Switzerland
| | - Guido Stirnimann
- University Clinic for Visceral Surgery and Medicine, University Hospital Inselspital and University of Bern, Bern, Switzerland
| | - Lorenzo Alberio
- Hemostasis and Platelet Research Laboratory, Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
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16
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Rao S, Aggarwal S, Mani S, Balasubramanian A, Veluswami K. Uncovering the Role of Direct Oral Anticoagulants in Stroke Prevention for Atrial Fibrillation: A Review of the Literature. Cureus 2024; 16:e63675. [PMID: 39092362 PMCID: PMC11293488 DOI: 10.7759/cureus.63675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/02/2024] [Indexed: 08/04/2024] Open
Abstract
Atrial fibrillation (AF) is a predominant contributor to morbidity and mortality, and stroke prevention remains the mainstay for the management of AF. The precise mechanism involved in thrombus formation remains unknown. However, factors such as stretch-induced fibrosis, endothelial dysfunction, disordered atrial contractions, and pro-thrombotic states have been postulated for the development of AF. Various risk assessment strategies have been acknowledged for determining the risk of stroke in AF, of which the congestive heart failure, hypertension, age ≥75, diabetes, stroke, vascular disease, age between 65-74, and female sex (CHA2DS2-VASc) score remains the ultimate risk stratification tool. For the longest time, vitamin K antagonists (VKA) were the only oral anticoagulants available but were associated with an increased risk of bleeding. Recently, direct oral anticoagulants (DOACs) were approved and considered more efficient and safer than or as secure as warfarin in stroke prevention and lowering intra-cranial bleeding events. The pharmacodynamics and pharmacokinetics of DOACs were also clarified in this article. This review article compiles current evidence-based data on the role of DOACs, uncovering their underlying mechanisms, and comparing their efficacy with warfarin in stroke prevention in AF.
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Affiliation(s)
- Sudipta Rao
- Internal Medicine, JSS Medical College, Mysore, IND
| | | | - Sweatha Mani
- Internal Medicine, K.A.P. Viswanatham Government Medical College, Tiruchirappalli, IND
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17
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Ranjan S, Leung D, Ghiaseddin AP, Taylor JW, Lobbous M, Dhawan A, Budhu JA, Coffee E, Melnick K, Chowdhary SA, Lu-Emerson C, Kurz SC, Burke JE, Lam K, Patel MP, Dunbar EM, Mohile NA, Peters KB. Practical guidance for direct oral anticoagulant use in the treatment of venous thromboembolism in primary and metastatic brain tumor patients. Cancer 2024; 130:1577-1589. [PMID: 38288941 DOI: 10.1002/cncr.35220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 11/17/2023] [Accepted: 11/27/2023] [Indexed: 04/13/2024]
Abstract
Management of venous thromboembolism (VTE) in patients with primary and metastatic brain tumors (BT) is challenging because of the risk of intracranial hemorrhage (ICH). There are no prospective clinical trials evaluating safety and efficacy of direct oral anticoagulants (DOACs), specifically in patients with BT, but they are widely used for VTE in this population. A group of neuro-oncology experts convened to provide practical clinical guidance for the off-label use of DOACs in treating VTE in patients with BT. We searched PubMed for the following terms: BTs, glioma, glioblastoma (GBM), brain metastasis, VTE, heparin, low-molecular-weight heparin (LWMH), DOACs, and ICH. Although prospective clinical trials are needed, the recommendations presented aim to assist clinicians in making informed decisions regarding DOACs for VTE in patients with BT.
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Affiliation(s)
- Surabhi Ranjan
- Department of Neurology, Cleveland Clinic Florida, Weston, Florida, USA
| | - Denise Leung
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
| | - Ashley P Ghiaseddin
- Department of Neurosurgery, University of Florida, Gainesville, Florida, USA
| | - Jennie W Taylor
- Department of Neurology, University of California, San Francisco, California, USA
| | - Mina Lobbous
- Rose Ella Burkhardt Brain Tumor & Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Andrew Dhawan
- Rose Ella Burkhardt Brain Tumor & Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Joshua A Budhu
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Elizabeth Coffee
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Kaitlyn Melnick
- Department of Neurosurgery, University of Florida, Gainesville, Florida, USA
| | - Sajeel A Chowdhary
- Tampa General Hospital Cancer Institute, Tampa General Hospital, Tampa, Florida, USA
| | - Christine Lu-Emerson
- Department of Neurology, Maine Medical Center and Maine Health Cancer Care, Portland, Maine, USA
| | - Sylvia C Kurz
- Department of Neurology & Interdisciplinary Neuro-Oncology, Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Joy E Burke
- Department of Neurology, Beth Israel Lahey Health, Lahey Hospital and Medical Center, Burlington, Massachusetts, USA
| | - Keng Lam
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Mallika P Patel
- Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina, USA
| | | | - Nimish A Mohile
- Department of Neurology, University of Rochester, Rochester, New York, USA
| | - Katherine B Peters
- Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina, USA
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18
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Udomnilobol U, Dunkoksung W, Sakares W, Jianmongkol S, Prueksaritanont T. Assessing the relative contribution of CYP3A-and P-gp-mediated pathways to the overall disposition and drug-drug interaction of dabigatran etexilate using a comprehensive mechanistic physiological-based pharmacokinetic model. Front Pharmacol 2024; 15:1356273. [PMID: 38515840 PMCID: PMC10955231 DOI: 10.3389/fphar.2024.1356273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 02/21/2024] [Indexed: 03/23/2024] Open
Abstract
Dabigatran etexilate (DABE) is a clinical probe substrate for studying drug-drug interaction (DDI) through an intestinal P-glycoprotein (P-gp). A recent in vitro study, however, has suggested a potentially significant involvement of CYP3A-mediated oxidative metabolism of DABE and its intermediate monoester BIBR0951 in DDI following microdose administration of DABE. In this study, the relative significance of CYP3A- and P-gp-mediated pathways to the overall disposition of DABE has been explored using mechanistic physiologically based pharmacokinetic (PBPK) modeling approach. The developed PBPK model linked DABE with its 2 intermediate (BIBR0951 and BIBR1087) and active (dabigatran, DAB) metabolites, and with all relevant drug-specific properties known to date included. The model was successfully qualified against several datasets of DABE single/multiple dose pharmacokinetics and DDIs with CYP3A/P-gp inhibitors. Simulations using the qualified model supported that the intestinal CYP3A-mediated oxidation of BIBR0951, and not the gut P-gp-mediated efflux of DABE, was a key contributing factor to an observed difference in the DDI magnitude following the micro-versus therapeutic doses of DABE with clarithromycin. Both the saturable CYP3A-mediated metabolism of BIBR0951 and the solubility-limited DABE absorption contributed to the relatively modest nonlinearity in DAB exposure observed with increasing doses of DABE. Furthermore, the results suggested a limited role of the gut P-gp, but an appreciable, albeit small, contribution of gut CYP3A in mediating the DDIs following the therapeutic dose of DABE with dual CYP3A/P-gp inhibitors. Thus, a possibility exists for a varying extent of CYP3A involvement when using DABE as a clinical probe in the DDI assessment, across DABE dose levels.
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Affiliation(s)
- Udomsak Udomnilobol
- Chulalongkorn University Drug Discovery and Drug Development Research Center (Chula4DR), Chulalongkorn University, Bangkok, Thailand
| | - Wilasinee Dunkoksung
- Chulalongkorn University Drug Discovery and Drug Development Research Center (Chula4DR), Chulalongkorn University, Bangkok, Thailand
| | - Watchara Sakares
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Suree Jianmongkol
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Thomayant Prueksaritanont
- Chulalongkorn University Drug Discovery and Drug Development Research Center (Chula4DR), Chulalongkorn University, Bangkok, Thailand
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Cross B, Turner RM, Zhang JE, Pirmohamed M. Being precise with anticoagulation to reduce adverse drug reactions: are we there yet? THE PHARMACOGENOMICS JOURNAL 2024; 24:7. [PMID: 38443337 PMCID: PMC10914631 DOI: 10.1038/s41397-024-00329-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 02/11/2024] [Accepted: 02/15/2024] [Indexed: 03/07/2024]
Abstract
Anticoagulants are potent therapeutics widely used in medical and surgical settings, and the amount spent on anticoagulation is rising. Although warfarin remains a widely prescribed oral anticoagulant, prescriptions of direct oral anticoagulants (DOACs) have increased rapidly. Heparin-based parenteral anticoagulants include both unfractionated and low molecular weight heparins (LMWHs). In clinical practice, anticoagulants are generally well tolerated, although interindividual variability in response is apparent. This variability in anticoagulant response can lead to serious incident thrombosis, haemorrhage and off-target adverse reactions such as heparin-induced thrombocytopaenia (HIT). This review seeks to highlight the genetic, environmental and clinical factors associated with variability in anticoagulant response, and review the current evidence base for tailoring the drug, dose, and/or monitoring decisions to identified patient subgroups to improve anticoagulant safety. Areas that would benefit from further research are also identified. Validated variants in VKORC1, CYP2C9 and CYP4F2 constitute biomarkers for differential warfarin response and genotype-informed warfarin dosing has been shown to reduce adverse clinical events. Polymorphisms in CES1 appear relevant to dabigatran exposure but the genetic studies focusing on clinical outcomes such as bleeding are sparse. The influence of body weight on LMWH response merits further attention, as does the relationship between anti-Xa levels and clinical outcomes. Ultimately, safe and effective anticoagulation requires both a deeper parsing of factors contributing to variable response, and further prospective studies to determine optimal therapeutic strategies in identified higher risk subgroups.
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Affiliation(s)
- Benjamin Cross
- Wolfson Centre for Personalised Medicine, Institute of Systems, Molecular and Integrative Biology, The University of Liverpool, 1-5 Brownlow Street, Liverpool, L69 3GL, UK
| | - Richard M Turner
- Wolfson Centre for Personalised Medicine, Institute of Systems, Molecular and Integrative Biology, The University of Liverpool, 1-5 Brownlow Street, Liverpool, L69 3GL, UK
- GSK, Stevenage, Hertfordshire, SG1 2NY, UK
| | - J Eunice Zhang
- Wolfson Centre for Personalised Medicine, Institute of Systems, Molecular and Integrative Biology, The University of Liverpool, 1-5 Brownlow Street, Liverpool, L69 3GL, UK
| | - Munir Pirmohamed
- Wolfson Centre for Personalised Medicine, Institute of Systems, Molecular and Integrative Biology, The University of Liverpool, 1-5 Brownlow Street, Liverpool, L69 3GL, UK.
