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Pattanaik S, Monchaud C. Pharmacokinetic Boosting of Calcineurin Inhibitors in Transplantation: Pros, Cons, and Perspectives. Ther Drug Monit 2025; 47:118-140. [PMID: 39774591 DOI: 10.1097/ftd.0000000000001288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 09/27/2024] [Indexed: 01/11/2025]
Abstract
ABSTRACT The concept of pharmacokinetic (PK) boosting of calcineurin inhibitors (CNI) emerged after the FDA approval of cyclosporine-A. Several studies followed, and the proof of concept was well established by the late 1990s. This also continued for the next blockbuster immunosuppressant, tacrolimus. The driver for such research was an endeavor to save costs, as both drugs were expensive due to patent protection. Two CYP inhibitors, ketoconazole and diltiazem, have been extensively studied in this context and continue to be prescribed off-label along with the CNI. It has been observed that using ketoconazole reduces the dose requirement of tacrolimus by about 50% and 30% with diltiazem, which is in conformity with their pharmacological actions. Off-label co-prescription of these drugs with CNI is often encountered in low and middle-income countries. The foremost reason cited is economic. This article collates the evidence from the clinical studies that evaluate the PK-boosting effects of CNI and also reviews the gaps in the current evidence base. The current knowledge prevents the transplant community from making meaningful inferences about the risks and benefits of such strategies. Although the PK-boosting strategy can lead to serious adverse events, emerging evidence suggests that it may be advantageous for individuals with high CNI dose requirements. Hence, PK boosting may be an unmet need in the therapeutics of CNI. Nevertheless, there are several unanswered questions surrounding such use, and therefore, this merits testing in well-designed clinical studies. Moreover, drugs with better safer profiles and a history of successful PK boosting may be considered for evaluation with CNI.
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Affiliation(s)
- Smita Pattanaik
- Clinical Pharmacology Unit, Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Caroline Monchaud
- Service de Pharmacologie, Toxicologie et Pharmacovigilance, CHU Limoges, Limoges, France
- INSERM UMR-1248 Pharmacologie et Transplantation, Université Limoges, Limoges, France; and
- FHU SUPORT, Limoges, France
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Tombolini E, Squizzato A, Podda GM, Aghemo A, Ferri N, Segato S, Poli D, Donadini MP. Drug-Drug Interactions Between DAAs and Anticoagulants or Antiplatelets: A Position Paper of the Italian Anticoagulation Clinics. Liver Int 2025; 45:e16177. [PMID: 39736105 DOI: 10.1111/liv.16177] [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: 09/05/2024] [Revised: 10/18/2024] [Accepted: 11/09/2024] [Indexed: 01/01/2025]
Abstract
The natural history of chronic hepatitis C virus (HCV) infection has changed after the introduction of direct-acting antiviral agents (DAAs). Screening programs have been ongoing to reach the World Health Organisation's goal of HCV elimination by 2030, and most infected people are eligible for treatment. Given the increased cardiovascular risk in people with HCV infection and the metabolic pathways of DAAs, it is not uncommon to face the issue of drug-drug interactions (DDIs) with antiplatelet or anticoagulant drugs. In the absence of clinical trials, we offer suggestions to deal with DDIs in case of treatment of patients with DAAs who are also receiving antiplatelet or anticoagulant drugs, based on the best available evidence from pharmacodynamics and pharmacokinetics studies in conjunction with clinical experience in the field of haemostasis and thrombosis.
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Affiliation(s)
- Elisabetta Tombolini
- Emergency Medicine and Thrombosis and Haemostasis Center, ASST Sette Laghi, Varese, Italy
| | - Alessandro Squizzato
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
- Research Center on Thromboembolic Disorders and Antithrombotic Therapies, ASST Lariana, University of Insubria, Como, Italy
| | - Gian Marco Podda
- Dipartimento di Scienza della Salute, S.C. Medicina Generale II, Ospedale San Paolo, ASST Santi Paolo e Carlo, Università Degli Studi di Milano, Milano, Italy
| | - Alessio Aghemo
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Nicola Ferri
- Department of Medicine, University of Padova, Padova, Italy
| | - Simone Segato
- Gastroenterology and Digestive Endoscopy, ASST Sette Laghi, Varese, Italy
| | - Daniela Poli
- Thrombosis Centre, Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy
| | - Marco Paolo Donadini
- Emergency Medicine and Thrombosis and Haemostasis Center, ASST Sette Laghi, Varese, Italy
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
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Marzolini C, Gibbons S, Seddon D, Khoo S. Drug-drug interactions potential with the HIV-1 capsid inhibitor lenacapavir. Expert Opin Drug Metab Toxicol 2025; 21:161-172. [PMID: 39411777 DOI: 10.1080/17425255.2024.2415295] [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: 08/14/2024] [Accepted: 10/08/2024] [Indexed: 02/02/2025]
Abstract
INTRODUCTION Lenacapavir is the first HIV-1 capsid inhibitor administered subcutaneously twice yearly. While lenacapavir is currently only indicated as salvage therapy, it has the potential to become a foundation of future treatments and to revolutionize HIV prevention. AREAS COVERED This review summarizes the pharmacology of lenacapavir with particular emphasis placed on its drug-drug interaction (DDI) potential as it is used in treatment-experienced individuals who often present multiple comorbidities and polypharmacy. The effect of lenacapavir on drug metabolizing enzymes and transporters as well as findings of DDI studies are summarized. These data were used to predict DDIs with 1073 comedications. Finally, the management of selected DDIs is discussed. Conferences/workshops abstracts (i.e. CROI, IAS, EACS, HIV Glasgow, PK workshop) were screened using the terms: 'lenacapavir,' 'capsid inhibitor,' 'GS-6207,' and a PubMed search was used to compile data until September 2024. EXPERT OPINION Lenacapavir has a favorable DDI profile with 80% of evaluated comedications estimated to have no clinically significant DDIs. More studies are needed to address pharmacological gaps including the pharmacokinetics of lenacapavir in special populations, its transfer across the blood-brain barrier or the placenta as well as the possibility to manage DDIs with moderate/strong inducers by reducing lenacapavir dosing interval.
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Affiliation(s)
- Catia Marzolini
- Service of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, University Hospital of Lausanne and University of Lausanne, Lausanne, Switzerland
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital of Basel and University of Basel, Basel, Switzerland
- Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Sara Gibbons
- Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Daniel Seddon
- Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Saye Khoo
- Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
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Zhang M, Zhang S, Wang L, Zhang Z, Hu Q, Liu D. Key Factors for Improving Predictive Accuracy and Avoiding Overparameterization of the PBPK Absorption Model in Food Effect Studies of Weakly Basic Water-Insoluble Compounds in Immediate Release Formulations. Pharmaceutics 2024; 16:1324. [PMID: 39458653 PMCID: PMC11511194 DOI: 10.3390/pharmaceutics16101324] [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: 08/08/2024] [Revised: 09/16/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
Background/Objectives: Physiologically based pharmacokinetic (PBPK) absorption models are instrumental for assessing drug absorption prior to clinical food effect studies, though discrepancies in predictive and actual outcomes are observed. This study focused on immediate release formulations of weakly basic water-insoluble compounds, namely rivaroxaban, ticagrelor, and PB-201, to investigate factors that could improve the predictive accuracy of PBPK models regarding food effects. Methods: Comprehensive in vitro experimental results provided the basis for the development of mechanistic absorption models, which were then combined with mechanistic disposition models to predict the systemic exposure of the model drugs in both fasted and fed states. Results: The developed PBPK models showed moderate to high predictive accuracy for food effects in Caucasian populations. For the Chinese population, the ticagrelor model's initial overestimation of fed-state absorption was addressed by updating the permeability parameters from Caco-2 cell assays to those derived from parallel artificial membrane permeability assays in FaSSIF and FeSSIF media. This refinement was also applied to the rivaroxaban and ticagrelor models, leading to a more accurate representation of absorption in Caucasians. Conclusions: This study highlights the importance of apparent permeability in enhancing the predictive accuracy of PBPK absorption models for weakly basic water-insoluble compounds. Furthermore, the precipitation of PB-201 in the two-stage transfer experiments suggests that precipitation may not be a universal phenomenon for such compounds in vivo. Consequently, the precipitation rate constant, a theoretically essential parameter, should be determined based on experimental evidence to avoid overparameterization and ensure robust predictive accuracy of PBPK models.
