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Hayato S, Hamuro L, Shimizu T, Yonemori K, Nishio S, Yunokawa M, Yoshida T, Nishio M, Matsumoto K, Takehara K, Hasegawa K, Kozuki T, Hirashima Y, Kato H, Miura T, Nomoto M, Zhao Y, Zhu L, Yasuda S. Pharmacokinetic and Exposure-Response Modeling Support Body Surface Area-Based Dosing of Farletuzumab Ecteribulin in Japanese Patients with Solid Tumors. J Clin Pharmacol 2025; 65:751-762. [PMID: 39853764 DOI: 10.1002/jcph.6187] [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: 09/11/2024] [Accepted: 12/30/2024] [Indexed: 01/26/2025]
Abstract
The first-in-human, Phase 1 Study 101 showed antitumor activity and a tolerable safety profile of farletuzumab ecteribulin in Japanese patients with platinum-resistant ovarian and non-small cell lung cancer. A pharmacometric assessment evaluated farletuzumab ecteribulin pharmacokinetics and exposure-response (E-R) relationships for efficacy and safety to support dose optimization. Patients received 0.3-1.2 mg/kg of farletuzumab ecteribulin intravenously every 3 weeks. A pharmacokinetics (PK) model was developed and used for E-R analyses. Efficacy was assessed via tumor response and safety via known treatment-emergent adverse events (TEAEs) of farletuzumab ecteribulin, particularly pneumonitis/interstitial lung disease (ILD). Dosing scenarios were simulated to identify dosing that maximizes the probability of an objective response while minimizing the risk of ILD. The farletuzumab ecteribulin PK dataset included 1261 observations from 82 patients. The final model included an estimated population mean value for farletuzumab ecteribulin clearance of 0.0162 L/h. Body surface area (BSA) was a significant PK covariate and was included in the model. Body weight (BW) was associated with higher farletuzumab ecteribulin exposure. Using BW-based dosing, farletuzumab ecteribulin AUC (area under the serum concentration-time curve) was higher in patients with tumor response or stable disease versus patients with progressive disease and higher in patients with ILD and other TEAEs. Dosing simulations showed that BSA-based dosing (33 mg/m2) yielded similar tumor responses to BW-based dosing (0.9 mg/kg) and decreased ILD rates. This study showed that BW-based dosing resulted in higher risks of ILD events for patients with a high BW versus low BW, whereas BSA-based dosing is predicted to reduce this risk while maintaining clinical efficacy.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Female
- Humans
- Male
- Middle Aged
- Antibodies, Monoclonal, Humanized/pharmacokinetics
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/adverse effects
- Antineoplastic Agents/pharmacokinetics
- Antineoplastic Agents/administration & dosage
- Antineoplastic Agents/adverse effects
- Body Surface Area
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Dose-Response Relationship, Drug
- Japan
- Lung Neoplasms/drug therapy
- Models, Biological
- Neoplasms/drug therapy
- Neoplasms/metabolism
- Ovarian Neoplasms/drug therapy
- East Asian People
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Affiliation(s)
| | | | - Toshio Shimizu
- Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
- Department of New Experimental Therapeutics and International Cancer New Drug Development Center, Kansai Medical University Hospital, Osaka, Japan
| | - Kan Yonemori
- Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Shin Nishio
- Department of Obstetrics and Gynecology, Kurume University School of Medicine, Fukuoka, Japan
| | - Mayu Yunokawa
- Department of Gynecologic Oncology, Cancer Institute Hospital, Tokyo, Japan
| | - Tatsuya Yoshida
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Makoto Nishio
- Department of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Koji Matsumoto
- Division of Medical Oncology, Hyogo Cancer Center, Hyogo, Japan
| | - Kazuhiro Takehara
- Department of Gynecologic Oncology, NHO Shikoku Cancer Center, Ehime, Japan
| | - Kosei Hasegawa
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Toshiyuki Kozuki
- Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Ehime, Japan
| | | | - Hidenori Kato
- Department of Gynecologic Oncology, Hokkaido Cancer Center, Sapporo, Japan
| | | | | | - Yue Zhao
- Bristol Myers Squibb, Princeton, NJ, USA
| | - Li Zhu
- Bristol Myers Squibb, Princeton, NJ, USA
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2
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Polášková L, Hartinger JM, Murínová I, Michálek P, Slanař O, Šíma M. Vancomycin loading dose individualization in a population of obese patients undergoing haemodialysis based on population pharmacokinetic model. J Chemother 2025; 37:121-129. [PMID: 38887026 DOI: 10.1080/1120009x.2024.2367937] [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: 02/06/2024] [Revised: 05/22/2024] [Accepted: 06/09/2024] [Indexed: 06/20/2024]
Abstract
This study aimed to develop a vancomycin population pharmacokinetic model in obese adult patients treated with intermittent haemodialysis and propose a model-based loading dose strategy ensuring attainment of newly recommended AUC-based PK/PD target. Retrospective cross-sectional analysis was performed among obese haemodialysis dependent adult patients treated with intravenous vancomycin. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were used to identify the optimal loading dose for PK/PD target attainment during the first 48 h of treatment. Therapeutic drug monitoring data from 27 patients with a BMI of 30.2-52.9 kg/m2 were analysed. Among all tested variables, only LBM as a covariate of vancomycin Vd significantly improved the model, while vancomycin CL did not correlate with any of the tested variables. The median (IQR) value from the conditional mean of individual estimates of Vd and CL was 68.4 (56.6-84.2) L and 0.86 (0.79-0.90) L/h, respectively. To ensure optimal vancomycin exposure during the first 48 h of therapy, the vancomycin loading dose of 1500, 1750, 2000, 2250, 2500 and 2750 mg should be administered to obese patients with a lean body mass of ˂50, 50-60, 60-70, 70-80, 80-85 and >85 kg, respectively.
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Affiliation(s)
- Lucie Polášková
- Department of Clinical Pharmacy, Military University Hospital Prague, Prague, Czech Republic
| | - Jan Miroslav Hartinger
- Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Irena Murínová
- Department of Clinical Pharmacy, Military University Hospital Prague, Prague, Czech Republic
- Department of Applied Pharmacy, Faculty of Pharmacy, Masaryk University, Brno, Czech Republic
| | - Pavel Michálek
- Department of Anaesthesia and Intensive Care, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Ondřej Slanař
- Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Martin Šíma
- Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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Shaik R, Mounika V, Begum S, Rajkumar A, Mallikarjun B, Sri Harshini V, Kolure R, Sreevani B, Thakur S. Monoclonal Antibodies in Clinical Trials for Breast Cancer Treatment. Monoclon Antib Immunodiagn Immunother 2025; 44:17-39. [PMID: 40171653 DOI: 10.1089/mab.2024.0018] [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: 04/04/2025] Open
Abstract
One of the most potent therapeutic and diagnostic agents in contemporary medicine is the monoclonal antibody (mAb). mAbs can perform a variety of tasks in breast cancer (BC), including identifying and delivering therapeutic medications to targets, preventing cell development, and suppressing immune system inhibitors including directly attacking cancer cells. mAbs are one of the most effective therapeutic options, particularly for HER2, but they have not been well studied for their use in treating other forms of BC, particularly triple negative breast tumors. Bispecific and trispecific mAbs have created new opportunities for more targeted specific efficacy, which has a positive impact on the viability of antigen specificity. They are more versatile and effective than other forms of treatment, emerging as most popular option for treating BC. However, mAbs have a limit in treatment due to certain adverse effects, including fever, shaking, exhaustion, headache, nausea, and vomiting, as well as rashes, bleeding, and difficulty breathing. To examine the current and prospective future capacities of mAbs with regard to the detection and treatment of BC, the present review highlights advantages and disadvantages of mAb approach.