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20
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Prakasham K, Pan TY, Tan CH, Wu CF, Chandra P, Cheng CM, Chen W, Tsai WC, Ponnusamy VK, Wu MT. A rapid and sensitive analytical methodology for the simultaneous biomonitoring of two direct oral anticoagulant drugs and their major metabolites in thromboembolic disordered patients samples for clinical evaluations. J Chromatogr A 2024; 1717:464689. [PMID: 38295740 DOI: 10.1016/j.chroma.2024.464689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 01/14/2024] [Accepted: 01/25/2024] [Indexed: 02/23/2024]
Abstract
Apixaban and dabigatran are the two major direct oral anticoagulant drugs to treat thromboembolic disordered patients. Increasing the clinical application for the thromboembolic disorder and monitoring the concentrations of apixaban, dabigatran, and their metabolites are essential in most clinical circumstances. In this work, we developed a rapid analytical methodology comprising of vortex-assisted salt-enhanced liquid-liquid microextraction technique coupled with UHPLC-MS/MS for the extraction and simultaneous determination of two major direct oral anticoagulant drugs (apixaban, dabigatran), and their two major metabolites from plasma, serum, and urine samples of patients. The developed method was optimized with various procedural steps and validated to study the analytical merits. The developed method yielded a good detection limit of 0.01 ∼ 0.37 ng/mL, 0.01 ∼ 0.32 ng/ml, and 0.01 ∼ 0.27 ng/mL for four target analytes in the plasma, serum, and urine matrices. Moreover, extraction recoveries ranged from 85.11 - 113.57% (for plasma), 89.63 - 110.47% (for serum), and 87.44 -106.79% (for urine samples) with 8.78% RSD. In addition, the method exhibited good R2 values of 0.999 for all four target analytes, and the specificity and carryover study revealed no carryover effect from the UHPLC-MS/MS system for determining the apixaban, dabigatran, and their metabolites. Due to the above advantages, the developed analytical technique was applied to examine 11 real-time clinical patients' samples, and the observed results were satisfactory for all three different sample matrices. Therefore, this analytical method can be applied for biomonitoring apixaban, dabigatran, and their two major metabolites with high sensitivity in a short time for various clinical applications.
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Affiliation(s)
- Karthikeyan Prakasham
- Research Center for Precision Environmental Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan; Ph.D. Program in Environmental and Occupational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan
| | - Tzu-Yu Pan
- Research Center for Precision Environmental Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan; Ph.D. Program in Environmental and Occupational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan
| | - Chun-Hsiang Tan
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan; Department of Family Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan
| | - Chia-Fang Wu
- Research Center for Precision Environmental Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan; International Master Program of Translational Medicine, National United University, Taiwan
| | - Pranjal Chandra
- Laboratory of Bio-Physio Sensors and Nanobioengineering, School of Biochemical, Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi 221005, India
| | - Ching-Mei Cheng
- Department of Laboratory Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung City, Taiwan
| | - Wei Chen
- Department of Public Health, Kaohsiung Medical University, Kaohsiung City, Taiwan
| | - Wei-Chung Tsai
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University, Hospital, Kaohsiung City, Taiwan; Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Taiwan.
| | - Vinoth Kumar Ponnusamy
- Research Center for Precision Environmental Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan; Ph.D. Program in Environmental and Occupational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan; Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung City-807, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan.
| | - Ming-Tsang Wu
- Research Center for Precision Environmental Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan; Ph.D. Program in Environmental and Occupational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan; Department of Family Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan; Department of Public Health, Kaohsiung Medical University, Kaohsiung City, Taiwan.
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21
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Ximenez JPB, de Andrade JM, Rocha A, Barbosa Coelho E, Suarez‐Kurtz G, Lanchote VL. Intestinal P-gp activity is reduced in postmenopausal women under breast cancer therapy. Clin Transl Sci 2024; 17:e13713. [PMID: 38226443 PMCID: PMC10801393 DOI: 10.1111/cts.13713] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 11/22/2023] [Accepted: 12/07/2023] [Indexed: 01/17/2024] Open
Abstract
Intestinal P-glycoprotein (P-gp) activity plays a crucial role in modulating the oral bioavailability of its substrates. Fexofenadine has commonly been used as a P-gp probe, although it is important to note the involvement of other drug transporters like, OATP1B1, OATP1B3, and OATP2B1. In vitro studies demonstrated an upregulation of P-gp protein in response to exposure to pregnancy-related hormones. The objective of this study was to investigate how intestinal P-gp activity is impacted by menopausal status. This study sampled fexofenadine plasma concentrations over 0-12 h after probe drug administration from two groups of patients with breast cancer: premenopausal (n = 20) and postmenopausal (n = 20). Fexofenadine plasma concentrations were quantified using liquid-chromatography tandem mass spectrometry. Area under the plasma concentration-time curve from zero to infinity (AUCinf ) was calculated through limited sampling strategies equation. Multiple linear regression was applied on AUCinf , maximum plasma concentration (Cmax ), and time to Cmax . Postmenopausal patients showed a significant increase in Cmax (geometric mean and 95% confidence interval [CI] 143.54, 110.95-176.13 vs. 223.54 ng/mL, 161.02-286.06 and in AUCinf 685.55, 534.98-878.50 vs. 933.54 ng·h/mL 735.45-1184.99) compared to premenopausal patients. The carriers of the ABCB1 3435 allele T displayed higher Cmax values of 166.59 (95% CI: 129.44-214.39) compared to the wild type at 147.47 ng/mL (95% CI: 111.91-194.34, p = 0.02). In postmenopausal individuals, the decrease in P-gp activity of ~40% may lead to an increased plasma exposure of orally administered P-gp substrates.
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Affiliation(s)
- Joao Paulo B. Ximenez
- School of Pharmaceutical Sciences of Ribeirao PretoUniversity of Sao PauloRibeirao PretoSao PauloBrazil
| | | | - Adriana Rocha
- School of Pharmaceutical Sciences of Ribeirao PretoUniversity of Sao PauloRibeirao PretoSao PauloBrazil
| | | | - Guilherme Suarez‐Kurtz
- Division of Clinical Research and Technological DevelopmentNational Cancer Institute of BrazilRio de JaneiroRJBrazil
| | - Vera Lucia Lanchote
- School of Pharmaceutical Sciences of Ribeirao PretoUniversity of Sao PauloRibeirao PretoSao PauloBrazil
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22
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Ren Y, Li C, Zhang Y. Preclinical Study on a Novel Fluoroderivative of Dabigatran Etexilate in Animal Models. J Cardiovasc Pharmacol 2024; 83:55-63. [PMID: 37830839 DOI: 10.1097/fjc.0000000000001493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 09/25/2023] [Indexed: 10/14/2023]
Abstract
ABSTRACT Here, the fluorinated derivative, R1, was synthesized from the fluorinated dabigatran derivative (R0). The in vivo pharmacokinetic characteristics of orally administered R1, R0 injection, and dabigatran etexilate in rats were compared. Safety evaluation results showed no significant changes in the QRS wave or PR and QT intervals in rat lead II electrocardiograms. The possible toxicity of R1 was studied using the limit test method, and no obvious toxicity occurred in mice after the acute oral administration of R1. R1 inhibited thrombin-induced platelet aggregation in a dose-dependent manner, had an inhibitory effect on platelet aggregation induced by arachidonic acid and adenosine diphosphate, could significantly prolong prothrombin time and activated partial thromboplastin time, and increased fibrinogen levels. R1 is the optimal candidate compound from among more than 100 candidate compounds designed and synthesized by our research group. It was first selected through preliminary in vitro anticoagulant activity screening and further through in vivo mouse activity testing. A systematic pharmacodynamic study showed that R1 was superior to the raw material drug dabigatran ester; particularly, the absolute bioavailability of R1 increased by 206%, and this can overcome the low bioavailability defect associated with the marketed drug dabigatran ester. Another safety assessment of R1 indicated that there were no risks of acute poisoning in rats and cardiac toxicity in mice or rats. Therefore, R1 can be considered a new candidate anticoagulant compound with great potential and significance for further clinical research.
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Affiliation(s)
- Yujie Ren
- Green and Intelligent Pharmaceutical College, Zhejiang Guangsha Vocational and Technical University of Construction, Dongyang, Zhejiang Province, China; and
| | - Chunlei Li
- Department of Pharmaceutical Engineering, Shanghai Pharmaceutical School, Shanghai, China
| | - Yujia Zhang
- Green and Intelligent Pharmaceutical College, Zhejiang Guangsha Vocational and Technical University of Construction, Dongyang, Zhejiang Province, China; and
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23
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Tran MD, Yasamanova AN, Avakian GG, Nikonova AA, Kamchatnov PR. [The multidirectional effects of thrombin and the possibility of their control in neurology]. Zh Nevrol Psikhiatr Im S S Korsakova 2024; 124:42-48. [PMID: 38512094 DOI: 10.17116/jnevro202412403242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2024]
Abstract
The review presents the main physiological functions of thrombin. The procoagulant and anticoagulant activities of the key serine protease are discussed in both physiological and pathological conditions of hemostasis. The involvement of thrombin in atherogenesis, as well as its role as a mediator of vascular dysfunction and inflammation in both the peripheral and central nervous system, is highlighted. A pronounced imbalance between the pro- and anticoagulant systems leads to an increase in thrombin formation and creates conditions for the development of thrombosis. Tests that allow direct or indirect assessment of thrombin's functional activity are presented. The potential applications of direct thrombin inhibitors and direct blockers of thrombin PAR receptors in vascular neurology are also considered.