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Affiliation(s)
- Miao Zhang
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China;
- Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, MA 02115, USA
| | - Shudong Zhang
- NMPA Key Laboratory for Research and Evaluation of Generic Drugs, Beijing Institute for Drug Control, Beijing 102206, China
| | - Lin Wang
- NMPA Key Laboratory for Research and Evaluation of Generic Drugs, Beijing Institute for Drug Control, Beijing 102206, China
| | - Zhe Zhang
- NMPA Key Laboratory for Research and Evaluation of Generic Drugs, Beijing Institute for Drug Control, Beijing 102206, China
| | - Qin Hu
- NMPA Key Laboratory for Research and Evaluation of Generic Drugs, Beijing Institute for Drug Control, Beijing 102206, China
| | - Dongyang Liu
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China;
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Kuhn AL, Singh J, Puri AS. Dual Antiplatelet Non-Responder: Resistance to Clopidogrel and Ticagrelor. Neurohospitalist 2024; 14:312-315. [PMID: 38894997 PMCID: PMC11181978 DOI: 10.1177/19418744241228630] [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: 06/21/2024] Open
Abstract
Background Dual antiplatelet therapy is often required for neurointerventional procedures, especially when a stent or flow diverter is placed in the cervical and intracranial vessels. Patients are usually started on aspirin and clopidogrel given the simplicity of the once daily regimen with reasonable cost. Unfortunately, about a third of patients do not show the desired antiplatelet response to clopidogrel and another agent needs to be introduced. Ticagrelor is a potent antiplatelet medication that has a favorable pharmacological profile and has emerged as a reliable alternative to clopidogrel in recent years. Despite ticagrelor non-responders being rare, they do exist, and identification of these patients is important. Results A 74-year-old female was incidentally found to harbor a right posterior communicating aneurysm which was successfully treated electively with stent-assisted coiling. Platelet inhibition testing revealed non-responsiveness to Clopidogrel. Ticagrelor was initiated but the patient's platelet reactivity unit remained in the normal range. Management algorithms to maximize a patient's ticagrelor response by facilitating enteral absorption were applied but no platelet inhibition was achieved. The patient was eventually identified as a true ticagrelor non-responder. Conclusion Resistance to antiplatelet medication can result in devastating complications with permanent neurological deficits. Ticagrelor non-responders are rare but do exist. Platelet inhibition testing should be part of the preprocedural workup for neurointerventions.
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Affiliation(s)
- Anna Luisa Kuhn
- Department of Radiology, Division of Neurointerventional Radiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Jasmeet Singh
- Department of Radiology, Division of Neurointerventional Radiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Ajit S. Puri
- Department of Radiology, Division of Neurointerventional Radiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
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Wang J, Hu Y, Li Q, Liu YN, Lin J, Xu RA. Effects of myricetin and quercetin on ticagrelor metabolism and the underlying mechanism. Chem Biol Interact 2024; 392:110924. [PMID: 38401715 DOI: 10.1016/j.cbi.2024.110924] [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: 07/21/2023] [Revised: 01/25/2024] [Accepted: 02/18/2024] [Indexed: 02/26/2024]
Abstract
The aim of this study was to investigate the potential drug-drug interactions (DDIs) between ticagrelor and other drugs as well as their underlying mechanisms. Rat liver microsome (RLM) reaction system was used to screen potential DDIs in vitro, and ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was applied to detect the levels of ticagrelor and AR-C124910XX, the main metabolite of ticagrelor. A total of 68 drugs were screened, 11 of which inhibited the production of AR-C124910XX to 20% or less, especially two flavonoids (myricetin and quercetin). The half-maximal inhibitory concentration (IC50) of myricetin on ticagrelor was 11.51 ± 0.28 μM in RLM and 17.96 ± 0.54 μM in human liver microsome (HLM). The IC50 of quercetin in inhibiting ticagrelor in RLM and HLM was 16.92 ± 0.49 μM and 60.15 ± 0.43 μM, respectively. They all inhibited the metabolism of ticagrelor through a mixed mechanism. In addition, Sprague-Dawley (SD) rats were used to study the interactions of ticagrelor with selected drugs in vivo. We found that the main pharmacokinetic parameters including AUC (0-t), AUC (0-∞) and Cmax of ticagrelor were significantly increased when ticagrelor was combined with these two flavonoids. Our results suggested that myricetin and quercetin of flavonoids both had significant effects on the metabolism of ticagrelor, providing reference data for the clinical individualized medication of ticagrelor.
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Affiliation(s)
- Jing Wang
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yingying Hu
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qingqing Li
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ya-Nan Liu
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jingjing Lin
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Ren-Ai Xu
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
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Chen J, Qu Y, Jiang M, Li H, Cui C, Liu D. Population Pharmacokinetic/Pharmacodynamic Models for P2Y12 Inhibitors: A Systematic Review and Clinical Appraisal Using Exposure Simulation. Clin Pharmacokinet 2024; 63:303-316. [PMID: 38244191 DOI: 10.1007/s40262-023-01335-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/07/2023] [Indexed: 01/22/2024]
Abstract
BACKGROUND AND OBJECTIVE Recent research indicates a correlation between plasma concentration of P2Y12 inhibitors and clinical events, particularly bleeding, which significantly impeded their clinical therapeutic performance. It is therefore vital to delve into the factors that might affect the plasma concentration. The study aims to summarize population pharmacokinetics/pharmacodynamics (PopPKPD) models for commonly prescribed P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor) and assess bleeding risk in specific individual groups. METHODS The PopPKPD models of P2Y12 inhibitors were collected and summarized based on predetermined inclusion and exclusion criteria. The collected models were replicated in simulations, which were used to assess factors affecting plasma concentrations of P2Y12 inhibitors. Simulation results for special populations were compared to therapeutic window based on reported exposure-effect relationships (PK/PD-related bleeding and thrombotic clinical outcomes) to predict bleeding risk in special populations with different dosing regimens and cumulative covariates. RESULT Finally, 12 studies were included for PK simulation, 7 of which that also included PD data were subjected to further analysis, with the majority being based on Phase I or II trials. Simulations showed that several covariates such as female gender, weight, elderly can significantly impact on exposure, with special populations reaching up to 179% of the general population. However, after dose adjustment, blood concentrations for special populations can reach approximately ±20% of general population exposure. Therefore, lowering the maintenance dose of ticagrelor from 90 to 60 mg bid was first recommended to reduce bleeding risk without significantly increasing ischemic risk, particularly in elderly, small-weight Asian females. CONCLUSION Lowering the maintenance dose of ticagrelor from 90 to 60 mg bid effectively reduces bleeding risk without increasing thrombotic infarction risk in elderly, small-weight Asian females.
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Affiliation(s)
- Jingcheng Chen
- Department of Cardiology, 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, China
| | - Yuchen Qu
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Muhan Jiang
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing, 100191, China
| | - Haiyan Li
- Department of Cardiology, 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, China
| | - Cheng Cui
- Department of Cardiology, 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, 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, China.
- Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Third Hospital, Beijing, China.
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Wei P, Wang X, Fu Q, Cao B. Progress in the clinical effects and adverse reactions of ticagrelor. Thromb J 2024; 22:8. [PMID: 38200557 PMCID: PMC10782624 DOI: 10.1186/s12959-023-00559-3] [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: 05/17/2022] [Accepted: 11/02/2023] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND Ticagrelor is a novel receptor antagonist that selectively binds to the P2Y12 receptor, thereby inhibiting adenosine diphosphate (ADP)-mediated platelet aggregation. Compared to clopidogrel, ticagrelor has the advantages of a fast onset, potent effects, and a reversible platelet inhibition function, which make this drug clinically suitable for treating acute coronary syndrome (ACS), especially acute ST-segment elevation myocardial infarction (STEMI). OBJECTIVE This review was performed to determine the basic characteristics, clinical effects, and adverse reactions of ticagrelor. METHODS Relevant trials and reports were obtained from the MEDLINE, Embase, and Cochrane Library databases. RESULTS Ticagrelor is rapidly absorbed by the body after oral administration, exhibits inherent activity without requiring metabolic activation, and binds reversibly to the P2Y12 receptor. Ticagrelor has been recommended in ACS treatment guidelines worldwide due to its advantageous pharmacological properties and significant clinical benefits. Ticagrelor inhibits platelet aggregation, inhibits inflammatory response, enhances adenosine function, and has cardioprotective effects. However, ticagrelor also causes adverse reactions such as bleeding tendency, dyspnea, ventricular pause, gout, kidney damage, and thrombotic thrombocytopenic purpura in clinical treatment. Therefore, it is necessary to pay attention to risk assessments when using ticagrelor. CONCLUSION Ticagrelor is a promising drug for the effective treatment of ACS. When using ticagrelor, individualized treatment should be provided based on the specific conditions of the patients to avoid serious adverse events.