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Affiliation(s)
- Rahaman Shaik
- School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, India
| | - Varikuppala Mounika
- Department of Pharmacology, St. Pauls College of Pharmacy, Turkayamjal, Hyderabad-501510, India
| | - Shireen Begum
- Department of Pharmacology, St. Pauls College of Pharmacy, Turkayamjal, Hyderabad-501510, India
| | - Agolapu Rajkumar
- Department of Pharmacology, St. Pauls College of Pharmacy, Turkayamjal, Hyderabad-501510, India
| | - Bathurasi Mallikarjun
- Department of Pharmacology, St. Pauls College of Pharmacy, Turkayamjal, Hyderabad-501510, India
| | - Vollala Sri Harshini
- Department of Pharmacology, St. Pauls College of Pharmacy, Turkayamjal, Hyderabad-501510, India
| | - Rajini Kolure
- Department of Pharmacology, St. Pauls College of Pharmacy, Turkayamjal, Hyderabad-501510, India
| | | | - Sneha Thakur
- Department of Pharmacognosy, St. Pauls College of Pharmacy, Turkayamjal, Hyderabad-501510, India
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Hall RG, Liu S, Pai MP, Putnam WC, Subramaniyan I, Kallem R, Haley B. Impact of obesity on doxorubicin pharmacokinetics in women with breast cancer. J Oncol Pharm Pract 2025:10781552251326045. [PMID: 40080880 DOI: 10.1177/10781552251326045] [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: 03/15/2025]
Abstract
IntroductionExperts suggest doxorubicin clearance is decreased in women with a body mass index (BMI) of ≥35 kg/m2. However, few data support this recommendation.MethodsWomen receiving doxorubicin for breast cancer in three BMI groups were recruited (n = 15). Doxorubicin dosing was determined by body surface area and was administered by 30-min intravenous infusion. Blood samples were obtained at 0 h (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 5, 12-24, and 24-72 h following the beginning of infusion. Concentrations of doxorubicin and its metabolite, doxorubicinol, were assayed by LC-MS/MS. Non-compartment analysis was done using PKanalix2021R2 for pharmacokinetic (PK) analyses.ResultsThe median [range] BMI and age were 30.3 [23.5-57] kg/m2 and 53 [31-69] years. Thirteen of the 15 women had samples available for analysis. Four of the 13 had a BMI ≥ 35.0 kg/m2. PK parameters ranged from 37.8% (AUC0-inf) to 91.0% (Vd). Doxorubicinol PK parameters ranged from 37.8% (Cmax) to 67.6% (AUC0-inf). The average doxorubicinol:doxorubicin AUClasts ratio was 0.26 (range: 0.04-0.88). A t-test didn't suggest a significant difference in individual PK parameters (BMI < 35 kg/m2 vs. ≥35.0 kg/m2). The two highest clearances (380 L/h and 250 L/h) had a BMI ≥ 35.0 kg/m2; also, the highest clearance (1114 L/h) for doxorubicinol was ≥35.0 kg/m2.ConclusionsLarge interindividual variabilities in doxorubicin PK were observed in women up to a BMI of 57 kg/m2 and a total body weight of 141.5 kg. Women with a BMI ≥ 35.0 kg/m2 and breast cancer did not appear to have lower clearances of doxorubicin.ClinicalTrials.gov IDNCT01537029.
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Affiliation(s)
- Ronald G Hall
- Department of Pharmacy Practice, Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy, Dallas, TX, USA
- Dose Optimization and Outcomes Research Program, Dallas, TX, USA
- Clinical Pharmacology and Experimental Therapeutics Center, Dallas, TX, USA
| | - Shuhan Liu
- University of Michigan, College of Pharmacy, Ann Arbor, MI, USA
| | - Manjunath P Pai
- University of Michigan, College of Pharmacy, Ann Arbor, MI, USA
| | - William C Putnam
- Department of Pharmacy Practice, Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy, Dallas, TX, USA
- Clinical Pharmacology and Experimental Therapeutics Center, Dallas, TX, USA
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy, Dallas, TX, USA
| | - Indhumathy Subramaniyan
- Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy, Dallas, TX, USA
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Xie D, Zhang Y, Li F, Yang Y, Che M, Li G, Zhang Y. Efficacy and safety of ciprofol for gastroscopy in patients with obesity: a randomised clinical controlled trial using different weight-based dosing scales. BMC Anesthesiol 2025; 25:112. [PMID: 40025458 PMCID: PMC11874440 DOI: 10.1186/s12871-025-02974-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 02/14/2025] [Indexed: 03/04/2025] Open
Abstract
BACKGROUND This study aimed to compare the efficacy and safety of ciprofol-induced doses based on three indices: total body weight (TBW), ideal body weight (IBW), and lean body weight (LBW) in patients with obesity undergoing gastroscopy. METHODS In a single-centre, prospective, randomised study conducted at an endoscopy centre, a total of 108 patients aged 18-65 years who underwent painless gastroscopy and had a body mass index (BMI) of 28-39.9 kg/m2 were included. Patients with obesity from the intended study population were randomised to receive a ciprofol infusion (0.4 mg/kg) for the induction of anaesthesia based on TBW (Group T), IBW (Group I), or LBW (Group L). A Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale score of < 1 was considered a marker of loss of consciousness, prompting gastroscopy. The primary outcomes were the success rate of anaesthesia for the procedures, and that of general anaesthesia achieved using the initial dose. Secondary outcomes included the frequency of remedial sedation, total ciprofol dose, and adverse events RESULTS: The procedure success rate was 100% in all three groups. Compared to Group L, the general anaesthesia success rate achieved with the initial dose was higher and the frequency of remedial sedation was lower in Groups T and I. Compared to Group L, fewer patients in Group T required additional medication. Compared to Group T, the occurrence of hypoxaemia was lower in the remaining two groups, and Group L had a lower incidence of posterior tongue drops and hypotension. CONCLUSIONS Induction doses of ciprofol based on TBW or IBW provided better anaesthesia than doses based on LBW for gastroscopy in patients with obesity. LBW-based induction doses of ciprofol improved cardiovascular stability and respiratory safety, whereas IBW-based induction doses of ciprofol reduced respiratory depression. TRIAL REGISTRATION This study was registered in the Chinese Clinical Trial Registry (ChiCTR2300073539 first registration date 13/07/2023).
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Affiliation(s)
- Danru Xie
- Department of Anaesthesiology, Shunde Hospital of Southern Medical University The First People's Hospital, Shunde District, Foshan City, Foshan, 528308, China
| | - Yanjing Zhang
- Department of Anaesthesiology, Shunde Hospital of Southern Medical University The First People's Hospital, Shunde District, Foshan City, Foshan, 528308, China
| | - Feifei Li
- Department of Anaesthesiology, Shunde Hospital of Southern Medical University The First People's Hospital, Shunde District, Foshan City, Foshan, 528308, China
| | - Yaoheng Yang
- Department of Anaesthesiology, Shunde Hospital of Southern Medical University The First People's Hospital, Shunde District, Foshan City, Foshan, 528308, China
| | - Mengjiao Che
- Department of Anaesthesiology, Shunde Hospital of Southern Medical University The First People's Hospital, Shunde District, Foshan City, Foshan, 528308, China
| | - Geng Li
- Department of Anaesthesiology, Shunde Hospital of Southern Medical University The First People's Hospital, Shunde District, Foshan City, Foshan, 528308, China
| | - Yiwen Zhang
- Department of Anaesthesiology, Shunde Hospital of Southern Medical University The First People's Hospital, Shunde District, Foshan City, Foshan, 528308, China.
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Yetmar ZA, Khodadadi RB, Chesdachai S, McHugh JW, Clement J, Challener DW, Wengenack NL, Bosch W, Seville MT, Beam E. Trimethoprim-sulfamethoxazole dosing and outcomes of pulmonary nocardiosis. Infection 2025; 53:83-94. [PMID: 38922564 PMCID: PMC11825568 DOI: 10.1007/s15010-024-02323-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 06/10/2024] [Indexed: 06/27/2024]
Abstract
BACKGROUND Nocardia often causes pulmonary infection among those with chronic pulmonary disease or immunocompromising conditions. Trimethoprim-sulfamethoxazole (TMP-SMX) is recommended as first-line treatment, though little data exists regarding outcomes of different dosing regimens. METHODS We performed a multicenter retrospective cohort study of adult patients with non-disseminated pulmonary nocardiosis initially treated with TMP-SMX monotherapy. Patients' initial TMP-SMX dosing was categorized as high- (> 10 mg/kg/day), intermediate- (5-10 mg/kg/day) or low-dose (< 5 mg/kg/day). Outcomes included one-year mortality, post-treatment recurrence, and dose adjustment or early discontinuation of TMP-SMX. SMX serum concentrations and their effect on management were also assessed. Inverse probability of treatment weighting was applied to Cox regression analyses. RESULTS Ninety-one patients were included with 24 (26.4%), 37 (40.7%), and 30 (33.0%) treated with high-, intermediate-, and low-dose TMP-SMX, respectively. Patients who initially received low-dose (HR 0.07, 95% CI 0.01-0.68) and intermediate-dose TMP-SMX (HR 0.27, 95% CI 0.07-1.04) had lower risk of one-year mortality than the high-dose group. Risk of recurrence was similar between groups. Nineteen patients had peak SMX serum concentrations measured which resulted in 7 (36.8%) dose changes and was not associated with one-year mortality or recurrence. However, 66.7% of the high-dose group required TMP-SMX dose adjustment/discontinuation compared to 24.3% of the intermediate-dose and 26.7% of the low-dose groups (p = 0.001). CONCLUSIONS Low- and intermediate-dose TMP-SMX for non-disseminated pulmonary nocardiosis were not associated with poor outcomes compared to high-dose therapy, which had a higher rate of dose adjustment/early discontinuation. Historically used high-dose TMP-SMX may not be necessary for management of isolated pulmonary nocardiosis.