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Affiliation(s)
- M D Tran
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - A N Yasamanova
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - G G Avakian
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - A A Nikonova
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - P R Kamchatnov
- Pirogov Russian National Research Medical University, Moscow, Russia
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24
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Yasaka M, Yokota H, Suzuki M, Asakura H, Yamane T, Ogi Y, Kimoto T, Nakayama D. Idarucizumab for Emergency Reversal of the Anticoagulant Effects of Dabigatran: Final Results of a Japanese Postmarketing Surveillance Study. Cardiol Ther 2023; 12:723-740. [PMID: 37845427 DOI: 10.1007/s40119-023-00333-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 09/11/2023] [Indexed: 10/18/2023] Open
Abstract
INTRODUCTION Idarucizumab, a monoclonal antibody fragment that rapidly reverses the anticoagulant effects of dabigatran, was approved in Japan in September 2016, at which time an all-case, postmarketing surveillance (PMS) study was initiated to collect data on idarucizumab in Japanese patients. Interim results were published previously, and the final results are reported herein. METHODS This multicenter, open-label, uncontrolled, non-interventional PMS study was conducted in Japanese patients who received idarucizumab at the approved dose (2 × 2.5 g/50 ml) and had uncontrolled bleeding (group A) or required an emergency procedure (group B). The primary endpoint was the frequency of adverse drug reactions (ADRs). The secondary endpoint was the maximum extent of reversal of the anticoagulant effects of dabigatran, within 4 h of idarucizumab administration, based on activated partial thromboplastin time (aPTT). RESULTS The final analysis included 804 patients. ADRs during the idarucizumab treatment and post-treatment periods were reported in 17 of 542 patients (3.1%) in group A and 12 of 240 patients (5.0%) in group B. Thrombotic events were reported in 22 patients (4.1%) in group A and 15 patients (6.3%) in group B, and hypersensitivity occurred in four (0.7%) and five patients (2.1%), respectively. Among 793 patients evaluated for effectiveness, 78 in group A and 26 in group B had aPTT data at baseline (immediately before idarucizumab administration) and within 4 h of idarucizumab administration; in these patients, median maximum percentage reversal within 4 h of idarucizumab administration was 100%. CONCLUSIONS The final analysis from the PMS study confirms previous findings suggesting that idarucizumab can safely and effectively reverse the anticoagulant effects of dabigatran in Japanese patients in clinical practice. The results support the continued use of idarucizumab in Japan. TRIAL REGISTRATION This study is registered with ClinicalTrials.gov (NCT02946931).
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Affiliation(s)
- Masahiro Yasaka
- Department of Cerebrovascular Medicine and Neurology, Cerebrovascular Center, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka Neurosurgical Hospital, 5-3-15 Osa, Minami-ku, Fukuoka, 811-1313, Japan.
| | - Hiroyuki Yokota
- Graduate School of Medical and Health Science, Nippon Sport Science University, Kanagawa, Japan
| | - Michiyasu Suzuki
- Department of Neurosurgery, Yamaguchi University School of Medicine, Yamaguchi, Japan
| | - Hidesaku Asakura
- Department of Hematology, Kanazawa University Hospital, Ishikawa, Japan
| | - Teiichi Yamane
- Department of Cardiology, Jikei University School of Medicine, Tokyo, Japan
| | - Yukako Ogi
- Medicine Division, Nippon Boehringer Ingelheim Co., Ltd., Tokyo, Japan
| | | | - Daisuke Nakayama
- Medicine Division, Nippon Boehringer Ingelheim Co., Ltd., Tokyo, Japan
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25
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Hindley B, Lip GYH, McCloskey AP, Penson PE. Pharmacokinetics and pharmacodynamics of direct oral anticoagulants. Expert Opin Drug Metab Toxicol 2023; 19:911-923. [PMID: 37991392 DOI: 10.1080/17425255.2023.2287472] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 11/21/2023] [Indexed: 11/23/2023]
Abstract
INTRODUCTION Direct oral anticoagulants (DOACs) have overtaken vitamin K antagonists to become the most widely used method of anticoagulation for most indications. Their stable and predictable pharmacokinetics combined with relatively simple dosing, and the absence of routine monitoring has made them an attractive proposition for healthcare providers. Despite the benefits of DOACs as a class, important differences exist between individual DOAC drugs in respect of their pharmacokinetic and pharmacodynamic profiles with implications for dosing and reversal in cases of major bleeding. AREAS COVERED This review summarizes the state of knowledge relating to the pharmacokinetics of dabigatran (factor IIa/thrombin inhibitor) and apixaban, edoxaban and rivaroxaban (factor Xa) inhibitors. We focus on pharmacokinetic differences between the drugs which may have clinically significant implications. EXPERT OPINION Patient-centered care necessitates a careful consideration of the pharmacokinetic and pharmacodynamic differences between DOACs, and how these relate to individual patient circumstances. Prescribers should be aware of the potential for pharmacokinetic drug interactions with DOACs which may influence prescribing decisions in patients with multiple comorbidities. In order to give an appropriate dose of DOAC drugs, accurate estimation of renal function using the Cockcroft-Gault formula using actual body weight is necessary. An increasing body of evidence supports the use of DOACs in patients who are obese, and this is becoming more routine in clinical practice.
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Affiliation(s)
- B Hindley
- Pharmacy Department, Aintree University Hospital, Liverpool, UK
- Clinical Pharmacy and Therapeutics Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
| | - G Y H Lip
- Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK
- Danish Center for Clinical Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - A P McCloskey
- Clinical Pharmacy and Therapeutics Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
- Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK
| | - P E Penson
- Clinical Pharmacy and Therapeutics Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
- Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK
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26
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Glavaš M, Gitlin-Domagalska A, Ptaszyńska N, Starego D, Freza S, Dębowski D, Helbik-Maciejewska A, Łęgowska A, Gilon C, Rolka K. Synthesis of Novel Arginine Building Blocks with Increased Lipophilicity Compatible with Solid-Phase Peptide Synthesis. Molecules 2023; 28:7780. [PMID: 38067510 PMCID: PMC10708530 DOI: 10.3390/molecules28237780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 11/15/2023] [Accepted: 11/23/2023] [Indexed: 12/18/2023] Open
Abstract
Arginine, due to the guanidine moiety, increases peptides' hydrophilicity and enables interactions with charged molecules, but at the same time, its presence in a peptide chain might reduce its permeability through biological membranes. This might be resolved by temporary coverage of the peptide charge by lipophilic, enzyme-sensitive alkoxycarbonyl groups. Unfortunately, such a modification of a guanidine moiety has not been reported to date and turned out to be challenging. Here, we present a new, optimized strategy to obtain arginine building blocks with increased lipophilicity that were successfully utilized in the solid-phase peptide synthesis of novel arginine vasopressin prodrugs.
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Affiliation(s)
- Mladena Glavaš
- Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland; (M.G.); (N.P.); (D.S.); (D.D.); (A.H.-M.); (A.Ł.); (K.R.)
- Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, 10 000 Zagreb, Croatia
| | - Agata Gitlin-Domagalska
- Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland; (M.G.); (N.P.); (D.S.); (D.D.); (A.H.-M.); (A.Ł.); (K.R.)
| | - Natalia Ptaszyńska
- Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland; (M.G.); (N.P.); (D.S.); (D.D.); (A.H.-M.); (A.Ł.); (K.R.)
| | - Dominika Starego
- Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland; (M.G.); (N.P.); (D.S.); (D.D.); (A.H.-M.); (A.Ł.); (K.R.)
| | - Sylwia Freza
- Department of Theoretical Chemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland;
| | - Dawid Dębowski
- Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland; (M.G.); (N.P.); (D.S.); (D.D.); (A.H.-M.); (A.Ł.); (K.R.)
| | - Aleksandra Helbik-Maciejewska
- Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland; (M.G.); (N.P.); (D.S.); (D.D.); (A.H.-M.); (A.Ł.); (K.R.)
| | - Anna Łęgowska
- Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland; (M.G.); (N.P.); (D.S.); (D.D.); (A.H.-M.); (A.Ł.); (K.R.)
| | - Chaim Gilon
- Department of Organic Chemistry, Institute of Chemistry, The Hebrew University, Jerusalem 91904, Israel;
| | - Krzysztof Rolka
- Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland; (M.G.); (N.P.); (D.S.); (D.D.); (A.H.-M.); (A.Ł.); (K.R.)
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27
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Kyriakaki I, Karanikola T, Lillis T, Kontonasaki E, Dabarakis N. Effect of direct oral anticoagulant dabigatran on early bone healing: An experimental study in rats. JOURNAL OF ADVANCED PERIODONTOLOGY & IMPLANT DENTISTRY 2023; 15:86-92. [PMID: 38357331 PMCID: PMC10862050 DOI: 10.34172/japid.2023.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 09/30/2023] [Indexed: 02/16/2024]
Abstract
Background Dabigatran belongs to the new generation of direct oral anticoagulants (DOACs). Its advantages are oral administration and no need for international normalized ratio (INR) monitoring. Although its use has increased, its potential side effects on bone healing and remodeling have not been fully investigated. The present study aimed to evaluate the possible effects of dabigatran on early bone healing. Methods Sixteen male Wistar rats were divided into two groups; in group A, 20-mg/kg dabigatran dose was administered orally daily for 15 days, while group B served as a control. Two circular bone defects (d=6 mm) were created on either side of the parietal bones. Two weeks after surgery and euthanasia of the animals, tissue samples (parietal bones that contained the defects) were harvested for histological and histomorphometric analysis. Statistical analysis was performed with a significance level of α=0.5. Results No statistically significant differences were found between the two groups regarding the regenerated bone (21.9% vs. 16.3%, P=0.172) or the percentage of bone bridging (63.3% vs. 53.5%, P=0.401). Conclusion Dabigatran did not affect bone regeneration, suggesting that it might be a safer drug compared to older anticoagulants known to lead to bone healing delay.
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Affiliation(s)
- Ioanna Kyriakaki
- Department of Dentoalveolar Surgery, Surgical Implantology and Roentgenology, Aristotle University, Thessaloniki, Greece
| | - Theodora Karanikola
- Private Practice, Clinical Instructor, Department of Oral Surgery, Implantology and Dental Radiology, School of Dentistry, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Theodoros Lillis
- Department of Dentoalveolar Surgery, Surgical Implantology and Roentgenology, Aristotle University, Thessaloniki, Greece
| | - Eleana Kontonasaki
- Department of Prosthodontics, School of Dentistry, Aristotle University of Thessaloniki, Greece
| | - Nikolaos Dabarakis
- Department of Dentoalveolar Surgery, Surgical Implantology and Roentgenology, Aristotle University, Thessaloniki, Greece
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Udomnilobol U, Jianmongkol S, Prueksaritanont T. The Potentially Significant Role of CYP3A-Mediated Oxidative Metabolism of Dabigatran Etexilate and Its Intermediate Metabolites in Drug-Drug Interaction Assessments Using Microdose Dabigatran Etexilate. Drug Metab Dispos 2023; 51:1216-1226. [PMID: 37230768 DOI: 10.1124/dmd.123.001353] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/06/2023] [Accepted: 05/15/2023] [Indexed: 05/27/2023] Open
Abstract
Dabigatran etexilate (DABE), a double ester prodrug of dabigatran, is a probe substrate of intestinal P-glycoprotein (P-gp) commonly used in clinical drug-drug interaction (DDI) studies. When compared with its therapeutic dose at 150 mg, microdose DABE (375 µg) showed approximately 2-fold higher in DDI magnitudes with CYP3A/P-gp inhibitors. In this study, we conducted several in vitro metabolism studies to demonstrate that DABE, at a theoretical gut concentration after microdosing, significantly underwent NADPH-dependent oxidation (~40%-50%) in parallel to carboxylesterase-mediated hydrolysis in human intestinal microsomes. Furthermore, NADPH-dependent metabolism of its intermediate monoester, BIBR0951, was also observed in both human intestinal and liver microsomes, accounting for 100% and 50% of total metabolism, respectively. Metabolite profiling using high resolution mass spectrometry confirmed the presence of several novel oxidative metabolites of DABE and of BIBR0951 in the NADPH-fortified incubations. CYP3A was identified as the major enzyme catalyzing the oxidation of both compounds. The metabolism of DABE and BIBR0951 was well described by Michaelis-Menten kinetics, with Km ranging 1-3 µM, significantly below the expected concentrations following the therapeutic dose of DABE. Overall, the present results suggested that CYP3A played a significant role in the presystemic metabolism of DABE and BIBR0951 following microdose DABE administration, thus attributing partly to the apparent overestimation in the DDI magnitude observed with the CYP3A/P-gp inhibitors. Therefore, DABE at the microdose, unlike the therapeutic dose, would likely be a less predictive tool and should be considered as a clinical dual substrate for P-gp and CYP3A when assessing potential P-gp-mediated impacts by dual CYP3A/P-gp inhibitors. SIGNIFICANT STATEMENT: This is the first study demonstrating a potentially significant role of cytochrome P450-mediated metabolism of the prodrug DABE following a microdose but not a therapeutic dose. This additional pathway, coupled with its susceptibility to P-glycoprotein (P-gp), may make DABE a clinical dual substrate for both P-gp and CYP3A at a microdose. The study also highlights the need for better characterization of the pharmacokinetics and metabolism of a clinical drug-drug interaction probe substrate over the intended study dose range for proper result interpretations.