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Affiliation(s)
- Peng Wei
- Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Xiaoqing Wang
- Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Qiang Fu
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou, 221009, Jiangsu, China.
| | - Bangming Cao
- Department of Gerontology, The Affiliated Hospital of Youjiang Medical University for Nationalities, No. 18# Zhongshan 2 Road, Baise, 533000, Guangxi Zhuang Autonomous Region, China.
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Xia X, Chen S, Cao C, Ye Y, Shen Y. New Score Models for Predicting Bleeding and Ischemic of Ticagrelor Therapy in Patients with Diabetes Mellitus. Clin Appl Thromb Hemost 2024; 30:10760296241254107. [PMID: 38780348 PMCID: PMC11119327 DOI: 10.1177/10760296241254107] [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: 02/22/2024] [Revised: 04/10/2024] [Accepted: 04/23/2024] [Indexed: 05/25/2024] Open
Abstract
PURPOSE Ticagrelor is an antiplatelet drug, and its use increases the risk of bleeding. Coronary artery disease is significantly influenced by the widespread occurrence of diabetes mellitus. In order to decrease the incidence of clinical adverse events, a novel bleeding and thrombosis score is developed in this research. METHODS We conducted a retrospective analysis of patient data from two medical centers who were diagnosed with diabetes mellitus and treated with ticagrelor. We gathered information on every patient from the electronic database of the hospital and follow-up. The collected data were statistically analyzed to obtain risk factors for bleeding and ischemic events. RESULTS A total of 851 patients with diabetes mellitus who have been administered ticagrelor are included in our investigation. A total of 76 patients have bleeding events and 80 patients have ischemic events. The analysis of multiple variables indicates that characteristics like the age of >65, having a previous occurrence of bleeding, experiencing anemia, using aspirin, and taking atorvastatin are linked to a higher likelihood of bleeding. Additionally, the age of >65, smoking, having a history of blood clots, and having a BMI ≥ 30 are found to increase the risk of ischemia. CONCLUSION The A4B score established in this study was better than the HAS-BLED score，and the same is true for the ABST score to the CHA2DS-VASc score. This new risk assessment model can potentially detect patients who are at high risk for bleeding and ischemic events. For high-risk patients, the dose of ticagrelor can be adjusted appropriately or the medication can be adjusted.(2023-09-11, ChiCTR2300075627).
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Affiliation(s)
- Xiaotong Xia
- Department of Pharmacy, Zhongshan Hospital (Xiamen), Fudan University, Fujian Xiamen, China
| | - Shu Chen
- Department of Pharmacy, Zhongshan Hospital (Xiamen), Fudan University, Fujian Xiamen, China
| | - Chang Cao
- Department of Pharmacy, Zhongshan Hospital (Xiamen), Fudan University, Fujian Xiamen, China
| | - YanRong Ye
- Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yun Shen
- Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
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Hashmi N, Jawaid M, Shah MR. Bioequivalence assessment of two Ticagrelor formulations under fasting condition in healthy Pakistani subjects. Pak J Med Sci 2023; 39:1647-1651. [PMID: 37936786 PMCID: PMC10626117 DOI: 10.12669/pjms.39.6.8203] [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: 03/26/2023] [Revised: 05/22/2023] [Accepted: 08/16/2023] [Indexed: 11/09/2023] Open
Abstract
Objective To investigate the Bioequivalence of Anplag® 90mg (Ticagrelor) tablet and Brilinta® 90 mg (Ticagrelor) tablet under fasting conditions in healthy Pakistani subjects. Method This was an open-label, cross-over, randomized, single-dose, two-period, single-center Bioequivalence Study conducted at Center of Bioequivalence Studies and Clinical Research (CBSCR), ICCBS, University of Karachi, Karachi, Pakistan from September 2020 to January 2021. This was an open-label, randomized, single-dose, two-period, cross-over Bioequivalence Study. After randomization, a single dose of Ticagrelor 90mg tablet (test or reference drug) were administered orally in 1:1 ratio to each subject under fasting conditions. Seven days washout period was kept between the two periods in order to avoid carry over. Blood samples were then taken up to 48th hours post-dose. Point estimates and 90% confidence intervals (CI) for the ratio of the log-transformed values were calculated. Bioequivalence assessment of both, the reference and the test drugs were based on the primary Pharmacokinetic PK metrics including peak maximum concentration (Cmax), area under the curve (AUC) from zero to last quantifiable concentration (AUClast), and AUC from zero to infinity (AUCtotal) after log-transformation of data with ANOVA. In this bioequivalence study, the primary pharmacokinetic parameters were assessed for both Ticagrelor and its Active Metabolite (AR-C124910XX). Safety endpoints were evaluated by monitoring adverse events (AEs). Results The 90% Confidence Intervals (CIs) of the Geometric Mean Ratio for primary PK parameters including Cmax, AUClast, and AUCtotal all were within the accepted bioequivalence range of 80%- 125%. In the current study, no serious adverse events were reported. Conclusion Our results showed that the two tested formulations of Ticagrelor tablets were bioequivalent and well tolerated.Trial Registration: ClinicalTrials.gov Identifier: NCT04941196.
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Affiliation(s)
- Naghma Hashmi
- Naghma Hashmi Center for Bioequivalence Studies and Clinical Research, Dr. Panjwani Center for Molecular Medicine and Drug Research International, Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Masood Jawaid
- Masood Jawaid Director Medical Affairs, PharmEvo Private Limited, 402, Business Avenue, Block-6, P.E.C.H.S., Shahrah-e-Faisal, Karachi, Pakistan
| | - Muhammad Raza Shah
- Muhammad Raza Shah Center for Bioequivalence Studies and Clinical Research, Dr. Panjwani Center for Molecular Medicine and Drug Research International, Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
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Azzahhafi J, Bergmeijer TO, van den Broek WWA, Chan Pin Yin DRPP, Rayhi S, Peper J, Bor WL, Claassens DMF, van Schaik RHN, ten Berg JM. Effects of CYP3A4*22 and CYP3A5 on clinical outcome in patients treated with ticagrelor for ST-segment elevation myocardial infarction: POPular Genetics sub-study. Front Pharmacol 2022; 13:1032995. [PMID: 36545312 PMCID: PMC9760790 DOI: 10.3389/fphar.2022.1032995] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022] Open
Abstract
Aims: To determine the clinical efficacy, adverse events and side-effect dyspnea of CYP3A4*22 and CYP3A5 expressor status in ticagrelor treated patients. Methods and results: Ticagrelor treated patients from the POPular Genetics randomized controlled trial were genotyped for CYP3A4*22 and CYP3A5*3 alleles. Patients were divided based on their genotype. In total 1,281 patients with ST-segment elevation myocardial infarction (STEMI) were included. CYP3A4*22 carriers (n = 152) versus CYP3A4*22 non-carrier status (n = 1,129) were not found to have a significant correlation with the primary thrombotic endpoint: cardiovascular death, myocardial infarction, definite stent thrombosis and stroke [1.3% vs. 2.5%, adjusted hazard ratio 1.81 (0.43-7.62) p = 0.42], or the primary bleeding endpoint: PLATO major and minor bleeding [13.2% vs. 11.3%, adjusted hazard ratio 0.93 (0.58-1.50) p = 0.77]. Among the CYP3A4*1/*1 patients, CYP3A5 expressors (n = 196) versus non-expressors (n = 926) did not show a significant difference for the primary thrombotic [2.6% vs. 2.5%, adjusted hazard ratio 1.03 (0.39-2.71) p = 0.95], or the primary bleeding endpoint [12.8% vs. 10.9%, adjusted hazard ratio 1.13 (0.73-1.76) p = 0.58]. With respect to dyspnea, no significant difference was observed between CYP3A4*22 carriers versus CYP3A4*22 non-carriers [44.0% vs. 45.0%, odds ratio 1.04 (0.45-2.42) p = 0.93], or in the CYP3A4*1/*1 group, CYP3A5 expressors versus CYP3A5 non-expressors [35.3% vs. 47.8%, odds ratio 0.60 (0.27-1.30) p = 0.20]. Conclusion: In STEMI patients treated with ticagrelor, neither the CYP3A4*22 carriers, nor the CYP3A5 expressor status had a statistical significant effect on thrombotic and bleeding event rates nor on dyspnea. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT01761786.