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Affiliation(s)
- Zachary A Yetmar
- Division of Public Health, Infectious Diseases, and Occupational Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
- Department of Infectious Disease, Cleveland Clinic Foundation, Cleveland, OH, USA.
| | - Ryan B Khodadadi
- Division of Public Health, Infectious Diseases, and Occupational Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Supavit Chesdachai
- Division of Public Health, Infectious Diseases, and Occupational Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Jack W McHugh
- Division of Public Health, Infectious Diseases, and Occupational Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Josh Clement
- Department of Pharmacy, Mayo Clinic, Rochester, MN, USA
| | - Douglas W Challener
- Division of Public Health, Infectious Diseases, and Occupational Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | | | - Wendelyn Bosch
- Division of Infectious Diseases, Mayo Clinic, Jacksonville, FL, USA
| | | | - Elena Beam
- Division of Public Health, Infectious Diseases, and Occupational Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
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Liu S, Wang L, Miller N, Waltje A, Abdelnabi M, Zhu HJ, Sun D, Rothberg AE, Pai MP. Examining the Impact of Diet-and-Exercise-Induced Weight Loss on Drug Metabolism and Gastric Emptying in Patients with Obesity. J Clin Pharmacol 2025. [PMID: 39840538 DOI: 10.1002/jcph.6192] [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: 11/13/2024] [Accepted: 01/10/2025] [Indexed: 01/23/2025]
Abstract
Obesity significantly influences drug pharmacokinetics (PK), which challenges optimal dosing. This study examines the effects of diet-and-exercise-induced weight loss on key drug-metabolizing enzymes and gastric emptying in patients with obesity, who frequently require medications for comorbidities. Participants followed a structured weight management program promoting weight loss over 3-6 months and were not concomitantly on potential CYP inducers or inhibitors. Using a drug cocktail of acetaminophen, caffeine, omeprazole, and midazolam, we assessed UGT1A1, CYP1A2, CYP2C19, and CYP3A4 enzyme activities before and after weight loss, respectively, by measuring parent and metabolite concentrations. The time to maximum acetaminophen plasma concentrations reflected the gastric emptying time. PK profiles were compared across two phases: baseline (Phase 1) and post-weight loss (Phase 2). Twenty-four participants enrolled, 21 completed Phase 1 and 12 completed both phases. Statistically significant (N = 12, P < .05) gains in CYP2C19 and CYP3A4 activity were observed after weight loss of 7.6% to 26.2%, with a median [25th, 75th percentile] increase in activity of 90.5 [15.0, 194.3] % and 43.0 [7.5, 68.0] %, respectively. A 2- or 3-h single plasma sample-based ratio of the metabolite to parent concentration strongly correlated with the respective AUC ratio for the drug metabolism phenotype (N = 21). Our findings provide provisional data for evaluation of the effects of non-pharmacologically and non-surgically induced weight loss on gastric emptying and drug metabolism for future physiologically based PK models. Development of mechanistic models to optimize drug dosing in obesity are necessary since weight and body composition shifts are expected with emerging new treatments.
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Affiliation(s)
- Shuhan Liu
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
| | - Lu Wang
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
| | - Nicole Miller
- Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Andrea Waltje
- Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Mohamed Abdelnabi
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
| | - Hao-Jie Zhu
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
| | - Duxin Sun
- Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA
| | - Amy E Rothberg
- Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Manjunath P Pai
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
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Marques L, Vale N. Improving Individualized Salbutamol Treatment: A Population Pharmacokinetic Model for Oral Salbutamol in Virtual Patients. Pharmaceutics 2024; 17:39. [PMID: 39861686 PMCID: PMC11768577 DOI: 10.3390/pharmaceutics17010039] [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: 12/02/2024] [Revised: 12/19/2024] [Accepted: 12/26/2024] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND Salbutamol, a short-acting β2-agonist used in asthma treatment, is available in multiple formulations, including inhalers, nebulizers, oral tablets, and intravenous, intramuscular, and subcutaneous routes. Each formulation exhibits distinct pharmacokinetic (PK) and pharmacodynamic (PD) profiles, influencing therapeutic outcomes and adverse effects. Although asthma management predominantly relies on inhaled salbutamol, understanding how these formulations interact with patient-specific characteristics could improve personalized medicine approaches, potentially uncovering the therapeutic benefits of alternative formulations for an individual patient. Herein, this study aims to analyze how covariates-such as age, weight, gender, body surface area (BSA), cytochrome P450 (CYP) expression, race, and health status-affect the therapeutic regime of orally administered salbutamol using population PK (popPK) modeling. The final model is intended as a tool to support the selection of optimal formulation and dosage regimen based on individual patient profiles. METHODS A dataset of 40 virtual patients derived from a physiologically based PK (PBPK) model of oral salbutamol was included in the popPK model. RESULTS A two-compartment model with first-order elimination and absorption, with a transit compartment, best described the plasma concentration-time profile following a 4 mg dose. Relationships were identified between gender and mean transit time (Mtt) and clearance (Cl), as well as the effects of weight and BSA on the volume of distribution of the central compartment (V1) and Cl, and a significant impact of health status on Cl. CONCLUSIONS Despite current contraindications for oral salbutamol, our findings suggest that certain individuals, particularly children, may benefit from oral treatment over inhalation. We also identified individual characteristics associated with increased salbutamol toxicity risk, indicating the need for dose adjustment or alternative administration. This study further highlights the potential of popPK modeling in personalized therapy through a fully in silico approach.
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Affiliation(s)
- Lara Marques
- PerMed Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
- Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
| | - Nuno Vale
- PerMed Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
- Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
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Zheng H, Zhan H. Body Surface Area in Obesity: Clinical Challenges and Call for Improvements. Ann Intern Med 2024; 177:1719-1721. [PMID: 39527819 DOI: 10.7326/m24-0574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2024] Open
Affiliation(s)
- Haoyi Zheng
- St. Francis Hospital, The Heart Center, Roslyn, New York (H.Zheng)
| | - Huichun Zhan
- Department of Medicine, Stony Brook School of Medicine, Stony Brook, and Medical Service, Northport VA Medical Center, Northport, New York (H.Zhan)
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10
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St Peter WL, Bzowyckyj AS, Anderson-Haag T, Awdishu L, Blackman M, Bland A, Chan E, Chmielewski C, Delgado C, Eyler R, Foster C, Hudson J, Kane-Gill SL, Kliethermes MA, Le T, Madabushi R, Martin B, Miller WG, Neumiller JJ, Philbrick AM, Roberts G, Schandorf V, Webb AJ, Wu D, Nolin TD. Moving forward from Cockcroft-Gault creatinine clearance to race-free estimated glomerular filtration rate to improve medication-related decision-making in adults across healthcare settings: A consensus of the National Kidney Foundation Workgroup for Implementation of Race-Free eGFR-Based Medication-Related Decisions. Am J Health Syst Pharm 2024:zxae317. [PMID: 39552516 DOI: 10.1093/ajhp/zxae317] [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: 11/19/2024] Open
Abstract
PURPOSE The goals of this paper are to (1) provide evidence and expert consensus to support a unified approach to estimating kidney filtration in adults with stable kidney function using race-free estimated glomerular filtration rate (eGFR) in place of Cockcroft-Gault estimated creatinine clearance (C-G eCrCL) for medical and medication-related decisions, and (2) demonstrate how adjusting eGFR results for an individual's body surface area (BSA) when it is higher or lower than 1.73 m2 will improve results for medication-related decisions. SUMMARY C-G eCrCL is predominantly used by US pharmacists to determine eGFR for the purposes of medication-related decisions, even though more accurate eGFR equations exist. Several driving factors make it the ideal time to shift clinical practice from using C-G eCrCL to eGFR. These factors include the following: (1) 2024 Food and Drug Administration (FDA) guidance for industry recommends eGFR over C-G eCrCL to evaluate the impact on pharmacokinetics in patients with impaired kidney function; (2) a joint National Kidney Foundation (NKF) and American Society of Nephrology task force recommends 3 race-free Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR equations for medical and medication-related decision-making; (3) the almost ubiquitous use of standardized serum creatinine assay methods in US clinical laboratories; and (4) increasing availability and use of serum cystatin C for eGFR assessment. This publication guides practitioners through the rationale for using race-free eGFR equations for medication-related decisions and how to implement this practice change. CONCLUSION The NKF Workgroup for Implementation of Race-Free eGFR-Based Medication-Related Decisions suggests that health systems, health settings, clinical laboratories, electronic health record systems, compendia and data vendors, and healthcare practitioners involved with medication-related decision-making transition away from C-G eCrCL and towards the race-free eGFR equations for more accurate assessment of kidney filtration and consistency in medication and medical decision-making across the US.