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Affiliation(s)
- Udomsak Udomnilobol
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences (U.U., S.J.) and Chulalongkorn University Drug Discovery and Drug Development Research Center (Chula4DR) (U.U., T.P.), Chulalongkorn University, Bangkok, Thailand
| | - Suree Jianmongkol
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences (U.U., S.J.) and Chulalongkorn University Drug Discovery and Drug Development Research Center (Chula4DR) (U.U., T.P.), Chulalongkorn University, Bangkok, Thailand
| | - Thomayant Prueksaritanont
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences (U.U., S.J.) and Chulalongkorn University Drug Discovery and Drug Development Research Center (Chula4DR) (U.U., T.P.), Chulalongkorn University, Bangkok, Thailand
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Juneja D, Nasa P, Jain R. Liver injury from direct oral anticoagulants. World J Hepatol 2023; 15:841-849. [PMID: 37397936 PMCID: PMC10308284 DOI: 10.4254/wjh.v15.i6.841] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 01/23/2023] [Accepted: 05/15/2023] [Indexed: 06/25/2023] Open
Abstract
BACKGROUND Drug-induced liver injury (DILI) can be caused by any prescribed drug and is a significant reason for the withdrawal of newly launched drugs. Direct-acting oral anticoagulants (DOACs) are non-vitamin K-based antagonists recently introduced and increasingly used for various clinical conditions. A meta-analysis of 29 randomised controlled trials and 152116 patients reported no increased risk of DILI with DOACs. However, it is challenging to predict the risk factors for DILI in individual patients with exclusion of patients with pre-existing liver disease from these studies. AIM To determine the risk factors and outcomes of patients who developed DILI secondary to DOACs by systematic review and meta-summary of recent case reports and series. METHODS A systematic search was conducted on multiple databases including PubMed, Science Direct, Reference Citation Analysis, and Google Scholar. The search terms included "Acute Liver Failure" OR "Acute-On-Chronic Liver Failure" OR "Acute Chemical and Drug Induced Liver Injury" OR "Chronic Chemical and Drug Induced Liver Injury" AND "Factor Xa Inhibitors" OR "Dabigatran" OR "Rivaroxaban" OR "apixaban" OR "betrixaban" OR "edoxaban" OR "Otamixaban". The results were filtered for literature published in English and on adult patients. Only case reports and case studies reporting cases of DILI secondary to DOACs were included. Data on demographics, comorbidities, medication history, laboratory investigations, imaging, histology, management, and outcomes were extracted. RESULTS A total of 15 studies (13 case reports and 2 case series) were included in the analysis, comprising 27 patients who developed DILI secondary to DOACs. Rivaroxaban was the most commonly implicated DOAC (n = 20, 74.1%). The mean time to onset of DILI was 40.6 d. The most common symptoms were jaundice (n = 15, 55.6%), malaise (n = 9, 33.3%), and vomiting (n = 9, 33.3%). Laboratory investigations showed elevated liver enzymes and bilirubin levels. Imaging studies and liver biopsies revealed features of acute hepatitis and cholestatic injury. Most patients had a favourable outcome, and only 1 patient (3.7%) died due to liver failure. CONCLUSION DOACs are increasingly used for various clinical conditions, and DILI secondary to DOACs is a rare but potentially serious complication. Prompt identification and cessation of the offending drug are crucial for the management of DILI. Most patients with DILI secondary to DOACs have a favourable outcome, but a small proportion may progress to liver failure and death. Further research, including post-marketing population-based studies, is needed to better understand the incidence and risk factors for DILI secondary to DOACs.
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Affiliation(s)
- Deven Juneja
- Institute of Critical Care Medicine, Max Super Specialty Hospital, New Delhi 110017, India
| | - Prashant Nasa
- Critical Care Medicine, NMC Specialty Hospital, Dubai 7832, United Arab Emirates
- Internal Medicine, College of Medicine and Health Sciences, Al Ain 15551, United Arab Emirates.
| | - Ravi Jain
- Critical Care Medicine, Mahatma Gandhi Medical College and Hospital, Jaipur 302001, Rajasthan, India
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30
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Thanavaro JL. Direct oral anticoagulant drugs for the management of venous thromboembolism. Nurse Pract 2023; 48:27-35. [PMID: 37227313 DOI: 10.1097/01.npr.0000000000000060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
ABSTRACT Direct oral anticoagulants (DOACs) are effective for both prevention and treatment of venous thromboembolism (VTE) and have favorable safety in comparison with warfarin. Although drug-drug interactions with DOACs are not as frequent as with warfarin, certain drugs can interfere with DOAC metabolism, affect DOAC efficacy, and potentially cause adverse reactions when used in combination with DOACs. The NP must determine which agent is most beneficial for the individual patient with VTE based on a number of factors. A knowledge of periprocedural management of DOACs will assist the NP in providing a smooth transition for patients undergoing minor and major procedures and surgeries.
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Affiliation(s)
- Joanne L Thanavaro
- Joanne L. Thanavaro is a professor of nursing and Associate Dean for Graduate Education at Saint Louis University Trudy Busch Valentine School of Nursing in St. Louis, Mo
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Bortman LV, Mitchell F, Naveiro S, Pérez Morales J, Gonzalez CD, Di Girolamo G, Giorgi MA. Direct Oral Anticoagulants: An Updated Systematic Review of Their Clinical Pharmacology and Clinical Effectiveness and Safety in Patients With Nonvalvular Atrial Fibrillation. J Clin Pharmacol 2023; 63:383-396. [PMID: 36433678 DOI: 10.1002/jcph.2184] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 11/09/2022] [Indexed: 11/27/2022]
Abstract
Direct oral anticoagulants have been an increasingly used class of drugs in the setting of nonvalvular atrial fibrillation, defying vitamin K antagonists' monopoly when it comes to anticoagulation due to its several limitations. Direct oral anticoagulants (DOACs) have entered the market as a noninferior and safer option in comparison with vitamin K antagonists, as their respective phase III clinical trials proved. The aim of this article was to update and summarize data on their clinical pharmacology and to review real-world data to know their comparative effectiveness and safety. We performed a systematic review using PubMed, Google Scholar, Embase, and Web of Science as search engines. Regarding pharmacodynamics, there were no substantial changes reported from their original profile. There were many advances in the knowledge about clinical pharmacokinetics of DOACs that have had a direct impact on their clinical use, mainly related to drug-drug interactions. In a real-world setting, DOACs have shown to be noninferior in preventing thromboembolic events compared to vitamin K antagonists. In regards to safety, DOACs have shown a lower bleeding risk relative to warfarin. Comparison between DOACs has demonstrated rivaroxaban to have the highest bleeding risk. Overall, the evidence gathered showed few changes from the original data presented in phase III clinical trials, concluding that their real-world use coincides greatly with them.
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Affiliation(s)
- Lucia Victoria Bortman
- Department of Pharmacology, School of Medicine, Instituto Universitario CEMIC, Buenos Aires, Argentina
| | - Florencia Mitchell
- Department of Pharmacology, School of Medicine, Instituto Universitario CEMIC, Buenos Aires, Argentina
| | - Sofia Naveiro
- Department of Pharmacology, School of Medicine, Instituto Universitario CEMIC, Buenos Aires, Argentina
| | - Juana Pérez Morales
- Department of Pharmacology, School of Medicine, Instituto Universitario CEMIC, Buenos Aires, Argentina
| | - Claudio Daniel Gonzalez
- Department of Pharmacology, School of Medicine, Instituto Universitario CEMIC, Buenos Aires, Argentina.,Health Economics and Technology Assessment, Unit. Instituto Universitario CEMIC, Buenos Aires, Argentina
| | - Guillermo Di Girolamo
- Department of Pharmacology, School of Medicine, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto Alberto C. Taquini de Investigaciones en Medicina Traslacional (IATIMET), Universidad de Buenos Aires - CONICET, Facultad de Medicina, Buenos Aires, Argentina
| | - Mariano Anibal Giorgi
- Department of Pharmacology, School of Medicine, Instituto Universitario CEMIC, Buenos Aires, Argentina.,Health Economics and Technology Assessment, Unit. Instituto Universitario CEMIC, Buenos Aires, Argentina
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Sia JEV, Lai X, Wu X, Zhang F, Li H, Cui C, Liu D. Physiologically-based pharmacokinetic modeling to predict drug-drug interactions of dabigatran etexilate and rivaroxaban in the Chinese older adults. Eur J Pharm Sci 2023; 182:106376. [PMID: 36626944 PMCID: PMC9883662 DOI: 10.1016/j.ejps.2023.106376] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 01/06/2023] [Accepted: 01/06/2023] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Drug-drug interaction (DDI) is one of the major concerns for the clinical use of NOACs in the older adults considering that coexistence of multiple diseases and comorbidity were common. Current guidelines on the DDI management were established based on clinical studies conducted in healthy adults and mainly focus on the Caucasians, whereas systemic and ethnic differences may lead to distinct management in the Chinese older adults. OBJECTIVES To investigate the impact of aging on the DDI magnitude between P-gp and/or CYP3A4 inhibitors with dabigatran etexilate and rivaroxaban in older adults, providing additional information for the use in clinical practice. RESULTS Compared with the simulated adult, the AUC of the simulated older adults increased by 42-88% (DABE) and 21-60% (rivaroxaban), respectively, during NOACs monotherapy. Simulation on DDIs predicted that verapamil and clarithromycin further increase the exposure of dabigatran by 29-72% and 40-47%, whereas clarithromycin, fluconazole, and ketoconazole increase the exposure of rivaroxaban by 21-30%, 16-24%, and 194-247% in the older adults. Overall, our simulation result demonstrated that aging and DDIs both increased the exposure of NOACs. However, aging does not have a drastic impact on the extent of DDIs. The DDI ratios of young and old older adults were similar to the adults and were also similar between Caucasians and Chinese. DISCUSSION We further simulated the interactions under steady-state based on the EHRA guideline (2021). Our simulation results revealed that recommended reduced dosing regimen of dabigatran etexilate during comedication with verapamil and clarithromycin (110 and 75 mg BID for Chinese young and old older adults) will result in exposure (trough concentration) that was either slightly higher or similar to the trough concentration of patients with any bleeding events. Routine monitoring of bleeding risk is encouraged. Further studies on the use of rivaroxaban in Chinese older adults are warranted. CONCLUSION Aging and DDI increases exposure of drug in Chinese older adults. However, aging does not have a drastic impact on the extent of DDIs. Clinical management of DDIs in Chinese older adults in the absence of complex polypharmacy can a priori be similar to the EHRA guideline but routine monitoring of bleeding risk is encouraged when dabigatran etexilate given with verapamil and clarithromycin.