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Affiliation(s)
- Jaouad Azzahhafi
- Department of Cardiology, St. Antonius Hospital, Nieuwegein, Netherlands,*Correspondence: Jaouad Azzahhafi,
| | | | | | | | - Senna Rayhi
- Department of Cardiology, St. Antonius Hospital, Nieuwegein, Netherlands
| | - Joyce Peper
- Department of Cardiology, St. Antonius Hospital, Nieuwegein, Netherlands
| | - Willem L. Bor
- Department of Cardiology, St. Antonius Hospital, Nieuwegein, Netherlands
| | - Daniel M. F. Claassens
- Department of Cardiology, St. Antonius Hospital, Nieuwegein, Netherlands,Department of Cardiology, Isala, Zwolle, Netherlands
| | - Ron H. N. van Schaik
- Department of Clinical Chemistry, Erasmus Medical Centre, Rotterdam, Netherlands
| | - Jurriën M. ten Berg
- Department of Cardiology, St. Antonius Hospital, Nieuwegein, Netherlands,Cardiovascular Research Institute Maastricht (CARIM), University Medical Center Maastricht, Maastricht, Netherlands
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12
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Abstract
INTRODUCTION Platelets play a key role in arterial thrombosis and antiplatelet therapy is pivotal in the treatment of cardiovascular disease. Current antiplatelet drugs target different pathways of platelet activation and show specific pharmacodynamic and pharmacokinetic characteristics, implicating clinically relevant drug-drug interactions. AREAS COVERED This article reviews the role of platelets in hemostasis and cardiovascular thrombosis, and discusses the key pharmacodynamics, drug-drug interactions and reversal strategies of clinically used antiplatelet drugs. EXPERT OPINION Antiplatelet therapies target distinct pathways of platelet activation: thromboxane A2 synthesis, adenosine diphosphate-mediated signaling, integrin αIIbβ3 (GPIIb/IIIa), thrombin-mediated platelet activation via the PAR1 receptor and phosphodiesterases. Key clinical drug-drug interactions of antiplatelet agents involve acetylsalicylic acid - ibuprofen, clopidogrel - omeprazole, and morphine - oral P2Y12 inhibitors, all of which lead to an attenuated antiplatelet effect. Platelet function and genetic testing and the use of scores (ARC-HBR, PRECISE-DAPT, ESC ischemic risk definition) may contribute to a more tailored antiplatelet therapy. High on-treatment platelet reactivity presents a key problem in the acute management of ST-elevation myocardial infarction (STEMI). A treatment strategy involving early initiation of an intravenous antiplatelet agent may be able to bridge the gap of insufficient platelet inhibition in high ischemic risk patients with STEMI.
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Affiliation(s)
- Georg Gelbenegger
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Bernd Jilma
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
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Zarif B, Soliman L, Sabry NA, Said E. Testing P2Y12 platelet inhibitors generics beyond bioequivalence: a parallel single-blinded randomized trial. Thromb J 2022; 20:44. [PMID: 35978315 PMCID: PMC9382000 DOI: 10.1186/s12959-022-00405-y] [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: 05/25/2022] [Accepted: 08/07/2022] [Indexed: 11/10/2022] Open
Abstract
Cardiovascular diseases are the leading cause of death worldwide. Ticagrelor is an oral antiplatelet drug used in acute coronary syndrome. Although generic drugs are approved for their bioequivalence to the original product, they are not necessarily to be therapeutically equivalent. This study was conducted to prove the efficacy and safety of ticagrelor generically named Ticaloguard® compared to its brand Brilique® in healthy volunteers. A loading dose of 180 mg ticagrelor named Brilique® or Ticaloguard® followed by a 90 mg twice daily regimen as maintenance dose was given to 14 and 15 volunteers in Tica and Brili groups, respectively. The platelet aggregation on the ADP agonist was assessed at baseline and repeated 1 h and 3 h after the loading dose, on day 4 (after reaching steady-state), 12 and 24 h after discontinuation of the antiplatelet drug. Adverse effects from trial medications were noted by direct questions. It was shown that generic Ticaloguard® provides a similar therapeutic effect and safety as its branded Brilique® (p > 0.05). This will permit safe and trusted use of the generic Ticaloguard® when treating it in the same manner as Brilique®. Testing generic drug effects rather than simple bioequivalency, especially for drugs that are used in critical life-threatening situations, is crucial. We advocate applying this form of a clinical trial to test surrogate clinical efficacy for generics used in critical indications before having real-world data whenever possible.
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Affiliation(s)
- Bassem Zarif
- Department of Cardiology, National Heart Institute, Cairo, Egypt
| | - Lamyaa Soliman
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Nirmeen A Sabry
- Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Kasr Alainy Street, Cairo, 11562, Egypt.
| | - Eman Said
- Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Kasr Alainy Street, Cairo, 11562, Egypt
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Liu S, Sodhi JK, Benet LZ. Analyzing Potential Intestinal Transporter Drug-Drug Interactions: Reevaluating Ticagrelor Interaction Studies. Pharm Res 2021; 38:1639-1644. [PMID: 34729703 DOI: 10.1007/s11095-021-03105-w] [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: 07/21/2021] [Accepted: 09/01/2021] [Indexed: 11/30/2022]
Abstract
PURPOSE Previous studies evaluating ticagrelor drug-drug interactions have not differentiated intestinal versus systemic mechanisms, which we do here. METHODS Using recently published methodologies from our laboratory to differentiate metabolic- from transporter-mediated drug-drug interactions, a critical evaluation of five published ticagrelor drug-drug interactions was carried out to investigate the purported clinical significance of enzymes and transporters in ticagrelor disposition. RESULTS The suggested CYP3A4 inhibitors, ketoconazole and diltiazem, displayed unchanged mean absorption time (MAT) and time of maximum concentration (Tmax) values as was expected, i.e., the interactions were mainly mediated by metabolic enzymes. The potential CYP3A4/P-gp inhibitor cyclosporine also showed an unchanged MAT value. Further analysis assuming there was no P-gp effect suggested that the increased AUC and unchanged t1/2 for ticagrelor after cyclosporine administration were attributed to the inhibition of intestinal CYP3A4 rather than P-gp. Rifampin, an inducer of CYP3As after multiple dosing, unexpectedly showed decreased MAT and Tmax values, which cannot be completely explained. In contrast, grapefruit juice, an intestinal CYP3A/P-gp/OATP inhibitor, significantly increased MAT and Tmax values for ticagrelor, which may be due to activation of P-gp or inhibition of OATPs expressed in intestine. CONCLUSIONS This study provides new insight into the role of transporter pathways in ticagrelor intestinal absorption by examining potential MAT and Tmax changes mediated by drug-drug interactions.
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Affiliation(s)
- Shuaibing Liu
- Department of Bioengineering and Therapeutics Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, California, 94143-0912, San Francisco, USA
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jasleen K Sodhi
- Department of Bioengineering and Therapeutics Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, California, 94143-0912, San Francisco, USA
- Department of Drug Metabolism and Pharmacokinetics, Plexxikon Inc, South San Francisco, California, USA
| | - Leslie Z Benet
- Department of Bioengineering and Therapeutics Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, California, 94143-0912, San Francisco, USA.
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15
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Schilling U, Dingemanse J, Ufer M. Pharmacokinetics and Pharmacodynamics of Approved and Investigational P2Y12 Receptor Antagonists. Clin Pharmacokinet 2021; 59:545-566. [PMID: 32056160 DOI: 10.1007/s40262-020-00864-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Coronary artery disease remains the major cause of mortality worldwide. Antiplatelet drugs such as acetylsalicylic acid and P2Y12 receptor antagonists are cornerstone treatments for the prevention of thrombotic events in patients with coronary artery disease. Clopidogrel has long been the gold standard but has major pharmacological limitations such as a slow onset and long duration of effect, as well as weak platelet inhibition with high inter-individual pharmacokinetic and pharmacodynamic variability. There has been a strong need to develop potent P2Y12 receptor antagonists with more favorable pharmacological properties. Prasugrel and ticagrelor are more potent and have a faster onset of action; however, they have shown an increased bleeding risk compared with clopidogrel. Cangrelor is highly potent and has a very rapid onset and offset of effect; however, its indication is limited to P2Y12 antagonist-naïve patients undergoing percutaneous coronary intervention. Two novel P2Y12 receptor antagonists are currently in clinical development, namely vicagrel and selatogrel. Vicagrel is an analog of clopidogrel with enhanced and more efficient formation of its active metabolite. Selatogrel is characterized by a rapid onset of action following subcutaneous administration and developed for early treatment of a suspected acute myocardial infarction. This review article describes the clinical pharmacology profile of marketed P2Y12 receptor antagonists and those under development focusing on pharmacokinetic, pharmacodynamic, and drug-drug interaction liability.