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Douglas RN, Niesen AD, Johnson RL, Olsen DA, Taunton MJ, Portner ER, Acker CT, Hanson AC, Kopp SL. A single center descriptive study of local anesthetic dose in knee arthroplasty: Was there evidence of local anesthetic systemic toxicity? J Clin Anesth 2024; 97:111534. [PMID: 38943851 DOI: 10.1016/j.jclinane.2024.111534] [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: 10/27/2023] [Revised: 03/01/2024] [Accepted: 06/13/2024] [Indexed: 07/01/2024]
Abstract
STUDY OBJECTIVE Describe dosing of local anesthetic when both a periarticular injection (PAI) and peripheral nerve block (PNB) are utilized for knee arthroplasty analgesia, and compare the dosing of local to suggested maximum dosing, and look for evidence of local anesthetic systemic toxicity (LAST). DESIGN A single center retrospective cohort study between May 2018 and November 2022. SETTING A major academic hospital. PATIENTS Patients who had both a PAI and PNB while undergoing primary, revision, total, partial, unilateral, or bilateral knee arthroplasty. INTERVENTIONS None. MEASUREMENTS Calculate the dose of local anesthetic given via PAI, PNB, and both routes combined as based on lean body weight and compare that to the suggested maximum dosing. Look for medications, clinical interventions, and critical event notes suggestive of a LAST event. MAIN RESULTS There were 4527 knee arthroplasties where both a PAI and PNB were performed during the study period. When combining PAI and PNB doses, >75% of patients received more than the suggested maximum dose of 3 mg/kg lean body weight. The median local anesthetic dosing over the study period, 4.4 mg/kg (IQR 3.5,5.9), was 147% of the suggested maximum dose (IQR 117,197). There was no conclusive evidence of LAST among any of the patients in the study. CONCLUSIONS Over the course of our study, we had 4527 knee arthroplasties with a median PAI and PNB local anesthetic dose that was 147% of the suggested maximum without any clear clinical evidence of a LAST event.
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Affiliation(s)
- Rachel N Douglas
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, United States of America.
| | - Adam D Niesen
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, United States of America.
| | - Rebecca L Johnson
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, United States of America.
| | - David A Olsen
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, United States of America.
| | - Michael J Taunton
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, United States of America.
| | - Erica R Portner
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States of America.
| | - Christopher T Acker
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States of America.
| | - Andrew C Hanson
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States of America.
| | - Sandra L Kopp
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, United States of America.
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Henning N, Kellermann TA, Smith C. Effect of Chronic Dolutegravir Administration on the Trace Amine Profile in Wistar Rats. Drugs R D 2024; 24:435-445. [PMID: 39177936 PMCID: PMC11455829 DOI: 10.1007/s40268-024-00484-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/05/2024] [Indexed: 08/24/2024] Open
Abstract
BACKGROUND Dolutegravir (DTG), an integrase strand inhibitor, is currently used as the first-line treatment for HIV. Despite relatively poor tissue penetration, the risk of adverse effects in metabolic and excretory systems should be considered. The trace aminergic system and trace amines are emerging as relevant role players in many chronic diseases that are commonly diagnosed but poorly understood. Trace amines are biogenic amines that are endogenously produced and can also be ingested by the intake of trace amine-rich food. Trace amines are known to differentially regulate inflammatory and neurological outcome. OBJECTIVE This study investigated the effects of DTG on the trace amine profile in a wistar rat model. METHODS A total of 24 healthy wistar rats were randomly divided into four experimental groups: male and female controls and male and female DTG-treated. Blood and tissue samples were collected following a 12-week DTG administration study. Liquid chromatography-tandem mass spectroscopy (LC-MS/MS) was used to determine trace amine concentrations in urine, plasma, brain, and gastrointestinal tissue. RESULTS Current data illustrate that polyamines differ significantly (p < 0.05) between males and females in various matrices. DTG significantly (p < 0.05) reduced jejunal tyramine and urinary synephrine levels. CONCLUSION Data do not raise major concerns about DTG in the context of the trace amine profile. However, given the importance of the dysregulated trace amine profile in various diseased states, including HIV, current data warrant clinical investigation to further evaluate the significance of DTG-associated effects on the trace amine profile.
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Affiliation(s)
- Natasha Henning
- Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- Experimental Medicine Research Group, Division of Internal Medicine, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Parow, Cape Town, 7505, South Africa
| | - Tracy A Kellermann
- Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Carine Smith
- Experimental Medicine Research Group, Division of Internal Medicine, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Parow, Cape Town, 7505, South Africa.
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Taylor ZL, Green FG, Hossain N, Burckart GJ, Pacanowski M, Schuck RN. Assessment of Dosing Strategies for Pediatric Drug Products. Clin Pharmacol Ther 2024; 116:716-723. [PMID: 38493367 PMCID: PMC11338733 DOI: 10.1002/cpt.3250] [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: 10/25/2023] [Accepted: 03/02/2024] [Indexed: 03/18/2024]
Abstract
Pediatric drug dosing is challenged by the heterogeneity of developing physiology and ethical considerations surrounding a vulnerable population. Often, pediatric drug dosing leverages findings from the adult population; however, recent regulatory efforts have motivated drug sponsors to pursue pediatric-specific programs to meet an unmet medical need and improve pediatric drug labeling. This paradigm is further complicated by the pathophysiological implications of obesity on drug distribution and metabolism and the roles that body composition and body size play in drug dosing. Therefore, we sought to understand the landscape of pediatric drug dosing by characterizing the dosing strategies from drug products recently approved for pediatric indications identified using FDA Drug Databases and analyze the impact of body size descriptors (age, body surface area, weight) on drug pharmacokinetics for several selected antipsychotics approved in pediatric patients. Our review of these pediatric databases revealed a dependence on body size-guided dosing, with 68% of dosing in pediatric drug labelings being dependent on knowing either the age, body surface area, or weight of the patient to guide dosing for pediatric patients. This dependence on body size-guided dosing drives the need for special consideration when dosing a drug in overweight and obese patients. Exploratory pharmacokinetic analyses in antipsychotics illustrate possible effects of drug exposure when applying different dosing strategies for this class of drugs. Future efforts should aim to further understand the pediatric drug dosing and obesity paradigm across pediatric age ranges and drug classes to optimize drug development and clinical care for this patient population.
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Affiliation(s)
- Zachary L. Taylor
- Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Francis G. Green
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Nayeem Hossain
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Gilbert J. Burckart
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Michael Pacanowski
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Robert N. Schuck
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
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Polášková L, Murínová I, Gregorová J, Slanař O, Šíma M. Vancomycin population pharmacokinetics and dosing proposal for the initial treatment in obese adult patients. Front Pharmacol 2024; 15:1364681. [PMID: 38895623 PMCID: PMC11183791 DOI: 10.3389/fphar.2024.1364681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 05/13/2024] [Indexed: 06/21/2024] Open
Abstract
Aim The aim of this study was to develop a vancomycin population pharmacokinetic model in adult obese patients and propose covariate-based dosing individualization in order to maximize the achievement of the newly recommended PK/PD target, according to a revised consensus guideline from 2020. Methods Therapeutic drug monitoring data from initial vancomycin therapy (first 3 days of treatment) in adult obese (BMI ≥ 30 kg/m2) patients from 2013 to 2022 were analyzed using a non-linear mixed-effects modeling method, and Monte Carlo simulations were then used to find the optimal dosage maximizing the PK/PD target attainment. Results A total of 147 vancomycin serum levels obtained from 138 patients were included in the analysis. Based on the covariate model diagnosis among all tested variables, no reliable predictor of vancomycin volume of distribution (Vd) was identified, while clearance (CL) was positively correlated with eGFR and lean body mass. Creatinine-based eGFR predicted vancomycin CL better than cystatin C-based eGFR. The median (interquartile range) value from conditional modes of individual estimates of Vd, CL, and elimination half-life in our population was 74.0 (70.5-75.4) L, 6.65 (4.95-8.42) L/h, and 7.7 (6.0-10.0) h, respectively. Conclusion We proposed dosing individualization based on the covariate found in order to maximize the achievement of the newly recommended PK/PD target of the AUC/MIC ratio of 400-600. Clinical pharmacy/pharmacology interventions may lead to an improvement in vancomycin dosing with a reflection in PK/PD target attainment.
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Affiliation(s)
- Lucie Polášková
- Department of Clinical Pharmacy, Military University Hospital Prague, Prague, Czechia
| | - Irena Murínová
- Department of Clinical Pharmacy, Military University Hospital Prague, Prague, Czechia
- Department of Applied Pharmacy, Faculty of Pharmacy, Masaryk University, Brno, Czechia
| | - Jana Gregorová
- Department of Clinical Pharmacy, Bulovka University Hospital, Prague, Czechia
| | - Ondřej Slanař
- Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia
| | - Martin Šíma
- Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia
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Sun Y, Cheng Y, Hertz DL. Using maximum plasma concentration (C max) to personalize taxane treatment and reduce toxicity. Cancer Chemother Pharmacol 2024; 93:525-539. [PMID: 38734836 DOI: 10.1007/s00280-024-04677-1] [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: 02/01/2024] [Accepted: 05/06/2024] [Indexed: 05/13/2024]
Abstract
Taxanes are a widely used class of anticancer agents that play a vital role in the treatment of a variety of cancers. However, toxicity remains a major concern of using taxane drugs as some toxicities are highly prevalent, they can not only adversely affect patient prognosis but also compromise the overall treatment plan. Among all kinds of factors that associated with taxane toxicity, taxane exposure has been extensively studied, with different pharmacokinetic (PK) parameters being used as toxicity predictors. Compared to other widely used predictors such as the area under the drug plasma concentration curve versus time (AUC) and time above threshold plasma drug concentration, maximum plasma concentration (Cmax) is easier to collect and shows promise for use in clinical practice. In this article, we review the previous research on using Cmax to predict taxane treatment outcomes. While Cmax and toxicity have been extensively studied, research on the relationship between Cmax and efficacy is lacking. Most of the articles find a positive relationship between Cmax and toxicity but several articles have contradictory findings. Future clinical trials are needed to validate the relationship between Cmax and treatment outcome and determine whether Cmax can serve as a useful surrogate endpoint of taxane treatment efficacy.