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Affiliation(s)
- Jie En Valerie Sia
- Geriatrics Department, Peking University Third Hospital, Beijing 100191, China,Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China,Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Xuan Lai
- Geriatrics Department, Peking University Third Hospital, Beijing 100191, China
| | - Xinyi Wu
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China,Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
| | - Fan Zhang
- Geriatrics Department, Peking University Third Hospital, Beijing 100191, China
| | - Haiyan Li
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China,Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
| | - Cheng Cui
- Geriatrics Department, Peking University Third Hospital, Beijing 100191, China; Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China; Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China.
| | - Dongyang Liu
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China; Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China; Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Third Hospital, Beijing 100191, China.
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Chung H, Kim JM, Park JW, Noh J, Kim KA, Park JY. Effects of Simvastatin on Pharmacokinetics and Anticoagulant Effects of Dabigatran in Healthy Subjects. Pharmaceuticals (Basel) 2023; 16:364. [PMID: 36986464 PMCID: PMC10056008 DOI: 10.3390/ph16030364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/17/2023] [Accepted: 02/23/2023] [Indexed: 03/06/2023] Open
Abstract
Higher risk of major hemorrhage associated with concomitant use of dabigatran and simvastatin compared to other statins was previously reported with a suggestion of P-glycoprotein-mediated interaction. The aim of this study was to evaluate the effects of simvastatin on pharmacokinetics and anticoagulant effects of dabigatran, a direct oral anticoagulant. A total of 12 healthy subjects were enrolled in an open-label, two-period, single sequence study. Subjects were given 150 mg of dabigatran etexilate followed by 40 mg of once-daily simvastatin for seven days. Dabigatran etexilate was administered with simvastatin on the seventh day of simvastatin administration. Blood samples for pharmacokinetic and pharmacodynamic analyses were obtained until 24 h post-dose of dabigatran etexilate with or without co-administration of simvastatin. Pharmacokinetic parameters were derived from noncompartmental analysis for dabigatran etexilate, dabigatran, and dabigatran acylglucuronide. When simvastatin was co-administered, geometric mean ratios of area under time-concentration curves for dabigatran etexilate, dabigatran, and dabigatran acylglucuronide were 1.47, 1.21, and 1.57, respectively, compared to when dabigatran etexilate was administered alone. Thrombin generation assay and coagulation assay showed similar profiles between before and after co-administration of simvastatin. This study provides evidence that simvastatin treatment plays a minor role in modulating pharmacokinetics and anticoagulant effects of dabigatran etexilate.
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Affiliation(s)
- Hyewon Chung
- Department of Clinical Pharmacology and Toxicology, Guro Hospital, Korea University College of Medicine, Seoul 08308, Republic of Korea
| | - Jong-Min Kim
- Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Jin-Woo Park
- Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul 02841, Republic of Korea
- Department of Neurology, Anam Hospital, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Jihyeon Noh
- Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Kyoung-Ah Kim
- Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Ji-Young Park
- Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul 02841, Republic of Korea
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Deng F, Sjöstedt N, Santo M, Neuvonen M, Niemi M, Kidron H. Novel inhibitors of breast cancer resistance protein (BCRP, ABCG2) among marketed drugs. Eur J Pharm Sci 2023; 181:106362. [PMID: 36529162 DOI: 10.1016/j.ejps.2022.106362] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 11/11/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
Drug-drug interactions (DDIs) are a major concern for the safe use of medications. Breast cancer resistance protein (BCRP) is a clinically relevant ATP-binding cassette (ABC) transporter for drug disposition. Inhibition of BCRP increases the plasma concentrations of BCRP substrate drugs, which potentially could lead to adverse drug reactions. The aim of the present study was to identify BCRP inhibitors amongst a library of 232 commonly used drugs and anticancer drugs approved by the United States Food and Drug Administration (FDA). BCRP inhibition studies were carried out using the vesicular transport assay. We found 75 drugs that reduced the relative transport activity of BCRP to less than 25% of the vehicle control and were categorized as strong inhibitors. The concentration required for 50% inhibition (IC50) was determined for 13 strong inhibitors that were previously poorly characterized for BCRP inhibition. The IC50 ranged from 1.1 to 11 µM, with vemurafenib, dabigatran etexilate and everolimus being the strongest inhibitors. According to the drug interaction guidance documents from the FDA and the European Medicines Agency (EMA), in vivo DDI studies are warranted if the theoretical intestinal luminal concentration of a drug exceeds its IC50 by tenfold. Here, the IC50 values for eight of the drugs were 100-fold lower than their theoretical intestinal luminal concentration. Moreover, a mechanistic static model suggested that vemurafenib, bexarotene, dabigatran etexilate, rifapentine, aprepitant, and ivacaftor could almost fully inhibit intestinal BCRP, increasing the exposure of concomitantly administered rosuvastatin over 90%. Therefore, clinical studies are warranted to investigate whether these drugs cause BCRP-mediated DDIs in humans.
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Affiliation(s)
- Feng Deng
- Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Tukholmankatu 8 C, P.O. Box 20, 00014, Finland; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Haartmaninkatu 8, P.O. Box 63, 00014, Finland
| | - Noora Sjöstedt
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland. Viikinkaari 5 E, P.O. Box 56, 00014, Finland
| | - Mariangela Santo
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland. Viikinkaari 5 E, P.O. Box 56, 00014, Finland
| | - Mikko Neuvonen
- Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Tukholmankatu 8 C, P.O. Box 20, 00014, Finland; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Haartmaninkatu 8, P.O. Box 63, 00014, Finland
| | - Mikko Niemi
- Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Tukholmankatu 8 C, P.O. Box 20, 00014, Finland; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Haartmaninkatu 8, P.O. Box 63, 00014, Finland; Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
| | - Heidi Kidron
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland. Viikinkaari 5 E, P.O. Box 56, 00014, Finland.
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35
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Nabeh OA. Gut microbiota and cardiac arrhythmia: a pharmacokinetic scope. Egypt Heart J 2022; 74:87. [PMID: 36583819 PMCID: PMC9803803 DOI: 10.1186/s43044-022-00325-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/27/2022] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Dealing with cardiac arrhythmia is a difficult challenge. Choosing between different anti-arrhythmic drugs (AADs) while being cautious about the pro-arrhythmic characteristics of some of these drugs and their diverse interaction with other drugs is a real obstacle. MAIN BODY Gut microbiota (GM), in our bodies, are now being considered as a hidden organ which can regulate our immune system, digest complex food, and secrete bioactive compounds. Yet, GM are encountered in the pathophysiology of arrhythmia and can affect the pharmacokinetics of AADs, as well as some anti-thrombotics, resulting in altering their bioavailability, therapeutic function and may predispose to some of their unpleasant adverse effects. CONCLUSIONS Knowledge of the exact role of GM in the pharmacokinetics of these drugs is now essential for better understanding of the art of arrhythmia management. Also, it will help deciding when to consider probiotics as an adjunctive therapy while treating arrhythmia. This should be discovered in the near future.
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Affiliation(s)
- Omnia Azmy Nabeh
- grid.7776.10000 0004 0639 9286Department of Medical Pharmacology, Kasr Alainy Faculty of Medicine, Cairo University, Cairo, Egypt
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36
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Influence of ABCB1, CYP3A5 and CYP3A4 gene polymorphisms on prothrombin time and the residual equilibrium concentration of rivaroxaban in patients with non-valvular atrial fibrillation in real clinical practice. Pharmacogenet Genomics 2022; 32:301-307. [PMID: 36256705 DOI: 10.1097/fpc.0000000000000483] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The study of ABCB1 and CYP3A4/3A5 gene polymorphism genes is promising in terms of their influence on prothrombin time variability, the residual equilibrium concentration of direct oral anticoagulants (DOACs) in patients with atrial fibrillation and the development of new personalized approaches to anticoagulation therapy in these patients. The aim of the study is to evaluate the effect of ABCB1 (rs1045642) C>T; ABCB1 (rs4148738) C>T and CYP3A5 (rs776746) A>G, CYP3A4*22(rs35599367) C>T gene polymorphisms on prothrombin time level and residual equilibrium concentration of rivaroxaban in patients with atrial fibrillation. METHODS In total 86 patients (42 men and 44 female), aged 67.24 ± 1.01 years with atrial fibrillation were enrolled in the study. HPLC mass spectrometry analysis was used to determine rivaroxaban residual equilibrium concentration. Prothrombin time data were obtained from patient records. RESULTS The residual equilibrium concentration of rivaroxaban in patients with ABCB1 rs4148738 CT genotype is significantly higher than in patients with ABCB1 rs4148738 CC (P = 0.039). The analysis of the combination of genotypes did not find a statistically significant role of combinations of alleles of several polymorphic markers in increasing the risk of hemorrhagic complications when taking rivaroxaban. CONCLUSION Patients with ABCB1 rs4148738 CT genotype have a statistically significantly higher residual equilibrium concentration of rivaroxaban in blood than patients with ABCB1 rs4148738 CC genotype, which should be considered when assessing the risk of hemorrhagic complications and risk of drug-drug interactions. Further studies of the effect of rivaroxaban pharmacogenetics on the safety profile and efficacy of therapy are needed.