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Affiliation(s)
- Uta Schilling
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
| | - Jasper Dingemanse
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123, Allschwil, Switzerland
| | - Mike Ufer
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123, Allschwil, Switzerland
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16
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Wang P, Hu XX, Li YH, Gao NY, Chen GQ, Chen JL. Inhibitory effect of resveratrol on the pharmacokinetics of ticagrelor in vivo and in vitro. Can J Physiol Pharmacol 2021; 99:821-826. [PMID: 33400617 DOI: 10.1139/cjpp-2020-0512] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
This study was to evaluate the effect of resveratrol on the pharmacokinetics of ticagrelor in rats and the metabolism of ticagrelor in human cytochrome P450 (CYP) 3A4 (CYP3A4) and liver microsomes. Eighteen Sprague-Dawley rats were randomly divided into three groups: group A (control group), group B (50 mg/kg resveratrol), and group C (150 mg/kg resveratrol). After 30 min administration of resveratrol, a single dose of ticagrelor (18 mg/kg) was administered orally. The in vitro experiment was performed to examine the influence of resveratrol on ticagrelor metabolism in CYP3A4*1, human, and rat liver microsomes. Serial biological samples were assayed by validated ultra high-performance liquid chromatography - tandem mass spectrometer methods. For the in vivo study, the area under the concentration-time curve and mean peak plasma concentrations of ticagrelor in group B and C appeared to be significantly higher than the control group, while volume of distribution in terminal phase and apparent clearance of ticagrelor in group B and C were significantly decreased. For the in vitro study, resveratrol exhibited an inhibitory effect on CYP3A4*1, human and rat liver microsomes. The half-maximal inhibitory concentration values of resveratrol were 56.75 μM, 69.07 μM, and 14.22 μM, respectively. Our results indicated that resveratrol had an inhibitory effect on the metabolism of ticagrelor in vitro and in vivo. Further research should focus on the clinical combination of resveratrol with ticagrelor, and ticagrelor plasma concentration should be monitored to avoid the occurrence of adverse reaction.
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Affiliation(s)
- Peng Wang
- Jinhua People's Hospital, Jinhua, Zhejiang, China
| | - Xiao-Xia Hu
- Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Ying-Hui Li
- Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Nan-Yong Gao
- Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Guo-Quan Chen
- Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Jia-le Chen
- Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
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17
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Lordkipanidzé M, Marquis-Gravel G, Tanguay JF, Mehta SR, So DY. Implications of the Antiplatelet Therapy Gap Left With Discontinuation of Prasugrel in Canada. CJC Open 2020; 3:814-821. [PMID: 34169260 PMCID: PMC8209390 DOI: 10.1016/j.cjco.2020.11.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 11/18/2020] [Indexed: 11/19/2022] Open
Abstract
Background The current Canadian Cardiovascular Society antiplatelet therapy guidelines recommend the use of ticagrelor or prasugrel over clopidogrel as first-line platelet P2Y12 receptor antagonists for treatment of moderate- to high-risk acute coronary syndromes. Recently, Effient (prasugrel [Eli Lilly Canada Inc, Toronto, Canada]) was discontinued by its distributor in Canada. Methods Five members of the Canadian Cardiovascular Society antiplatelet therapy 2018 guidelines committee undertook an independent, evidence-based review to outline patients for whom prasugrel should be the optimal P2Y12 agent and discuss alternative strategies to consider without prasugrel. Results Several clinical scenarios where prasugrel should be indicated are identified and discussed. Considerations to be undertaken for alternative therapies are summarized, including a review of national and international guidelines for de-escalation of P2Y12 receptor antagonists. Conclusions The discontinuation of prasugrel poses a challenge for clinicians. Clinicians must consider key factors in determining the best alternate therapy.
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Affiliation(s)
- Marie Lordkipanidzé
- Montreal Heart Institute, Montreal, Quebec, Canada
- Faculty of pharmacy, Université de Montréal, Montreal, Quebec, Canada
| | - Guillaume Marquis-Gravel
- Montreal Heart Institute, Montreal, Quebec, Canada
- Faculty of medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Jean-François Tanguay
- Montreal Heart Institute, Montreal, Quebec, Canada
- Faculty of medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Shamir R. Mehta
- McMaster University, Hamilton, Ontario, Canada
- Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Derek Y.F. So
- University of Ottawa Heart Institute, Ottawa, Ontario, Canada
- Corresponding author: Dr Derek Y.F. So, University of Ottawa Heart Institute, 40 Ruskin St, Room H3408, Ottawa, Ontario K1Y 4W7, Canada. Tel: +1-613-761-5387.
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18
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Liu S, Wang Z, Hou L, Tian X, Zhang X, Cai W. Predicting the effect of tea polyphenols on ticagrelor by incorporating transporter-enzyme interplay mechanism. Chem Biol Interact 2020; 330:109228. [PMID: 32827518 DOI: 10.1016/j.cbi.2020.109228] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 08/09/2020] [Accepted: 08/18/2020] [Indexed: 12/19/2022]
Abstract
This study aimed at exploring the potential mechanism of decreased in vivo exposure of the antiplatelet agent, ticagrelor and its active metabolite, AR-C124910XX, mediated by tea polyphenols, which was first revealed by our previous study, as well as predicting the in vivo drug-drug interaction (DDI) potential utilizing an in vitro to in vivo extrapolation (IVIVE) approach. The bidirectional transport and uptake kinetics of ticagrelor were determined using Caco-2 cells. Inhibition potency of major components of tea polyphenols, epigallocatechin gallate (EGCG) and epigallocatechin (EGC) were obtained from Caco-2 cells, human intestinal and hepatic microsomes (HIMs and HLMs) in vitro. A mean efflux ratio of 2.28 ± 0.38 and active uptake behavior of ticagrelor were observed in Caco-2 cell studies. Further investigation showed that the IC50 values of EGCG and EGC on the uptake of ticagrelor were 42.0 ± 5.1 μM (95% CI 31.9-54.8 μM) and 161 ± 13 μM (95% CI 136-191 μM), respectively. EGCG and EGC also displayed moderate to weak reversible inhibition on the formation of AR-C124910XX and the inactive metabolite, AR-C133913XX in HIMs and HLMs, while no clinically significant time-dependent inhibition was observed for either compound. IVIVE indicated a significant inhibition effect of EGCG on the uptake process of ticagrelor, while no potential DDI risk was found based on microsomal data. A 45% decrease in ticagrelor in vivo exposure was mechanistically predicted by incorporating intestinal and hepatic metabolism as well as intestinal absorption. This dual inhibition of tea polyphenols on ticagrelor revealed the underlying potential of transporter-enzyme interplay, in which the altered uptake process was more critical.
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Affiliation(s)
- Shuaibing Liu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Ziteng Wang
- Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Lei Hou
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xin Tian
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xiaojian Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Weimin Cai
- Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, 201203, China.
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19
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Smolders EJ, Ter Horst PJG, Wolters S, Burger DM. Cardiovascular Risk Management and Hepatitis C: Combining Drugs. Clin Pharmacokinet 2020; 58:565-592. [PMID: 30259390 PMCID: PMC6451722 DOI: 10.1007/s40262-018-0710-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Direct-acting antivirals (DAAs) are known victims (substrate) and perpetrators (cause) of drug–drug interactions (DDIs). These DAAs are used for the treatment of hepatitis C virus (HCV) infections and are highly effective drugs. Drugs used for cardiovascular risk management are frequently used by HCV-infected patients, whom also are treated with DAAs. Therefore, the aim of this review was to describe DDIs between cardiovascular drugs (CVDs) and DAAs. An extensive literature search was performed containing search terms for the marketed DAAs and CVDs (β-blocking agents, ACE inhibitors, angiotensin II antagonists, renin inhibitors, diuretics, calcium channel blockers, statins/ezetimibe, fibrates, platelet aggregation inhibitors, vitamin K antagonists, heparins, direct Xa inhibitors, nitrates, amiodarone, and digoxin). In particular, the drug labels from the European Medicines Agency and the US Food and Drug Administration were used. A main finding of this review is that CVDs are mostly victims of DDIs with DAAs. Therefore, when possible, monitoring of pharmacodynamics is recommended when coadministering these drugs with DAAs. Nevertheless, it is sometimes better to discontinue a drug on a temporary basis (statins, ezetimide). The DAAs are victims of DDIs in combination with bisoprolol, carvedilol, labetalol, verapamil, and gemfibrozil. Despite there are many DDIs predicted in this review, most of these DDIs can be managed by monitoring the efficacy and toxicity of the victim drug or by switching to another CVD/DAA.