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Affiliation(s)
- Yuchen Sun
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, USA
| | - Yue Cheng
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, USA
| | - Daniel L Hertz
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, USA.
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Van Cauwenberge J, Van Baelen K, Maetens M, Geukens T, Nguyen HL, Nevelsteen I, Smeets A, Deblander A, Neven P, Koolen S, Wildiers H, Punie K, Desmedt C. Reporting on patient's body mass index (BMI) in recent clinical trials for patients with breast cancer: a systematic review. Breast Cancer Res 2024; 26:81. [PMID: 38778365 PMCID: PMC11112918 DOI: 10.1186/s13058-024-01832-7] [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: 11/27/2023] [Accepted: 04/30/2024] [Indexed: 05/25/2024] Open
Abstract
BACKGROUND The proportion of patients with breast cancer and obesity is increasing. While the therapeutic landscape of breast cancer has been expanding, we lack knowledge about the potential differential efficacy of most drugs according to the body mass index (BMI). Here, we conducted a systematic review on recent clinical drug trials to document the dosing regimen of recent drugs, the reporting of BMI and the possible exclusion of patients according to BMI, other adiposity measurements and/or diabetes (leading comorbidity of obesity). We further explored whether treatment efficacy was evaluated according to BMI. METHODS A search of Pubmed and ClinicalTrials.gov was performed to identify phase I-IV trials investigating novel systemic breast cancer treatments. Dosing regimens and exclusion based on BMI, adiposity measurements or diabetes, documentation of BMI and subgroup analyses according to BMI were assessed. RESULTS 495 trials evaluating 26 different drugs were included. Most of the drugs (21/26, 81%) were given in a fixed dose independent of patient weight. BMI was an exclusion criterion in 3 out of 495 trials. Patients with diabetes, the leading comorbidity of obesity, were excluded in 67/495 trials (13.5%). Distribution of patients according to BMI was mentioned in 8% of the manuscripts, subgroup analysis was performed in 2 trials. No other measures of adiposity/body composition were mentioned in any of the trials. Retrospective analyses on the impact of BMI were performed in 6 trials. CONCLUSIONS Patient adiposity is hardly considered as most novel drug treatments are given in a fixed dose. BMI is generally not reported in recent trials and few secondary analyses are performed. Given the prevalence of patients with obesity and the impact obesity can have on pharmacokinetics and cancer biology, more attention should be given by investigators and study sponsors to reporting patient's BMI and evaluating its impact on treatment efficacy and toxicity.
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Affiliation(s)
- Josephine Van Cauwenberge
- Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Herestraat 49, Box 808, 3000, Louvain, Belgium
- Department of Gynecological Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Karen Van Baelen
- Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Herestraat 49, Box 808, 3000, Louvain, Belgium
- Department of Gynecological Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Marion Maetens
- Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Herestraat 49, Box 808, 3000, Louvain, Belgium
| | - Tatjana Geukens
- Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Herestraat 49, Box 808, 3000, Louvain, Belgium
- Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Ha Linh Nguyen
- Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Herestraat 49, Box 808, 3000, Louvain, Belgium
| | - Ines Nevelsteen
- Department of Surgical Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Ann Smeets
- Department of Surgical Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Anne Deblander
- Department of Gynecological Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Patrick Neven
- Department of Gynecological Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Stijn Koolen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
- Department of Hospital Pharmacy, Erasmus MC, Rotterdam, The Netherlands
| | - Hans Wildiers
- Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Kevin Punie
- Department of Medical Oncology, GZA Hospitals Sint-Augustinus, Wilrijk, Belgium
| | - Christine Desmedt
- Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Herestraat 49, Box 808, 3000, Louvain, Belgium.
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17
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Gouju J, Jourdan C, Legeay S. [An online tool to personalize the drug-doses for obese adults]. Therapie 2024; 79:379-392. [PMID: 37865563 DOI: 10.1016/j.therap.2023.07.004] [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: 01/25/2023] [Revised: 07/03/2023] [Accepted: 07/21/2023] [Indexed: 10/23/2023]
Abstract
BACKGROUND Between 1975 and 2014, the number of people suffering from obesity tripled, reaching 17% of the adult population in France and more than 35% in the United States. Obesity is defined by a Body Mass Index (BMI)>30kg/m2 and characterized by a significant accumulation of adipose tissue responsible for the increase in weight. This accumulation leads to physiological changes capable of modifying the pharmacokinetics of drugs, which can lead to the administration of inappropriate doses. For this reason, some significant dosage adjustments are necessary for obese patients. However, data on these adaptations are not easily accessible and sometimes complex to implement in practice. AIM To perform a new online tool allowing to calculate and propose an adjusted dose of a drug that should be administered to an obese patient. METHOD (i) carrying out an extensive bibliographic research according to the PRISMA methodology; and (ii) the development of a new website site proposing an adjusted dose for obese patients. RESULTS Firstly, 49 reviews concerning the dose adaptation have been evaluated and, secondly, 319 articles have been selected. Among them, 204 articles have been included in the database to justify the adjusted dose of 84 drugs and administration methods including antibiotics, antifungals, anticoagulants or even cancer drugs. This database is available online through a calculator on the website named Adapt'Obese. Thus, with the sex, height and weight of an obese patient, Adapt'Obese proposes a personalized and adjusted dose of the drug to administer. PERSPECTIVES Other drugs will be added soon, and functional improvements are planned, with the aim of adapting the dosages in obese patients, as for patients with renal insufficiency.
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Affiliation(s)
- Julien Gouju
- Inserm U1066, MINT, CNRS 6021, SFR-ICAT 4208, IBS, CHU d'Angers, université d'Angers, 49933 Angers, France; CHU d'Angers, 49933 Angers, France.
| | | | - Samuel Legeay
- Inserm U1066, MINT, CNRS 6021, SFR-ICAT 4208, IBS, CHU d'Angers, université d'Angers, 49933 Angers, France
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Fu Y, Xiang Y, Wei Q, Ilatovskaya D, Dong Z. Rodent models of AKI and AKI-CKD transition: an update in 2024. Am J Physiol Renal Physiol 2024; 326:F563-F583. [PMID: 38299215 PMCID: PMC11208034 DOI: 10.1152/ajprenal.00402.2023] [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: 12/13/2023] [Revised: 01/29/2024] [Accepted: 01/29/2024] [Indexed: 02/02/2024] Open
Abstract
Despite known drawbacks, rodent models are essential tools in the research of renal development, physiology, and pathogenesis. In the past decade, rodent models have been developed and used to mimic different etiologies of acute kidney injury (AKI), AKI to chronic kidney disease (CKD) transition or progression, and AKI with comorbidities. These models have been applied for both mechanistic research and preclinical drug development. However, current rodent models have their limitations, especially since they often do not fully recapitulate the pathophysiology of AKI in human patients, and thus need further refinement. Here, we discuss the present status of these rodent models, including the pathophysiologic compatibility, clinical translational significance, key factors affecting model consistency, and their main limitations. Future efforts should focus on establishing robust models that simulate the major clinical and molecular phenotypes of human AKI and its progression.
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Affiliation(s)
- Ying Fu
- Department of Nephrology, Institute of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, People's Republic of China
| | - Yu Xiang
- Department of Nephrology, Institute of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, People's Republic of China
| | - Qingqing Wei
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, United States
| | - Daria Ilatovskaya
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
| | - Zheng Dong
- Department of Nephrology, Institute of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, People's Republic of China
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, United States
- Research Department, Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, United States
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Shen J, Moore KT, Shukla S, Yeo KR, Venkatakrishnan K. Inclusion of Obese Participants in Drug Development: Reflections on the Current Landscape and a Call for Action. J Clin Pharmacol 2024; 64:13-18. [PMID: 37888612 DOI: 10.1002/jcph.2377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 10/23/2023] [Indexed: 10/28/2023]
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Hall, RG, Liu S, Putnam WC, Kallem R, Gumbo T, Pai MP. Optimizing anidulafungin exposure across a wide adult body size range. Antimicrob Agents Chemother 2023; 67:e0082023. [PMID: 37850741 PMCID: PMC10649049 DOI: 10.1128/aac.00820-23] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 09/06/2023] [Indexed: 10/19/2023] Open
Abstract
Echinocandins like anidulafungin are first-line therapies for candidemia and invasive candidiasis, but their dosing may be suboptimal in obese patients. Our objective was to quantify anidulafungin exposure in a cohort of adults across a wide body size range to test if body size affects anidulafungin pharmacokinetics (PK). We enrolled 20 adults between the ages of 18 and 80 years, with an equal distribution of patients above and below a body mass index of 30 kg/m2. A single 100-mg dose of anidulafungin was administered, followed by intensive sampling over 72 h. Population PK analysis was used to identify and compare covariates of anidulafungin PK parameters. Monte Carlo simulations were performed to compute the probability of target attainment (PTA) based on alternative dosing regimens. Participants (45% males) had a median (range) age of 45 (21-78) years and a median (range) weight of 82.7 (42.4-208.3) kg. The observed median (range) of AUC0-∞ was 106.4 (51.9, 138.4) mg∙h/L. Lean body weight (LBW) and adjusted body weight (AdjBW) were more influential than weight as covariates of anidulafungin PK parameters. The conventional 100 mg daily maintenance is predicted to have a PTA below 90% in adults with an LBW > 55 kg or an AdjBW > 75 kg. A daily maintenance dose of 150-200 mg is predicted in these heavier adults. Anidulafungin AUC0-∞ declines with increasing body size. A higher maintenance dose will increase the PTA compared to the current approach in obese patients.