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Chang LS, Nishida T, Hosokawa K, Fujii Y, Osugi N, Sugimoto A, Mukai K, Nakamatsu D, Matsumoto K, Hayashi S, Yamamoto M, Inada M. Impact of anticoagulants on the clinical outcomes of colonic diverticular bleeding comparing warfarin and direct oral anticoagulants. Sci Rep 2022; 12:16795. [PMID: 36207370 PMCID: PMC9547017 DOI: 10.1038/s41598-022-21166-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 09/23/2022] [Indexed: 11/08/2022] Open
Abstract
Recently, direct oral anticoagulants (DOACs) have been widely used as antithrombotic agents to replace warfarin, but their clinical impact in patients with gastrointestinal bleeding is unclear. We compared the effects of warfarin and DOACs on the outcomes of patients with colonic diverticular bleeding. The patients were divided into warfarin and DOAC groups. We compared the clinical outcomes and the effect of the DOAC dosing and examined any readmissions due to colonic diverticular bleeding within 1 year. A total of 95 events (warfarin group: n = 43 and DOAC group: n = 52) were included. Compared with the warfarin group, the DOAC group was significantly older, had a lower rate of concomitant antiplatelet agents, and a shorter hospital stay, but no significant differences were found in the other clinical outcomes. Thirty-seven patients (71.2%) in the DOAC group had appropriate dosing, whereas 15 patients (28.9%) had an inappropriate dose. The patients with overdose or contraindications had significantly lower minimum hemoglobin levels. In the univariate analysis, prior hospitalization for colonic diverticular bleeding was a significant predictor of readmission. Compared with warfarin, patients with colonic diverticular bleeding treated with DOACs were older and had shorter hospital stays, and the inappropriate use of DOACs may worsen outcomes.
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Affiliation(s)
- Li-Sa Chang
- Department of Gastroenterology, Toyonaka Municipal Hospital, 4-14-1 Shibahara, Toyonaka, Osaka, 560-8565, Japan
| | - Tsutomu Nishida
- Department of Gastroenterology, Toyonaka Municipal Hospital, 4-14-1 Shibahara, Toyonaka, Osaka, 560-8565, Japan.
| | - Kana Hosokawa
- Department of Gastroenterology, Toyonaka Municipal Hospital, 4-14-1 Shibahara, Toyonaka, Osaka, 560-8565, Japan
| | - Yoshifumi Fujii
- Department of Gastroenterology, Toyonaka Municipal Hospital, 4-14-1 Shibahara, Toyonaka, Osaka, 560-8565, Japan
| | - Naoto Osugi
- Department of Gastroenterology, Toyonaka Municipal Hospital, 4-14-1 Shibahara, Toyonaka, Osaka, 560-8565, Japan
| | - Aya Sugimoto
- Department of Gastroenterology, Toyonaka Municipal Hospital, 4-14-1 Shibahara, Toyonaka, Osaka, 560-8565, Japan
| | - Kaori Mukai
- Department of Gastroenterology, Toyonaka Municipal Hospital, 4-14-1 Shibahara, Toyonaka, Osaka, 560-8565, Japan
| | - Dai Nakamatsu
- Department of Gastroenterology, Toyonaka Municipal Hospital, 4-14-1 Shibahara, Toyonaka, Osaka, 560-8565, Japan
| | - Kengo Matsumoto
- Department of Gastroenterology, Toyonaka Municipal Hospital, 4-14-1 Shibahara, Toyonaka, Osaka, 560-8565, Japan
| | - Shiro Hayashi
- Department of Gastroenterology, Toyonaka Municipal Hospital, 4-14-1 Shibahara, Toyonaka, Osaka, 560-8565, Japan
| | - Masashi Yamamoto
- Department of Gastroenterology, Toyonaka Municipal Hospital, 4-14-1 Shibahara, Toyonaka, Osaka, 560-8565, Japan
| | - Masami Inada
- Department of Gastroenterology, Toyonaka Municipal Hospital, 4-14-1 Shibahara, Toyonaka, Osaka, 560-8565, Japan
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Neuropharmacology in the Intensive Care Unit. Crit Care Clin 2022; 39:171-213. [DOI: 10.1016/j.ccc.2022.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Carboxylesterase-2 plays a critical role in dabigatran etexilate active metabolite formation. Drug Metab Pharmacokinet 2022; 47:100479. [DOI: 10.1016/j.dmpk.2022.100479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 09/13/2022] [Accepted: 10/11/2022] [Indexed: 11/22/2022]
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von der Forst M, Morath B, Schwald M, Weigand MA, Schmitt FCF. [Principles of the perioperative management of direct oral anticoagulants]. DIE ANAESTHESIOLOGIE 2022; 71:565-576. [PMID: 35925055 DOI: 10.1007/s00101-022-01142-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 05/19/2022] [Indexed: 06/17/2023]
Abstract
Within the approved indications direct oral anticoagulants (DOAC) are increasingly gaining acceptance instead of vitamin K antagonists (VKA). In the last 12 months 5 guidelines relevant to the perioperative management of DOACs have been updated. This article summarizes the current recommendations for the perioperative management of treatment with DOACs. The available substances and their pharmacological properties as well as the possibilities for specific laboratory diagnostics of the effect of DOAC are explained. Special focus is placed on anesthesiologically important aspects of substance-specific preoperative and postoperative intermission intervals, the procedure for neuraxial regional anesthesia and antagonization with specific antidotes in cases of life-threatening bleeding.
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Affiliation(s)
- Maik von der Forst
- Klinik für Anästhesiologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 420, 69120, Heidelberg, Deutschland
| | - Benedict Morath
- Krankenhausapotheke, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 670, 69120, Heidelberg, Deutschland
| | - Martina Schwald
- Krankenhausapotheke, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 670, 69120, Heidelberg, Deutschland
| | - Markus A Weigand
- Klinik für Anästhesiologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 420, 69120, Heidelberg, Deutschland
| | - Felix C F Schmitt
- Klinik für Anästhesiologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 420, 69120, Heidelberg, Deutschland.
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Zhang J, Xiao M, Ji X, Lai YS, Song Q, Zhang Y, Ip CM, Ng WL, Zuo Z. Inhibition of Radix Scutellariae flavones on carboxylesterase mediated activations of prodrugs. Life Sci 2022; 305:120743. [PMID: 35780840 DOI: 10.1016/j.lfs.2022.120743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/22/2022] [Accepted: 06/25/2022] [Indexed: 10/17/2022]
Abstract
AIMS Carboxylesterase (CES) plays an essential role in the hydrolysis of ester prodrugs. Our study explored the inhibitions of Radix Scutellariae flavones, including baicalein (B), baicalin (BG), wogonin (W), wogonoside (WG), oroxylin A (OXA) and oroxylin A-7-O-glucuronide (OAG), on CES-mediated hydrolysis of seven prodrugs (capecitabine, clopidogrel, mycophenolate mofetil, dabigatran etexilate, acetylsalicylic acid, prasugrel and irinotecan). MAIN METHODS In vitro screenings were developed by incubating the flavones with prodrugs in rat plasma, intestine S9 and liver S9. Docking simulations were conducted using AMDock v1.5.2. In vivo evaluations were performed in rats co-administered with the selected flavone and prodrug via oral gavage/intravenous administration for five consecutive days. KEY FINDINGS The in vitro investigation showed that B and OXA demonstrated strongest inhibitions on the hydrolysis of irinotecan followed by dabigatran in rat plasma, intestine S9 and liver S9. Consistent results showed in the molecular docking analyses. Additionally, in rats receiving irinotecan, B/OXA intravenous and oral pre-treatments both led to reduction trends on the active metabolite SN-38 formation in plasma. Besides, significant decreases of SN-38/irinotecan plasma concentration ratios were found in the B/OXA oral pre-treatment group with quicker and stronger inhibition potential in OXA pre-treatment than that from B pre-treatment. OXA oral pre-treatment was also found to be able to significantly inhibit intestinal CES2 activities at 0.5 h and 5 h after irinotecan administration. SIGNIFICANCE Our current findings for the first time alert on potential CES-mediated HDIs between RS flavones and prodrugs, which provide a constructive information referring to rational drug combinations in clinical practice.
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Affiliation(s)
- Jun Zhang
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region
| | - Min Xiao
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region
| | - Xiaoyu Ji
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region
| | - Yuen Sze Lai
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region
| | - Qianbo Song
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region
| | - Yufeng Zhang
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region
| | - Chung Man Ip
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region
| | - Wai Lung Ng
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region
| | - Zhong Zuo
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region.
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In Vitro Antithrombotic, Hematological Toxicity, and Inhibitor Studies of Protocatechuic, Isovanillic, and p-Hydroxybenzoic Acids from Maclura Tricuspidata (Carr.) Bur. Molecules 2022; 27:molecules27113496. [PMID: 35684431 PMCID: PMC9181887 DOI: 10.3390/molecules27113496] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/16/2022] [Accepted: 05/26/2022] [Indexed: 12/10/2022] Open
Abstract
In blood coagulation, circulating platelets and coagulation factors are crucial for the primary process because thrombi are generated by fibrin clotting with fibrinogen, thrombin, FXIIIa, and platelet activation. Therefore, strategies to reduce the activity of key coagulation factors, or interfere with their functions and delay the activation of platelets can be used as important tools to suppress excessive blood clot formation and platelet hyperactivation. This study examined the antithrombotic activity and hematological toxicity of PA, IVA, and 4-HA isolated from M. tricuspidata (Carr.) Bur in several in vitro experiments and inhibitor assays. We found that PA, IVA, and 4-HA attenuated the formation of fibrin polymers/clots and degraded the blood clots. These compounds inhibited the activities of procoagulant proteases and fibrinoligase, and prolonged the coagulation time. There was a significant reduction in platelet function and ATP or serotonin levels in thrombin-activated platelets. An inhibitor study showed that PA exhibited a mixed inhibition type for thrombin, an uncompetitive inhibition type for FXa, and a non-competitive inhibition type for FXIIIa and IVA, while 4-HA exhibited an uncompetitive inhibition type for thrombin and non-competitive inhibition type for FXa and FXIIIa. These three compounds (up to 50 μg/mL) were not toxic to blood cells.