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Affiliation(s)
- Elise J Smolders
- Department of Pharmacy, Isala Hospital, Dokter van Heesweg 2, 8025 AB, Zwolle, The Netherlands. .,Department of Pharmacy, Radboud university medical center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands.
| | - Peter J G Ter Horst
- Department of Pharmacy, Isala Hospital, Dokter van Heesweg 2, 8025 AB, Zwolle, The Netherlands
| | - Sharon Wolters
- Department of Pharmacy, Isala Hospital, Dokter van Heesweg 2, 8025 AB, Zwolle, The Netherlands
| | - David M Burger
- Department of Pharmacy, Radboud university medical center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands
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Ticagrelor Increases SIRT1 and HES1 mRNA Levels in Peripheral Blood Cells from Patients with Stable Coronary Artery Disease and Chronic Obstructive Pulmonary Disease. Int J Mol Sci 2020; 21:ijms21051576. [PMID: 32106619 PMCID: PMC7084534 DOI: 10.3390/ijms21051576] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 02/21/2020] [Accepted: 02/22/2020] [Indexed: 12/13/2022] Open
Abstract
Ticagrelor is a powerful P2Y12 inhibitor with pleiotropic effects in the cardiovascular system. Consistently, we have reported that in patients with stable coronary artery disease (CAD) and concomitant chronic obstructive pulmonary disease (COPD) who underwent percutaneous coronary intervention (PCI), 1-month treatment with ticagrelor was superior in improving biological markers of endothelial function, compared with clopidogrel. The objective of this study was to investigate the mechanisms underlying these beneficial effects of ticagrelor by conducting molecular analyses of RNA isolated from peripheral blood cells of these patients. We determined mRNAs levels of markers of inflammation and oxidative stress, such as RORγt (T helper 17 cells marker), FoxP3 (regulatory T cells marker), NLRP3, ICAM1, SIRT1, Notch ligands JAG1 and DLL4, and HES1, a Notch target gene. We found that 1-month treatment with ticagrelor, but not clopidogrel, led to increased levels of SIRT1 and HES1 mRNAs. In patients treated with ticagrelor or clopidogrel, we observed a negative correlation among changes in both SIRT1 and HES1 mRNA and serum levels of Epidermal Growth Factor (EGF), a marker of endothelial dysfunction found to be reduced by ticagrelor treatment in our previous study. In conclusion, we report that in stable CAD/COPD patients ticagrelor positively regulates HES1 and SIRT1, two genes playing a protective role in the context of inflammation and oxidative stress. Our observations confirm and expand previous studies showing that the beneficial effects of ticagrelor in stable CAD/COPD patients may be, at least in part, mediated by its capacity to reduce systemic inflammation and oxidative stress.
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Effect of Ticagrelor, a Cytochrome P450 3A4 Inhibitor, on the Pharmacokinetics of Tadalafil in Rats. Pharmaceutics 2019; 11:pharmaceutics11070354. [PMID: 31330787 PMCID: PMC6680770 DOI: 10.3390/pharmaceutics11070354] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 07/15/2019] [Accepted: 07/17/2019] [Indexed: 02/06/2023] Open
Abstract
Tadalafil is a cytochrome P450 (CYP) 3A4 substrate. Because there are few data on drug-drug interactions, it is advisable to take sufficient consideration when co-administering tadalafil with CYP3A4 inducers or inhibitors. This study was conducted to assess the effect of ticagrelor, a CYP3A4 inhibitor, on the pharmacokinetic properties of tadalafil after oral administration to rats. A total of 20 Sprague–Dawley male rats were randomly divided into the non-pretreated group and ticagrelor-pretreated group, and tadalafil was orally administered to each group after pretreatment with or without ticagrelor. Blood samples were collected at predetermined time points after oral administration of tadalafil. As a result, systemic exposure of tadalafil in the ticagrelor-pretreated group was significantly increased compared to the non-pretreated group (1.61-fold), and the clearance of tadalafil in the ticagrelor-pretreated group was significantly reduced than the non-pretreated group (37%). The prediction of the drug profile through the one-compartment model could explain the differences of pharmacokinetic properties of tadalafil in the non-pretreated and ticagrelor-pretreated groups. This study suggests that ticagrelor reduces a CYP3A-mediated tadalafil metabolism and that tadalafil and a combination regimen with tadalafil and ticagrelor requires dose control and specific pharmacotherapy.
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Maideen NMP. Drug interactions of dipeptidyl peptidase 4 inhibitors involving CYP enzymes and P-gp efflux pump. World J Meta-Anal 2019; 7:156-161. [DOI: 10.13105/wjma.v7.i4.156] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 04/21/2019] [Accepted: 04/23/2019] [Indexed: 02/06/2023] Open
Abstract
Dipeptidyl peptidase 4 (DPP4) inhibitors are oral antidiabetic drugs approved to manage type 2 diabetes mellitus. Saxagliptin is a substrate of CYP3A4/5 enzymes while other DPP4 inhibitors such as sitagliptin, linagliptin, gemigliptin and teneligliptin are weak substrates of CYP3A4. DPP4 inhibitors have also been identified as substrates of P-gp. Hence, the drugs inhibiting or inducing CYP3A4/5 enzymes and/or P-gp can alter the pharmacokinetics of DPP4 inhibitors. This review is aimed to identify the drugs interacting with DPP4 inhibitors. The plasma concentrations of saxagliptin have been reported to be increased significantly by the concomitant administration of ketoconazole or diltiazem while no significant interactions between various DPP4 inhibitors and drugs like warfarin, digoxin or cyclosporine have been identified.
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Zhang M, You X, Ke M, Jiao Z, Wu H, Huang P, Lin C. Prediction of Ticagrelor and its Active Metabolite in Liver Cirrhosis Populations Using a Physiologically Based Pharmacokinetic Model Involving Pharmacodynamics. J Pharm Sci 2019; 108:2781-2790. [PMID: 30928308 DOI: 10.1016/j.xphs.2019.03.028] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 03/17/2019] [Accepted: 03/19/2019] [Indexed: 12/14/2022]
Abstract
Ticagrelor, a P2Y12 receptor antagonist, has been highly recommended for use in acute coronary syndrome. The major active metabolite (AM) is similar to the parent drug, which exhibits antiplatelet activity. The inhibition of platelet aggregation (IPA) is used as an assay to demonstrate the anticoagulant efficacy of ticagrelor. In this study, we developed a physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of ticagrelor and its AM and combined this model with a pharmacodynamics model to reflect potential pharmacodynamic alterations in liver cirrhosis populations. The simulated results obtained using the PBPK model were validated by fold error values, which were all smaller than 2. Comparisons of exposure in different classifications of liver cirrhosis indicated that exposure to ticagrelor increased significantly with an increase in the degree of cirrhosis severity, whereas exposure to AM was decreased. The total concentration of ticagrelor and AM was related to the IPA included in the Sigmoid Emax model. The PBPK model of ticagrelor and AM could predict the pharmacokinetics of all populations, and a combination of PD models was used to extrapolate for predicting unknown scenarios. Liver cirrhosis may result in prolonged IPA, depending on the severity degree of this disease. The combined PBPK model including IPA can reveal changes in pharmacokinetics and pharmacodynamics in populations affected by liver cirrhosis and indicate the risk potential.
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Affiliation(s)
- Min Zhang
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, 20 Cha Zhong M. Rd, Fuzhou 350005, People's Republic of China
| | - Xiang You
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, 20 Cha Zhong M. Rd, Fuzhou 350005, People's Republic of China
| | - Meng Ke
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, 20 Cha Zhong M. Rd, Fuzhou 350005, People's Republic of China
| | - Zheng Jiao
- Department of Pharmacy, Huashan Hospital of Fudan University, 12 Wu Lu Mu Qi M. Rd, Shanghai 20040, People's Republic of China.
| | - Hongwei Wu
- Department of Antibiotics, Xiamen Institute for Food and Drug Quality Control, 33 Hai Shan. Rd, Xiamen 361012, People's Republic of China
| | - Pinfang Huang
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, 20 Cha Zhong M. Rd, Fuzhou 350005, People's Republic of China
| | - Cuihong Lin
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, 20 Cha Zhong M. Rd, Fuzhou 350005, People's Republic of China.