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Affiliation(s)
- Ronald G. Hall,
- Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Dallas, Texas, USA
| | - Shuhan Liu
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - William C. Putnam
- Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Dallas, Texas, USA
| | - Rajareddy Kallem
- Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Dallas, Texas, USA
| | | | - Manjunath P. Pai
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
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Pett TB, Petry B, Martyn T, Grainger MNC, Baker JF. Plasma concentration of prophylactic cefazolin best correlates with lean body mass measured by bioimpedance analysis in lumbar spine surgery: Results of a pilot study. J Clin Neurosci 2023; 116:55-59. [PMID: 37625221 DOI: 10.1016/j.jocn.2023.08.013] [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: 06/14/2023] [Revised: 08/12/2023] [Accepted: 08/12/2023] [Indexed: 08/27/2023]
Abstract
The aim of this study was to determine the association between measures of body composition and the concentration of plasma and paraspinal muscle cefazolin. Secondly, we aimed to confirm the efficacy of our hospital dosing regimen in achieving the minimum inhibitory concentration (MIC) at the surgical site. Patients undergoing posterior-based lumbar spine surgery had body composition analysed using bioimpedance analysis. All received 2 g of cefazolin at anaesthetic induction in line with hospital guidelines. Cefazolin concentration was measured in plasma (30-minites) and muscle (30- and 60-minuites) using high-performance liquid chromatography. 20 patients were recruited (mean age 61.5 years; 12 female). Mean plasma cefazolin concentrations were 34.1 +/- 10.2 mg/L; mean muscle concentrations 44.4 +/- 18.6 mg/kg and 43.8 +/- 20.4 mg/kg at 30- and 60-minutes respectively. Univariate analysis showed significant correlation between plasma cefazolin concentration and lean mass weight, absolute body weight, height, dry lean mass, total water, total body water, extracellular and intracellular water volume. Linear regression analysis showed lean mass weight the best predictor of plasma cefazolin concentration. Muscle cefazolin concentration was dependent on the plasma concentration. Using a MIC of 2 mg/L and 2 mg/kg for Staphylococcus aureus, MIC was achieved in all samples. In summary, plasma cefazolin concentration was best predicted by lean body mass. Further work should consider the influence of body composition on antibiotic delivery in extremes of body mass index. Local hospital guidelines are effective at achieving MIC against S. aureus.
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Affiliation(s)
- Thomas B Pett
- Department of Orthopaedic Surgery, Waikato Hospital, Hamilton, New Zealand
| | - Benjamin Petry
- Department of Orthopaedic Surgery, Waikato Hospital, Hamilton, New Zealand
| | - Tanushk Martyn
- Department of Orthopaedic Surgery, Waikato Hospital, Hamilton, New Zealand
| | | | - Joseph F Baker
- Department of Orthopaedic Surgery, Waikato Hospital, Hamilton, New Zealand; Department of Surgery, University of Auckland, Auckland, New Zealand.
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22
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Miller W, January S, Klaus J, Neuner E, Pande A, Krekel T. Safety and efficacy of weight-based ganciclovir dosing strategies in overweight/obese patients. Transpl Infect Dis 2023; 25:e14134. [PMID: 37615196 DOI: 10.1111/tid.14134] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/18/2023] [Accepted: 08/14/2023] [Indexed: 08/25/2023]
Abstract
BACKGROUND The management of cytomegalovirus (CMV) is particularly challenging as both CMV and its usual first-line treatment, ganciclovir, are associated with neutropenia. Ganciclovir dosing is weight-based, most commonly utilizing total body weight (TBW). The subsequent high doses of ganciclovir in overweight/obese patients may increase the risk of toxicity. Utilizing adjusted body weight (AdjBW) dosing may help mitigate this risk. Therefore, the objective of this study was to evaluate the difference in toxicity and efficacy between TBW and AdjBW ganciclovir dosing strategies in overweight/obese patients. METHODS This retrospective study conducted safety and efficacy analyses of ganciclovir courses (≥72 h) used as CMV treatment. The primary safety outcome was the incidence of neutropenia (absolute neutrophil count <1000 cells/μL), and the primary efficacy outcome was a 2-log decrease in CMV polymerase chain reaction within 4 weeks following ganciclovir initiation. In both analyses, courses were excluded in which ganciclovir was dosed outside of specified renal dosing parameters for >20% of the course. RESULTS Among the 253 courses in the safety cohort, there was no difference in the incidence of neutropenia (17.4% vs. 13.5%, p = .50) in AdjBW compared to TBW dosing. In the 62 courses evaluating efficacy, there was no statistical difference between AdjBW and TBW dosing (60.0% vs. 45.2%, p = .28). No subgroups were identified in which AdjBW dosing was advantageous. CONCLUSION Utilization of AdjBW ganciclovir dosing did not result in decreased neutropenia or treatment efficacy as compared to TBW dosing. Further studies with larger patient populations would be beneficial to confirm these findings.
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Affiliation(s)
- William Miller
- Department of Pharmacy, Deaconess Hospital, Evansville, Indiana, USA
| | - Spenser January
- Department of Pharmacy, Barnes-Jewish Hospital, Saint Louis, Missouri, USA
| | - Jeff Klaus
- Department of Pharmacy, Barnes-Jewish Hospital, Saint Louis, Missouri, USA
| | - Elizabeth Neuner
- Department of Pharmacy, Barnes-Jewish Hospital, Saint Louis, Missouri, USA
| | - Anupam Pande
- Division of Infectious Disease, Washington University in St Louis School of Medicine, Saint Louis, Missouri, USA
| | - Tamara Krekel
- Department of Pharmacy, Barnes-Jewish Hospital, Saint Louis, Missouri, USA
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23
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Hejal R, Popa A, Rangel ML, Remy KE. What's New in Critical Illness and Injury Science? Weighing the evidence for dexmedetomidine dosing in critically ill patients with obesity. Int J Crit Illn Inj Sci 2023; 13:45-47. [PMID: 37547191 PMCID: PMC10401556 DOI: 10.4103/ijciis.ijciis_25_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 06/11/2023] [Accepted: 06/12/2023] [Indexed: 08/08/2023] Open
Affiliation(s)
- Rana Hejal
- Department of Medicine, Case Western Reserve University School of Medicine, University Hospitals of Cleveland, Ohio, USA
| | - Andrea Popa
- Department of Medicine, Case Western Reserve University School of Medicine, University Hospitals of Cleveland, Ohio, USA
- Department of Pharmacy, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Maribel Llamas Rangel
- Department of Pharmacy, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Kenneth E. Remy
- Department of Medicine, Case Western Reserve University School of Medicine, University Hospitals of Cleveland, Ohio, USA
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24
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Pai MP, Sitaruno S, Abdelnabi M. Removing race and body surface area indexation for estimated kidney function based drug dosing: Aminoglycosides as justification of these principles. Pharmacotherapy 2023; 43:35-42. [PMID: 36401789 PMCID: PMC10098929 DOI: 10.1002/phar.2746] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/09/2022] [Accepted: 11/10/2022] [Indexed: 11/20/2022]
Abstract
STUDY OBJECTIVE The use of race in medicine can contribute to health inequity. Updated equations for estimated glomerular filtration rate (eGFR) without race have been published. Likewise, de-indexation of eGFR to body surface area (BSA) has been recommended by regulatory guidance for drug dosing in renal impairment. Clinical data justifying these recommendations for drug dosing are sparse. We examined the gain or loss of precision in drug dosing with estimated creatinine clearance (eCLcr) and eGFR using serum creatinine (eGFRcr) with and without race and BSA indexation by evaluating the population pharmacokinetics of the aminoglycosides as a classic drug class to probe kidney function. DESIGN Medical records from adult patients treated with gentamicin or tobramycin over a 13-year period were queried. Population pharmacokinetic analyses were performed using a 1-compartment base structural model. Models compared body size descriptors as covariates of the volume of distribution (V). Estimated creatinine clearance and eGFRcr using multiple contemporary equations with and without BSA indexation were tested as covariates of clearance (CL). MAIN RESULTS The final data set included 2968 patients treated with either gentamicin (20.2%) or tobramycin (79.8%). Patients self-identified as Caucasian (82%), African-American (10%), or other. The median [5th, 95th percentile] weight and BSA were 80.5 [49.4, 136] kg and 1.94 [1.48, 2.56] m2 , respectively. Models of eCLcr and eGFRcr without indexation to BSA had a better model fit than eGFRcr indexed to BSA for aminoglycoside CL. The 2021 Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) eGFRcr equation (no race, no BSA indexation) provided a comparable model fit to the 2009 CKD-EPI eGFRcr equation (with race, no BSA indexation) for aminoglycoside CL. CONCLUSIONS Race is not a relevant covariate of aminoglycoside CL. The 2021 CKD-EPI eGFR equation without race and BSA indexation is a better method for gentamicin and tobramycin CL estimation. Confirmation of these results for other drugs can support the harmonization of dosing by kidney function.