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Cutaneous Ulcer Caused by Apixaban Treatment Is Resolved after Replacement with Dabigatran. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58050691. [PMID: 35630109 PMCID: PMC9146744 DOI: 10.3390/medicina58050691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/19/2022] [Accepted: 05/20/2022] [Indexed: 11/24/2022]
Abstract
Nowadays, novel oral anticoagulants (NOACs) have shown improved safety profile and efficacy compared to vitamin K antagonists in the prevention of thromboembolic events occurring during different pathological conditions. However, there are concerns and safety issues, mostly related to adverse events following interactions with other drugs, in real-world practice. We report the case of an 83-year-old woman who developed a non-bleeding leg ulcer not caused by trauma or other evident pathological conditions after 10 days of treatment with apixaban 5 mg/q.d. She was switched from apixaban to dabigatran and the leg ulcer rapidly improved and completely cicatrized in 40 days. The resolution of the ulcer and the toleration of dabigatran therapy suggest an apixaban-specific reaction; however, the pathological mechanism of ulcer onset is currently unclear. Careful evaluation of hospital databases of Molise region (Southern Italy) hospitals identified two similar cases between 2019 and 2021. These cases underline the necessity of careful post-marketing surveillance, considering the rapidly increasing number of patients treated with NOACs and patient’s risk factors such as old age, high polypharmacy rate, co-morbidities, and peculiar genetic background related to NOACs pharmacokinetic features.
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44
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Xie Q, Li Y, Liu Z, Mu G, Zhang H, Zhou S, Wang Z, Wang Z, Jiang J, Li X, Xiang Q, Cui Y. SLC4A4, FRAS1, and SULT1A1 Genetic Variations Associated With Dabigatran Metabolism in a Healthy Chinese Population. Front Genet 2022; 13:873031. [PMID: 35646073 PMCID: PMC9136018 DOI: 10.3389/fgene.2022.873031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 04/07/2022] [Indexed: 12/21/2022] Open
Abstract
Background: The purpose of this study was to identify genetic variations associated with the metabolism of dabigatran in healthy Chinese subjects, with particular focus given to pharmacokinetics (PK) and pharmacodynamics (PD).Methods: Healthy Chinese adults aged 18–65 years with unknown genotypes from a bioequivalence trial were included according to the protocol registered at ClinicalTrial.org (NCT03161496). All subjects received a single dose (150 mg) of dabigatran etexilate. PK (main outcomes: area under the concentration-time, AUC0-t, of total and free dabigatran) and PD (main outcomes: anti-FIIa activity, APTT, and PT) parameters were evaluated. Whole-exome sequencing and genome-wide association analyses were performed. Additionally, candidate gene association analyses related to dabigatran were conducted.Results: A total of 118 healthy Chinese subjects were enrolled in this study. According to the p-value suggestive threshold (1.0 × 10−4), the following three SNPs were found to be associated with the AUC0–t of total dabigatran: SLC4A4 SNP rs138389345 (p = 5.99 × 10−5), FRAS1 SNP rs6835769 (p = 6.88 × 10−5), and SULT1A1 SNP rs9282862 (p = 7.44 × 10−5). Furthermore, these SNPs were also found to have significant influences on the AUC0–t of free dabigatran, maximum plasma concentration, and anti-FIIa activity (p < 0.05). Moreover, we identified 30 new potential SNPs of 13 reported candidate genes (ABCB1, ABCC2, ABCG2, CYP2B6, CYP1A2, CYP2C19, CYP3A5, CES1, SLCO1B1, SLC22A1, UGT1A1, UGT1A9, and UGT2B7) that were associated with drug metabolism.Conclusion: Genetic variations were indeed found to impact dabigatran metabolism in a population of healthy Chinese subjects. Further research is needed to explore the more detailed functions of these SNPs. Additionally, our results should be verified in studies that use larger sample sizes and investigate other ethnicities.
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Affiliation(s)
- Qiufen Xie
- Department of Pharmacy, Peking University First Hospital, Beijing, China
| | - Yuan Li
- Department of Pharmacy, The Third Hospital of Changsha, Changsha, China
| | - Zhiyan Liu
- Department of Pharmacy, Peking University First Hospital, Beijing, China
| | - Guangyan Mu
- Department of Pharmacy, Peking University First Hospital, Beijing, China
| | - Hanxu Zhang
- Department of Pharmacy, Peking University First Hospital, Beijing, China
- School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
| | - Shuang Zhou
- Department of Pharmacy, Peking University First Hospital, Beijing, China
- School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
| | - Zhe Wang
- Department of Pharmacy, Peking University First Hospital, Beijing, China
- School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
| | - Zining Wang
- Department of Pharmacy, Peking University First Hospital, Beijing, China
| | - Jie Jiang
- Department of Cardiology, Peking University First Hospital, Beijing, China
| | - Xin Li
- Department of Pharmacy, The Third Hospital of Changsha, Changsha, China
| | - Qian Xiang
- Department of Pharmacy, Peking University First Hospital, Beijing, China
| | - Yimin Cui
- Department of Pharmacy, Peking University First Hospital, Beijing, China
- School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
- Institute of Clinical Pharmacology, Peking University, Beijing, China
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Abd Allah FI, Ali Almrasy A, Abdelhmaid A, Abd-Elmegid OA, Alkashlan A, El-Attar AAMM. Development and Validation of UPLC-MS/MS Method for Quantifying of Free and Total Dabigatran in Human Plasma: An Application for a Bioequivalence Study. Biomed Chromatogr 2022; 36:e5382. [PMID: 35389511 DOI: 10.1002/bmc.5382] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 01/20/2022] [Accepted: 02/07/2022] [Indexed: 11/11/2022]
Abstract
Dabigatran etexilate mesylate (DABE), a prodrug, quickly changes in our bodies after its oral administration into dabigatran (DAB). Accordingly, detecting DABE in plasma is practically unmanageable. A UPLC-MS/MS technique was developed and validated to compute free DAB in participants. For the first time, the central composite design- a type of response surface methodology- was utilized for optimizing variables affecting the cleavage of glucuronide bond. Additionally, the pharmacokinetic parameters of generic medication (okanadab) were determined, and the obtained outcomes were compared to those of branded drug (pradaxa®). The sample preparation was done using methanol as a protein precipitant and the separation was achieved via ACQUITY UPLC BEH C18 column (2.1x50mm, 1.7μm). The elution was isocratically conducted using 10mM ammonium formate: methanol (72:28, v/v) as a mobile phase (MP) and the flow rate was 0.25mL/min. Multiple reaction monitoring (MRM) and positive electrospray ionization (ESI) were used. The determination was performed within 1min, and the calibration growth curve was established over a range of (1.19 - 475) ng/mL using dabigatran-d3 as a tagged internal standard (IS). Bioequivalence research was validated following FDA guidelines for bio-analytical procedures and acceptable outcomes were achieved. The outcomes for okanadab and pradaxa® did not differ significantly.
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Affiliation(s)
- Fathy Ibrahim Abd Allah
- Department of Pharmaceutics, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.,International Center for Bioavailability, Pharmaceutical, and Clinical Research
| | - Ahmed Ali Almrasy
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo11751, Egypt
| | - Ahmed Abdelhmaid
- International Center for Bioavailability, Pharmaceutical, and Clinical Research
| | - Osama A Abd-Elmegid
- International Center for Bioavailability, Pharmaceutical, and Clinical Research
| | - Akram Alkashlan
- International Center for Bioavailability, Pharmaceutical, and Clinical Research
| | - Abdul-Aziz M M El-Attar
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo11751, Egypt
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de Andrade RP, Caldeira TG, Vasques BV, Morais Ruela AL, de Souza J. Biopharmaceutics considerations for direct oral anticoagulants. Drug Dev Ind Pharm 2022; 47:1881-1894. [PMID: 35377263 DOI: 10.1080/03639045.2022.2062377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Vitamin K antagonists (VKA) and direct oral anticoagulants (DOACs) have been clinically used in the treatment of coagulation disorders. There are four DOACs approved since 2010 (dabigatran etexilate, rivaroxaban, apixaban, and edoxaban), and they were designed to overcome the practical limitations of VKA. This review summarized biopharmaceutics considerations about DOACs, which are critically discussed, applying risk analyses to subside the further classification of these drugs according to the Biopharmaceutics Classification System (BCS). These discussions included data compiled about physicochemical properties, equilibrium solubility, permeability, and drug dissolution of DOACs. From the biopharmaceutics characteristics is possible to identify critical variables related to the absorption process, which can help in the design of new formulations. The data were compared with the criteria recommended by regulatory agencies for the biopharmaceutics classification according to the BCS. From that, these data may be used to discuss the approval of generic medicines by the BCS-based biowaiver, and the clinical risks arising from novel formulations with DOACs. However, although there are indications of biopharmaceutics classifications for DOACs, conclusive information to classify these compounds according to the BCS is lacking, requiring more experimental studies to achieve this aim. Conclusive information is essential for a safe decision about the biowaiver, as well as to guide the development of new formulations containing the DOACs.
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Affiliation(s)
- Rafael Pereira de Andrade
- Laboratório de Controle de Qualidade, Programa de Pós-Graduação em Ciências Farmacêuticas, Escola de Farmácia, Universidade Federal de Ouro Preto, Campus Universitário Morro do Cruzeiro, Ouro Preto, Minas Gerais, Brazil
| | - Tamires Guedes Caldeira
- Laboratório de Controle de Qualidade, Programa de Pós-Graduação em Ciências Farmacêuticas, Escola de Farmácia, Universidade Federal de Ouro Preto, Campus Universitário Morro do Cruzeiro, Ouro Preto, Minas Gerais, Brazil
| | - Bárbara Vasconcelos Vasques
- Laboratório de Controle de Qualidade, Programa de Pós-Graduação em Ciências Farmacêuticas, Escola de Farmácia, Universidade Federal de Ouro Preto, Campus Universitário Morro do Cruzeiro, Ouro Preto, Minas Gerais, Brazil
| | - André Luís Morais Ruela
- Laboratório de Controle de Qualidade, Programa de Pós-Graduação em Ciências Farmacêuticas, Escola de Farmácia, Universidade Federal de Ouro Preto, Campus Universitário Morro do Cruzeiro, Ouro Preto, Minas Gerais, Brazil
| | - Jacqueline de Souza
- Laboratório de Controle de Qualidade, Programa de Pós-Graduação em Ciências Farmacêuticas, Escola de Farmácia, Universidade Federal de Ouro Preto, Campus Universitário Morro do Cruzeiro, Ouro Preto, Minas Gerais, Brazil
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47
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Macedo Silva V, Freitas M, Arieira C, Xavier S, Boal Carvalho P, Rosa B, Moreira MJ, Cotter J. Direct oral anticoagulants are associated with potentially bleeding lesions in suspected mid-gastrointestinal bleeding. Scand J Gastroenterol 2022; 57:486-492. [PMID: 34895009 DOI: 10.1080/00365521.2021.2014951] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/28/2021] [Accepted: 11/29/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIM Direct oral anticoagulants (DOACs) became a widespread alternative in anticoagulant therapy. Nevertheless, concerns are raised about their safety, with increased gastrointestinal bleeding rates being described. There are scarce studies regarding DOACs effect on small-bowel capsule endoscopy (SBCE) findings. We aimed to assess if the detection of lesions with high bleeding potential on SBCE was significantly different in patients treated with DOACs when compared to non-anticoagulated patients and to patients anticoagulated with other agents. METHODS Cohort study including consecutive patients who underwent SBCE for suspected mid-gastrointestinal bleeding (MGIB) in 2019 and 2020. RESULTS From 148 patients, 38 (25.7%) were anticoagulated, of which 26 (68.4%) with DOACs. P2 lesions were detected in 36.5% (n = 54) of the patients. These lesions were more frequently detected in patients under DOACs treatment when compared to non-anticoagulated patients (69.2% vs. 29.1%; p=.001), and also when compared to patients treated with other anticoagulants (69.2% vs. 33.3%; p=.037). No differences in P2 lesions detection were observed between patients treated with other anticoagulants and non-anticoagulated patients (33.3% vs. 29.1%; p=.747). In multivariate analysis, DOACs usage was significantly associated with higher detection rates of P2 lesions on SBCE, when adjusted for classical risk factors for MGIB (OR: 3.38; 95%CI = 1.23-9.26; p=.018). CONCLUSIONS Despite their undeniable cardiovascular benefits and easy applicability, DOACs should still be considered with caution. These drugs were significantly associated with higher risk of potentially bleeding lesions on SBCE when compared to other anticoagulants and represent an independent risk factor for MGIB when adjusted for other variables.