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24
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Holmberg MT, Tornio A, Paile-Hyvärinen M, Tarkiainen EK, Neuvonen M, Neuvonen PJ, Backman JT, Niemi M. CYP3A4*22 Impairs the Elimination of Ticagrelor, But Has No Significant Effect on the Bioactivation of Clopidogrel or Prasugrel. Clin Pharmacol Ther 2018; 105:448-457. [PMID: 29998574 DOI: 10.1002/cpt.1177] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 07/03/2018] [Indexed: 11/09/2022]
Abstract
CYP3A enzymes participate in the elimination of ticagrelor and the bioactivation of clopidogrel and prasugrel. We studied the effects of functional CYP3A genetic variants (CYP3A4*22; rs35599367 and CYP3A5*3; rs776746) on the pharmacokinetics and pharmacodynamics of ticagrelor, clopidogrel, and prasugrel. Six healthy volunteers with the CYP3A4*1/*22 and CYP3A5*3/*3 genotype (CYP3A4*22 carriers), eight with the CYP3A4*1/*1 and CYP3A5*1/*3 genotype (CYP3A5 expressors), and 11-13 with the CYP3A4*1/*1 and CYP3A5*3/*3 genotypes (controls) ingested single doses of ticagrelor, clopidogrel, and prasugrel on separate occasions. Ticagrelor area under the plasma concentration-time curve (AUC) was 89% (P = 0.004) higher in CYP3A4*22 carriers than in controls. CYP3A4*22 carriers also showed more pronounced platelet inhibition at 24 hours after ticagrelor ingestion than the controls (43% vs. 21%; P = 0.029). The CYP3A5 genotype did not affect ticagrelor pharmacokinetics. Neither CYP3A5 nor CYP3A4 genotypes significantly affected prasugrel or clopidogrel. In conclusion, the CYP3A4*22 allele markedly impairs ticagrelor elimination enhancing its antiplatelet effect.
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Affiliation(s)
- Mikko T Holmberg
- Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland
| | - Aleksi Tornio
- Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland
| | - Maria Paile-Hyvärinen
- Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland
| | - E Katriina Tarkiainen
- Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland
| | - Mikko Neuvonen
- Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland
| | - Pertti J Neuvonen
- Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland
| | - Janne T Backman
- Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland
| | - Mikko Niemi
- Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland
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25
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Adamski P, Buszko K, Sikora J, Niezgoda P, Barańska M, Ostrowska M, Paciorek P, Navarese EP, Gorog DA, Kubica J. Metabolism of ticagrelor in patients with acute coronary syndromes. Sci Rep 2018; 8:11746. [PMID: 30082687 PMCID: PMC6078957 DOI: 10.1038/s41598-018-29619-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 07/03/2018] [Indexed: 11/10/2022] Open
Abstract
Ticagrelor is a state-of-the-art antiplatelet agent used for the treatment of patients with acute coronary syndromes (ACS). Unlike remaining oral P2Y12 receptor inhibitors ticagrelor does not require metabolic activation to exert its antiplatelet action. Still, ticagrelor is extensively metabolized by hepatic CYP3A enzymes, and AR-C124910XX is its only active metabolite. A post hoc analysis of patient-level (n = 117) pharmacokinetic data pooled from two prospective studies was performed to identify clinical characteristics affecting the degree of AR-C124910XX formation during the first six hours after 180 mg ticagrelor loading dose in the setting of ACS. Both linear and multiple regression analyses indicated that ACS patients presenting with ST-elevation myocardial infarction or suffering from diabetes mellitus are more likely to have decreased rate of ticagrelor metabolism during the acute phase of ACS. Administration of morphine during ACS was found to negatively influence transformation of ticagrelor into AR-C124910XX when assessed with linear regression analysis, but not with multiple regression analysis. On the other hand, smoking appears to increase the degree of ticagrelor transformation in ACS patients. Mechanisms underlying our findings and their clinical significance warrant further research.
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Affiliation(s)
- Piotr Adamski
- Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
| | - Katarzyna Buszko
- Department of Theoretical Foundations of Biomedical Science and Medical Informatics, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Joanna Sikora
- Department of Pharmacology and Therapy, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Piotr Niezgoda
- Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Malwina Barańska
- Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Małgorzata Ostrowska
- Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Przemysław Paciorek
- Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Eliano P Navarese
- Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.,Inova Heart and Vascular Institute, Inova Center for Thrombosis Research and Drug Development, Fairfax, VA, USA.,SIRIO MEDICINE research network, Inova Heart and Vascular Institute, Inova Center for Thrombosis Research and Drug Development, Fairfax, VA, USA
| | - Diana A Gorog
- National Heart & Lung Institute, Imperial College, London, United Kingdom
| | - Jacek Kubica
- Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
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26
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Divanji P, Shunk K. Modern Antiplatelet Therapy: When Is Clopidogrel the Right Choice? CARDIOVASCULAR INNOVATIONS AND APPLICATIONS 2018. [DOI: 10.15212/cvia.2017.0049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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27
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Teng R, Hammarberg M, Carlson GF, Bokelund-Singh S, Ruderfelt T, Blychert E. Pharmacokinetic Profiles of Ticagrelor Orodispersible Tablets in Healthy Western and Japanese Subjects. Clin Drug Investig 2018; 37:1035-1045. [PMID: 28856602 PMCID: PMC5643369 DOI: 10.1007/s40261-017-0554-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background and Objectives Ticagrelor is an antiplatelet agent for patients with acute coronary syndrome or a history of myocardial infarction. Two studies compared pharmacokinetic profiles of orodispersible (OD) ticagrelor tablets versus immediate-release (IR) tablets in Western and Japanese subjects. Methods Both studies were open-label, randomized, crossover, single-center trials. Thirty-six healthy subjects (94% white, 6% other race; Western study NCT02400333) and 42 Japanese healthy subjects (Japanese study NCT02436577) received a single 90-mg ticagrelor dose as an OD tablet [with/without water, and via a nasogastric tube (Western study only)], and an IR tablet; washout between treatments was ≥7 days. Assessments included ticagrelor and AR-C124910XX (active metabolite) plasma concentrations for pharmacokinetic analyses, and safety evaluations. Results In the Western study, the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for ticagrelor and AR-C124910XX maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) were within the acceptance interval (80%–125%) for OD tablets (with/without water, via a nasogastric tube) versus the IR tablet; except for an ~15% lowering of ticagrelor Cmax (90% CI: 76.77%–93.78%) for the OD tablet taken with water. In the Japanese study, 90% CIs of the GMRs for AUC and Cmax of both ticagrelor and AR-C124910XX were all within the acceptance intervals for the OD (with/without water) versus IR tablet. No new safety issues were identified. Conclusions Ticagrelor administered as an OD tablet to Western (without water, and via a nasogastric tube) and Japanese (with/without water) subjects was bioequivalent to the IR tablet. Electronic supplementary material The online version of this article (doi:10.1007/s40261-017-0554-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Renli Teng
- AstraZeneca LP, One MedImmune Way, Gaithersburg, MD, USA.
| | - Maria Hammarberg
- AstraZeneca Pharmaceutical Technology and Development, Gothenburg, Sweden
| | | | | | | | - Eva Blychert
- AstraZeneca Pharmaceutical Technology and Development, Gothenburg, Sweden
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28
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Rosa GM, Bianco D, Valbusa A, Massobrio L, Chiarella F, Brunelli C. Pharmacokinetics and pharmacodynamics of ticagrelor in the treatment of cardiac ischemia. Expert Opin Drug Metab Toxicol 2016; 12:1491-1502. [PMID: 27715344 DOI: 10.1080/17425255.2016.1244524] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Gian Marco Rosa
- Division of Cardiology, IRCCS AOU San Martino – IST, University of Genoa, Genova, Italy
| | - Daniele Bianco
- Division of Cardiology, IRCCS AOU San Martino – IST, University of Genoa, Genova, Italy
| | - Alberto Valbusa
- Division of Cardiology, IRCCS AOU San Martino – IST, University of Genoa, Genova, Italy
| | - Laura Massobrio
- Division of Cardiology, IRCCS AOU San Martino – IST, University of Genoa, Genova, Italy
| | - Francesco Chiarella
- Division of Cardiology, IRCCS AOU San Martino – IST, University of Genoa, Genova, Italy
| | - Claudio Brunelli
- Division of Cardiology, IRCCS AOU San Martino – IST, University of Genoa, Genova, Italy
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29
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Marsousi N, Samer CF, Fontana P, Reny JL, Rudaz S, Desmeules JA, Daali Y. Coadministration of ticagrelor and ritonavir: Toward prospective dose adjustment to maintain an optimal platelet inhibition using the PBPK approach. Clin Pharmacol Ther 2016; 100:295-304. [PMID: 27264793 DOI: 10.1002/cpt.407] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 05/27/2016] [Accepted: 06/01/2016] [Indexed: 11/09/2022]
Abstract
Ticagrelor is a potent antiplatelet drug metabolized by cytochrome (CYP)3A. It is contraindicated in patients with human immunodeficiency virus (HIV) because of the expected CYP3A inhibition by most protease inhibitors, such as ritonavir and an increased bleeding risk. In this study, a physiologically based pharmacokinetic (PBPK) model was created for ticagrelor and its active metabolite (AM). Based on the simulated interaction between ticagrelor 180 mg and ritonavir 100 mg, a lower dose of ticagrelor was calculated to obtain, when coadministered with ritonavir, the same pharmacokinetic (PK) and platelet inhibition as ticagrelor administered alone. A clinical study was thereafter conducted in healthy volunteers. Observed PK profiles of ticagrelor and its AM were successfully predicted with the model. Platelet inhibition was nearly complete in both sessions despite administration of a fourfold lower dose of ticagrelor in the second session. This PBPK model could be prospectively used to broaden the usage of ticagrelor in patients with ritonavir-treated HIV regardless of the CYP3A inhibition.