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Affiliation(s)
- Manjunath P Pai
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Sirima Sitaruno
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla, Thailand
| | - Mohamed Abdelnabi
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
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25
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Ferrario CM, Saha A, VonCannon JL, Meredith WJ, Ahmad S. Does the Naked Emperor Parable Apply to Current Perceptions of the Contribution of Renin Angiotensin System Inhibition in Hypertension? Curr Hypertens Rep 2022; 24:709-721. [PMID: 36272015 DOI: 10.1007/s11906-022-01229-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2022] [Indexed: 01/31/2023]
Abstract
PURPOSE OF REVIEW To address contemporary hypertension challenges, a critical reexamination of therapeutic accomplishments using angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, and a greater appreciation of evidence-based shortcomings from randomized clinical trials are fundamental in accelerating future progress. RECENT FINDINGS Medications targeting angiotensin II mechanism of action are essential for managing primary hypertension, type 2 diabetes, heart failure, and chronic kidney disease. While the ability of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers to control blood pressure is undisputed, practitioners, hypertension specialists, and researchers hold low awareness of these drugs' limitations in preventing or reducing the risk of cardiovascular events. Biases in interpreting gained knowledge from data obtained in randomized clinical trials include a pervasive emphasis on using relative risk reduction over absolute risk reduction. Furthermore, recommendations for clinical practice in international hypertension guidelines fail to address the significance of a residual risk several orders of magnitude greater than the benefits. We analyze the limitations of the clinical trials that have led to current recommended treatment guidelines. We define and quantify the magnitude of the residual risk in published hypertension trials and explore how activation of alternate compensatory bioprocessing components within the renin angiotensin system bypass the ability of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers to achieve a significant reduction in total and cardiovascular deaths. We complete this presentation by outlining the current incipient but promising potential of immunotherapy to block angiotensin II pathology alone or possibly in combination with other antihypertensive drugs. A full appreciation of the magnitude of the residual risk associated with current renin angiotensin system-based therapies constitutes a vital underpinning for seeking new molecular approaches to halt or even reverse the cardiovascular complications of primary hypertension and encourage investigating a new generation of ACE inhibitors and ARBs with increased capacity to reach the intracellular compartments at which Ang II can be generated.
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Affiliation(s)
- Carlos M Ferrario
- Laboratory of Translational Hypertension and Vascular Research, Department of General Surgery, Wake Forest School of Medicine, Medical Center Blvd, Atrium Health Wake Forest Baptist, Winston Salem, NC, 27157, USA.
| | - Amit Saha
- Department of Anesthesiology, Wake Forest School of Medicine, Medical Center Blvd, Atrium Health Wake Forest Baptist, Winston Salem, NC, 27157, USA
| | - Jessica L VonCannon
- Laboratory of Translational Hypertension and Vascular Research, Department of General Surgery, Wake Forest School of Medicine, Medical Center Blvd, Atrium Health Wake Forest Baptist, Winston Salem, NC, 27157, USA
| | - Wayne J Meredith
- Laboratory of Translational Hypertension and Vascular Research, Department of General Surgery, Wake Forest School of Medicine, Medical Center Blvd, Atrium Health Wake Forest Baptist, Winston Salem, NC, 27157, USA
| | - Sarfaraz Ahmad
- Laboratory of Translational Hypertension and Vascular Research, Department of General Surgery, Wake Forest School of Medicine, Medical Center Blvd, Atrium Health Wake Forest Baptist, Winston Salem, NC, 27157, USA
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26
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McCarthy BE, McClelland RL, Appleby DH, Moutchia JS, Minhas JK, Min J, Mazurek JA, Smith KA, Fritz JS, Pugliese SC, Urbanowicz RJ, Holmes JH, Palevsky HI, Kawut SM, Al-Naamani N. BMI and Treatment Response in Patients With Pulmonary Arterial Hypertension: A Meta-analysis. Chest 2022; 162:436-447. [PMID: 35247393 PMCID: PMC9470735 DOI: 10.1016/j.chest.2022.02.041] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 02/17/2022] [Accepted: 02/21/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Obesity is increasingly prevalent in pulmonary arterial hypertension (PAH) but is associated with improved survival, creating an "obesity paradox" in PAH. It is unknown if the improved outcomes could be attributable to obese patients deriving a greater benefit from PAH therapies. RESEARCH QUESTION Does BMI modify treatment effectiveness in PAH? STUDY DESIGN AND METHODS Using individual participant data, a meta-analysis was conducted of phase III, randomized, placebo-controlled trials of treatments for PAH submitted for approval to the U.S. Food and Drug Administration from 2000 to 2015. Primary outcomes were change in 6-min walk distance (6MWD) and World Health Organization (WHO) functional class. RESULTS A total of 5,440 participants from 17 trials were included. Patients with overweight and obesity had lower baseline 6MWD and were more likely to be WHO functional class III or IV. Treatment was associated with a 27.01-m increase in 6MWD (95% CI, 21.58-32.45; P < .001) and lower odds of worse WHO functional class (OR, 0.58; 95% CI, 0.48-0.70; P < .001). For every 1 kg/m2 increase in BMI, 6MWD was reduced by 0.66 m (P = .07); there was no significant effect modification of treatment response in 6MWD according to BMI (P for interaction = .34). Higher BMI was not associated with odds of WHO functional class at end of follow-up; however, higher BMI attenuated the treatment response such that every 1 kg/m2 increase in BMI increased odds of worse WHO functional class by 3% (OR, 1.03; P for interaction = .06). INTERPRETATION Patients with overweight and obesity had lower baseline 6MWD and worse WHO functional class than patients with normal weight with PAH. Higher BMI did not modify the treatment response for change in 6MWD, but it attenuated the treatment response for WHO functional class. PAH trials should include participants representative of all weight groups to allow for assessment of treatment heterogeneity and mechanisms.
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Affiliation(s)
- Breanne E McCarthy
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Robyn L McClelland
- Department of Biostatistics, University of Washington School of Public Health, Seattle, WA
| | - Dina H Appleby
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Jude S Moutchia
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Jasleen K Minhas
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Jeff Min
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Jeremy A Mazurek
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - K Akaya Smith
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Jason S Fritz
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Steven C Pugliese
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Ryan J Urbanowicz
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - John H Holmes
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Harold I Palevsky
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Steven M Kawut
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Nadine Al-Naamani
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
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27
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Abouir K, Gosselin P, Guerrier S, Daali Y, Desmeules J, Grosgurin O, Reny J, Samer C, Calmy A, Ing Lorenzini KR. Dexamethasone exposure in normal-weight and obese hospitalized COVID-19 patients: An observational exploratory trial. Clin Transl Sci 2022; 15:1796-1804. [PMID: 35706350 PMCID: PMC9283739 DOI: 10.1111/cts.13297] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/16/2022] [Accepted: 04/24/2022] [Indexed: 12/15/2022] Open
Abstract
During the latest pandemic, the RECOVERY study showed the benefits of dexamethasone (DEX) use in COVID-19 patients. Obesity has been proven to be an independent risk factor for severe forms of infection, but little information is available in the literature regarding DEX dose adjustment according to body weight. We conducted a prospective, observational, exploratory study at Geneva University Hospitals to assess the impact of weight on DEX pharmacokinetics (PK) in normal-weight versus obese COVID-19 hospitalized patients. Two groups of patients were enrolled: normal-weight and obese (body mass index [BMI] 18.5-25 and >30 kg/m2 , respectively). All patients received the standard of care therapy of 6 mg DEX orally. Blood samples were collected, and DEX concentrations were measured. The mean DEX AUC0-8 and Cmax were lower in the obese compared to the normal-weight group (572.02 ± 258.96 vs. 926.92 ± 552.12 ng h/ml and 138.67 ± 68.03 vs. 203.44 ± 126.30 ng/ml, respectively). A decrease in DEX AUC0-8 of 4% per additional BMI unit was observed, defining a significant relationship between weight and DEX AUC0-8 (p = 0.004, 95% CI 2-7%). In women, irrespective of the BMI, DEX AUC0-8 increased by 214% in comparison to men (p < 0.001, 95% CI 154-298%). Similarly, the mean Cmax increased by 205% in women (p < 0.001, 95% CI 141-297%). Conversely, no significant difference between the obese and normal-weight groups was observed for exploratory treatment outcomes, such as the length of hospitalization. BMI, weight, and gender significantly affected DEX AUC. We conclude that dose adjustment would be needed if the aim is to achieve the same exposures in normal-weight and obese patients.