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Affiliation(s)
- Vítor Macedo Silva
- Gastroenterology Department, Hospital da Senhora da Oliveira, Guimarães, Portugal
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Marta Freitas
- Gastroenterology Department, Hospital da Senhora da Oliveira, Guimarães, Portugal
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Cátia Arieira
- Gastroenterology Department, Hospital da Senhora da Oliveira, Guimarães, Portugal
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Sofia Xavier
- Gastroenterology Department, Hospital da Senhora da Oliveira, Guimarães, Portugal
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Pedro Boal Carvalho
- Gastroenterology Department, Hospital da Senhora da Oliveira, Guimarães, Portugal
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Bruno Rosa
- Gastroenterology Department, Hospital da Senhora da Oliveira, Guimarães, Portugal
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Maria João Moreira
- Gastroenterology Department, Hospital da Senhora da Oliveira, Guimarães, Portugal
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - José Cotter
- Gastroenterology Department, Hospital da Senhora da Oliveira, Guimarães, Portugal
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
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Smeda M, Stojak M, Przyborowski K, Sternak M, Suraj-Prazmowska J, Kus K, Derszniak K, Jasztal A, Kij A, Kurpinska A, Kieronska-Rudek A, Wojnar-Lason K, Buczek E, Mohaissen T, Chlopicki S. Direct Thrombin Inhibitor Dabigatran Compromises Pulmonary Endothelial Integrity in a Murine Model of Breast Cancer Metastasis to the Lungs; the Role of Platelets and Inflammation-Associated Haemostasis. Front Pharmacol 2022; 13:834472. [PMID: 35295330 PMCID: PMC8918823 DOI: 10.3389/fphar.2022.834472] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 01/24/2022] [Indexed: 11/13/2022] Open
Abstract
Activation of the coagulation cascade favours metastatic spread, but antithrombotic therapy might also have detrimental effects on cancer progression. In this study, we characterized the effects of dabigatran, a direct reversible thrombin inhibitor, on the pulmonary endothelial barrier and metastatic spread in a murine model of breast cancer metastasis. Dabigatran etexilate (100 mg kg−1) was administered to mice twice daily by oral gavage. Pulmonary metastasis, pulmonary endothelium permeability in vivo, and platelet reactivity were evaluated after intravenous injection of 4T1 breast cancer cells into BALB/c mice. The effect of dabigatran on platelet-dependent protection of pulmonary endothelial barrier in the presence of an inflammatory stimulus was also verified in vitro using human lung microvascular endothelial cell (HLMVEC) cultures. Dabigatran-treated mice harbored more metastases in their lungs and displayed increased pulmonary endothelium permeability after cancer cell injection. It was not associated with altered lung fibrin deposition, changes in INFγ, or complement activation. In the in vitro model of the pulmonary endothelial barrier, dabigatran inhibited platelet-mediated protection of pulmonary endothelium. In a murine model of breast cancer metastasis, dabigatran treatment promoted pulmonary metastasis by the inhibition of platelet-dependent protection of pulmonary endothelial barrier integrity.
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Affiliation(s)
- Marta Smeda
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
- *Correspondence: Marta Smeda, ; Stefan Chlopicki,
| | - Marta Stojak
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Kamil Przyborowski
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Magdalena Sternak
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Joanna Suraj-Prazmowska
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Kamil Kus
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Katarzyna Derszniak
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
- Faculty of Chemistry, Jagiellonian University, Krakow, Poland
| | - Agnieszka Jasztal
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Agnieszka Kij
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Anna Kurpinska
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Anna Kieronska-Rudek
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
- Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland
| | - Kamila Wojnar-Lason
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
- Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland
| | - Elzbieta Buczek
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Tasnim Mohaissen
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
- Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
| | - Stefan Chlopicki
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
- Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland
- *Correspondence: Marta Smeda, ; Stefan Chlopicki,
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Therapeutic Strategies for Disseminated Intravascular Coagulation Associated with Aortic Aneurysm. Int J Mol Sci 2022; 23:ijms23031296. [PMID: 35163216 PMCID: PMC8836167 DOI: 10.3390/ijms23031296] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/05/2022] [Accepted: 01/22/2022] [Indexed: 01/22/2023] Open
Abstract
Aortic aneurysms are sometimes associated with enhanced-fibrinolytic-type disseminated intravascular coagulation (DIC). In enhanced-fibrinolytic-type DIC, both coagulation and fibrinolysis are markedly activated. Typical cases show decreased platelet counts and fibrinogen levels, increased concentrations of fibrin/fibrinogen degradation products (FDP) and D-dimer, and increased FDP/D-dimer ratios. Thrombin-antithrombin complex or prothrombin fragment 1 + 2, as markers of coagulation activation, and plasmin-α2 plasmin inhibitor complex, a marker of fibrinolytic activation, are all markedly increased. Prolongation of prothrombin time (PT) is not so obvious, and the activated partial thromboplastin time (APTT) is rather shortened in some cases. As a result, DIC can be neither diagnosed nor excluded based on PT and APTT alone. Many of the factors involved in coagulation and fibrinolysis activation are serine proteases. Treatment of enhanced-fibrinolytic-type DIC requires consideration of how to control the function of these serine proteases. The cornerstone of DIC treatment is treatment of the underlying pathology. However, in some cases surgery is either not possible or exacerbates the DIC associated with aortic aneurysm. In such cases, pharmacotherapy becomes even more important. Unfractionated heparin, other heparins, synthetic protease inhibitors, recombinant thrombomodulin, and direct oral anticoagulants (DOACs) are agents that inhibit serine proteases, and all are effective against DIC. Inhibition of activated coagulation factors by anticoagulants is key to the treatment of DIC. Among them, DOACs can be taken orally and is useful for outpatient treatment. Combination therapy of heparin and nafamostat allows fine-adjustment of anticoagulant and antifibrinolytic effects. While warfarin is an anticoagulant, this agent is ineffective in the treatment of DIC because it inhibits the production of coagulation factors as substrates without inhibiting activated coagulation factors. In addition, monotherapy using tranexamic acid in cases of enhanced-fibrinolytic-type DIC may induce fatal thrombosis. If tranexamic acid is needed for DIC, combination with anticoagulant therapy is of critical importance.
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Lafaie L, Célarier T, Monreal M, Mismetti P, Delavenne X, Bertoletti L. The impact of advanced age on anticoagulant therapy for acute venous thromboembolism. Expert Opin Drug Metab Toxicol 2022; 18:27-37. [PMID: 35195483 DOI: 10.1080/17425255.2022.2045273] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Management of venous thromboembolic events (VTE) has been completely changed after the introduction of direct oral anticoagulants (DOAC). VTE is common in the geriatric population, but the management of DOACs remains complex because of the lack of specific data in this polymedicated fragile population.An exhaustive search of anticoagulants in the indication of VTE was performed on PubMed, including data from clinical trials, observational studies, real-world data, drug-drug interaction studies, as well as various guidelines from scientific societies. AREAS COVERED The present review aims to summarize our current knowledge on the era of DOACs in the management of VTE in the elderly. This involves learning the pharmacokinetics/pharmacodynamics of drugs specific to geriatrics, the problem of drug-drug interactions, and the main randomized clinical trials validating the use of DOACs. EXPERT OPINION DOACs have become an essential part of the management of VTE in the elderly, both for their efficacy and safety. However, we are faced with a list of unmet needs, such as the relevance of DOACs in the very elderly, cancer patients, and those with renal impairment. Clinicians and pharmacists must remain cautious about comedications, as well as about the patient's comorbidities.
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Affiliation(s)
- Ludovic Lafaie
- Loire, Inserm, UMR1059, Equipe Dysfonction Vasculaire Et Hémostase, Université de Lyon Saint-Etienne, Saint-Etienne, France.,Département de Gérontologie Clinique, Chu de Saint-Etienne, Saint-Etienne, France
| | - Thomas Célarier
- Département de Gérontologie Clinique, Chu de Saint-Etienne, Saint-Etienne, France
| | - Manuel Monreal
- Department of Internal Medicine, Universidad Católica de Murcia, Hospital Universitario Germans Trias I Pujol de Badalona, Spain
| | - Patrick Mismetti
- Loire, Inserm, UMR1059, Equipe Dysfonction Vasculaire Et Hémostase, Université de Lyon Saint-Etienne, Saint-Etienne, France.,Loire, Unité de Recherche Clinique Innovation Et Pharmacologie, Chu de Saint-Etienne, Saint-Etienne, France
| | - Xavier Delavenne
- Loire, Inserm, UMR1059, Equipe Dysfonction Vasculaire Et Hémostase, Université de Lyon Saint-Etienne, Saint-Etienne, France.,Loire, Laboratoire de Pharmacologie Toxicologie, Chu de Saint-Etienne, Saint-Etienne, France
| | - Laurent Bertoletti
- Loire, Inserm, UMR1059, Equipe Dysfonction Vasculaire Et Hémostase, Université de Lyon Saint-Etienne, Saint-Etienne, France.,Loire, Service de Médecine Vasculaire Et Thérapeutique, Chu de Saint-Etienne, Saint-Etienne, France
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