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Affiliation(s)
- N Marsousi
- Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, Switzerland.,School of Pharmaceutical Sciences, Geneva University, Switzerland
| | - C F Samer
- Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, Switzerland.,Swiss Center for Applied Human Toxicology (SCAHT), University of Geneva, Switzerland
| | - P Fontana
- Division of Angiology and Haemostasis, Geneva University Hospitals, Switzerland.,Geneva Platelet Group, Faculty of Medicine, University of Geneva, Switzerland
| | - J L Reny
- Geneva Platelet Group, Faculty of Medicine, University of Geneva, Switzerland.,Department of General Internal Medicine, Rehabilitation and Geriatrics, Geneva University Hospitals, Switzerland
| | - S Rudaz
- School of Pharmaceutical Sciences, Geneva University, Switzerland.,Swiss Center for Applied Human Toxicology (SCAHT), University of Geneva, Switzerland
| | - J A Desmeules
- Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, Switzerland.,School of Pharmaceutical Sciences, Geneva University, Switzerland.,Swiss Center for Applied Human Toxicology (SCAHT), University of Geneva, Switzerland
| | - Y Daali
- Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, Switzerland.,School of Pharmaceutical Sciences, Geneva University, Switzerland.,Swiss Center for Applied Human Toxicology (SCAHT), University of Geneva, Switzerland
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30
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Abstract
Despite advancements in treatments for acute coronary syndromes over the last 10 years, they continue to be life-threatening disorders. Currently, the standard of treatment includes dual antiplatelet therapy consisting of aspirin plus a P2Y12 receptor antagonist. The thienopyridine class of P2Y12 receptor antagonists, clopidogrel and prasugrel, have demonstrated efficacy. However, their use is associated with several limitations, including the need for metabolic activation and irreversible P2Y12 receptor binding causing prolonged recovery of platelet function. In addition, response to clopidogrel is variable and efficacy is reduced in patients with certain genotypes. Although prasugrel is a more consistent inhibitor of platelet aggregation than clopidogrel, it is associated with an increased risk of life-threatening and fatal bleeding. Ticagrelor is an oral antiplatelet agent of the cyclopentyltriazolopyrimidine class and also acts through the P2Y12 receptor. In contrast to clopidogrel and prasugrel, ticagrelor does not require metabolic activation and binds rapidly and reversibly to the P2Y12 receptor. In light of new data, this review provides an update on the pharmacokinetic, pharmacodynamic and pharmacogenetic profiles of ticagrelor in different study populations. Recent studies report that no dose adjustment for ticagrelor is required on the basis of age, gender, ethnicity, severe renal impairment or mild hepatic impairment. The non-P2Y12 actions of ticagrelor are reviewed, showing indirect positive effects on cellular adenosine concentration and biological activity, by inhibition of equilibrative nucleoside transporter-1 independently of the P2Y12 receptor. CYP2C19 and ABCB1 genotypes do not appear to influence ticagrelor pharmacodynamics. A summary of drug interactions is also presented.
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31
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An open-label, randomized bioavailability study with alternative methods of administration of crushed ticagrelor tablets in healthy volunteers. Int J Clin Pharmacol Ther 2015; 53:182-9. [PMID: 25500486 PMCID: PMC4302705 DOI: 10.5414/cp202202] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/22/2015] [Indexed: 12/26/2022] Open
Abstract
Objective: To compare the bioavailability and safety profile of crushed ticagrelor tablets suspended in water and administered orally or via nasogastric tube, with that of whole tablets administered orally. Methods: In this single-center, open-label, randomized, three-treatment crossover study, 36 healthy volunteers were randomized to receive a single 90-mg dose of ticagrelor administered orally as a whole tablet or as crushed tablets suspended in water and given orally or via a nasogastric tube into the stomach, with a minimum 7-day wash-out between treatments. Plasma concentrations of ticagrelor and AR-C124910XX were assessed at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours post-ticagrelor dose for pharmacokinetic analyses. Safety and tolerability was assessed throughout the study. Results: At 0.5 hours postdose, plasma concentrations of ticagrelor and AR-C124910XX were higher with crushed tablets administered orally (148.6 ng/mL and 13.0 ng/mL, respectively) or via nasogastric tube (264.6 ng/mL and 28.6 ng/mL, respectively) compared with whole-tablet administration (33.3 ng/mL and 5.2 ng/mL, respectively). A similar trend was observed at 1 hour postdose. Ticagrelor tmax was shorter following crushed vs. whole-tablet administration (1 vs. 2 hours, respectively). Geometric mean ratios between treatments for AUC and Cmax were contained within the bioequivalence limits of 80 – 125% for ticagrelor and AR-C124910XX. All treatments were generally well tolerated. Conclusions: Ticagrelor administered as a crushed tablet is bioequivalent to whole-tablet administration, independent of mode of administration (oral or via nasogastric tube), and resulted in increased plasma concentrations of ticagrelor and AR-C124910XX at early timepoints.
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33
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Teng R, Kujacic M, Hsia J. Evaluation of the Pharmacokinetic Interaction Between Ticagrelor and Venlafaxine, a Cytochrome P-450 2D6 Substrate, in Healthy Subjects. Clin Ther 2014; 36:1217-25. [DOI: 10.1016/j.clinthera.2014.06.024] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Revised: 05/30/2014] [Accepted: 06/23/2014] [Indexed: 02/01/2023]
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Dobesh PP, Oestreich JH. Ticagrelor: pharmacokinetics, pharmacodynamics, clinical efficacy, and safety. Pharmacotherapy 2014; 34:1077-90. [PMID: 25164528 PMCID: PMC4282310 DOI: 10.1002/phar.1477] [Citation(s) in RCA: 145] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Dual antiplatelet therapy, composed of aspirin plus a P2Y12-receptor antagonist, is the cornerstone of treatment for patients with acute coronary syndrome (ACS). A number of U.S. Food and Drug Administration–approved P2Y12-receptor antagonists are available for treating patients with ACS, including the thienopyridine compounds clopidogrel and prasugrel. Ticagrelor, the first of a new class of antiplatelet agents, is a noncompetitive, direct-acting P2Y12-receptor antagonist. Unlike the thienopyridine compounds, ticagrelor does not require metabolism for activity. Also, whereas clopidogrel and prasugrel are irreversible inhibitors of the P2Y12 receptor, ticagrelor binds reversibly to inhibit receptor signaling and subsequent platelet activation. In pharmacodynamic studies, ticagrelor demonstrated faster onset and more potent inhibition of platelet aggregation than clopidogrel. These properties of ticagrelor may contribute to reduced rates of thrombotic outcomes compared with clopidogrel, as demonstrated in a phase III clinical trial. However, in addition to bleeding, distinctive adverse effects of this new chemical entity have not been reported with the thienopyridine P2Y12-receptor inhibitors. Although ticagrelor represents an advancement in P2Y12-receptor inhibition therapy, a thorough understanding of this compound as an antiplatelet therapy remains to be elucidated.
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Affiliation(s)
- Paul P Dobesh
- College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska
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35
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Pharmacokinetic Interaction Study of Ticagrelor and Cyclosporine in Healthy Volunteers. Clin Drug Investig 2014; 34:529-36. [DOI: 10.1007/s40261-014-0205-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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36
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Patti G, Proscia C, Di Sciascio G. Antiplatelet Therapy in Patients With Diabetes Mellitus and Acute Coronary Syndrome. Circ J 2014; 78:33-41. [DOI: 10.1253/circj.cj-13-0742] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Giuseppe Patti
- Department of Cardiovascular Sciences, Campus Bio-Medico University of Rome
| | - Claudio Proscia
- Department of Cardiovascular Sciences, Campus Bio-Medico University of Rome
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