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Affiliation(s)
- Kenza Abouir
- Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care and Emergency MedicineGeneva University HospitalsGenevaSwitzerland
- School of Pharmaceutical SciencesUniversity of GenevaGenevaSwitzerland
| | - Pauline Gosselin
- Division of General Internal MedicineGeneva University HospitalsGenevaSwitzerland
| | - Stéphane Guerrier
- School of Pharmaceutical SciencesUniversity of GenevaGenevaSwitzerland
- Geneva School of Economics and ManagementUniversity of GenevaGenevaSwitzerland
| | - Youssef Daali
- Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care and Emergency MedicineGeneva University HospitalsGenevaSwitzerland
- School of Pharmaceutical SciencesUniversity of GenevaGenevaSwitzerland
- Swiss Centre for Applied Human Toxicology (SCAHT)GenevaSwitzerland
- Faculty of MedicineUniversity of GenevaGenevaSwitzerland
| | - Jules Desmeules
- Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care and Emergency MedicineGeneva University HospitalsGenevaSwitzerland
- School of Pharmaceutical SciencesUniversity of GenevaGenevaSwitzerland
- Swiss Centre for Applied Human Toxicology (SCAHT)GenevaSwitzerland
- Faculty of MedicineUniversity of GenevaGenevaSwitzerland
| | - Olivier Grosgurin
- Division of General Internal MedicineGeneva University HospitalsGenevaSwitzerland
- Faculty of MedicineUniversity of GenevaGenevaSwitzerland
| | - Jean‐Luc Reny
- Division of General Internal MedicineGeneva University HospitalsGenevaSwitzerland
- Faculty of MedicineUniversity of GenevaGenevaSwitzerland
| | - Caroline Samer
- Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care and Emergency MedicineGeneva University HospitalsGenevaSwitzerland
- Swiss Centre for Applied Human Toxicology (SCAHT)GenevaSwitzerland
- Faculty of MedicineUniversity of GenevaGenevaSwitzerland
| | - Alexandra Calmy
- Faculty of MedicineUniversity of GenevaGenevaSwitzerland
- Division of Infectious DiseasesGeneva University HospitalsGenevaSwitzerland
| | - Kuntheavy Roseline Ing Lorenzini
- Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care and Emergency MedicineGeneva University HospitalsGenevaSwitzerland
- Faculty of MedicineUniversity of GenevaGenevaSwitzerland
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28
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Xu KY, Li D, Hu ZJ, Zhao CC, Bai J, Du WL. Vancomycin dosing in an obese patient with acute renal failure: A case report and review of literature. World J Clin Cases 2022; 10:6218-6226. [PMID: 35949852 PMCID: PMC9254177 DOI: 10.12998/wjcc.v10.i18.6218] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/19/2022] [Accepted: 04/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Vancomycin is the most commonly used drug for methicillin-resistant Staphylococcus aureus. The empirical clinical doses of vancomycin based on non-obese patients may not be optimal for obese ones.
CASE SUMMARY This study reports a case of vancomycin dosing adjustment in an obese patient (body mass index 78.4 kg/m2) with necrotizing fasciitis of the scrotum and left lower extremity accompanied with acute renal failure. Dosing adjustment was performed based on literature review and factors that influence pharmacokinetic parameters are analyzed. The results of the blood drug concentration monitoring confirmed the successful application of our dosing adjustment strategy in this obese patient. Total body weight is an important consideration for vancomycin administration in obese patients, which affects the volume of distribution and clearance of vancomycin. The alterations of pharmacokinetic parameters dictate that vancomycin should be dose-adjusted when applied to obese patients. At the same time, the pathophysiological status of patients, such as renal function, which also affects the dose adjustment of the patient, should be considered.
CONCLUSION Monitoring vancomycin blood levels in obese patients is critical to help adjust the dosing regimen to ensure that vancomycin concentrations are within the effective therapeutic range and to reduce the incidence of renal injury.
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Affiliation(s)
- Kun-Yan Xu
- Department of Pharmacy, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Dan Li
- Department of Pharmacy, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Zhen-Jie Hu
- Department of Intensive Care Unit, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Cong-Cong Zhao
- Department of Intensive Care Unit, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Jing Bai
- Department of Pharmacy, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Wen-Li Du
- Department of Pharmacy, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
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29
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The Association of Abdominal Adiposity with Premature Discontinuation of Postoperative Chemotherapy in Colon Cancer. Clin Nutr 2022; 41:1600-1604. [DOI: 10.1016/j.clnu.2022.05.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 05/04/2022] [Accepted: 05/20/2022] [Indexed: 11/17/2022]
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30
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Bian X, Qu X, Zhang J, Nang SC, Bergen PJ, Tony Zhou Q, Chan HK, Feng M, Li J. Pharmacokinetics and pharmacodynamics of peptide antibiotics. Adv Drug Deliv Rev 2022; 183:114171. [PMID: 35189264 PMCID: PMC10019944 DOI: 10.1016/j.addr.2022.114171] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 01/23/2022] [Accepted: 02/16/2022] [Indexed: 01/05/2023]
Abstract
Antimicrobial resistance is a major global health challenge. As few new efficacious antibiotics will become available in the near future, peptide antibiotics continue to be major therapeutic options for treating infections caused by multidrug-resistant pathogens. Rational use of antibiotics requires optimisation of the pharmacokinetics and pharmacodynamics for the treatment of different types of infections. Toxicodynamics must also be considered to improve the safety of antibiotic use and, where appropriate, to guide therapeutic drug monitoring. This review focuses on the pharmacokinetics/pharmacodynamics/toxicodynamics of peptide antibiotics against multidrug-resistant Gram-negative and Gram-positive pathogens. Optimising antibiotic exposure at the infection site is essential for improving their efficacy and minimising emergence of resistance.
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Affiliation(s)
- Xingchen Bian
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, Shanghai, China; National Health Commission & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China; School of Pharmacy, Fudan University, Shanghai, China
| | - Xingyi Qu
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, Shanghai, China; National Health Commission & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China; School of Pharmacy, Fudan University, Shanghai, China; Phase I Unit, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Jing Zhang
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, Shanghai, China; National Health Commission & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China; Phase I Unit, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Sue C Nang
- Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Australia
| | - Phillip J Bergen
- Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Australia
| | - Qi Tony Zhou
- Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, IN, USA
| | - Hak-Kim Chan
- Advanced Drug Delivery Group, School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Meiqing Feng
- School of Pharmacy, Fudan University, Shanghai, China
| | - Jian Li
- Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Australia.
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31
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Wright L, Childress DT, Brown ML, Wilkerson W, Maldonado R, Durham SH. Which "weigh" to Go? Alternative Vancomycin Dosing Strategies in Obese Patients. J Pharm Pract 2022:8971900221087122. [PMID: 35360993 DOI: 10.1177/08971900221087122] [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] [Indexed: 11/16/2022]
Abstract
PURPOSE This study aims to compare the performance of alternative weight-based vancomycin dosing strategies to traditional dosing in obese patients using area under the curve (AUC) monitoring. METHODS This retrospective study compared target attainment of an AUC between 400-600mcg*H/mL using alternative vancomycin dosing strategies. All patients received allometrically dosed vancomycin, with patient-specific AUCs calculated using 2 post-infusion steady-state vancomycin serum concentrations using the trapezoidal rule. Predicted AUCs were calculated using the following: 15 mg/kg total body weight (TBW), 15 mg/kg corrected body weight (CBW), and 12.5 mg/kg TBW. Predicted AUCs from the traditional 15 mg/kg TBW dosing were then compared to alternative dosing strategies using the predicted AUCs from 12.5 mg/kg TBW, 15 mg/kg CBW, and the actual AUCs calculated using allometrically scaled vancomycin dosing. The primary outcome was attainment of initial AUC within the target range of 400-600mcg*H/mL for each dosing method. RESULTS Eighty-four patients were included. When AUCs were compared to traditional 15 mg/kg dosing strategy, the CBW, 12.5 mg/kg, and allometric dosing strategies were significantly more likely to result in initial attainment of an AUC within a target range of 400-600 mcg*H/mL (P = 0.0003, 0.0135, and 0.0088, respectively). No significant differences were seen between each of the alternative dosing methods (P = 0.73). CONCLUSION The 3 alternative vancomycin dosing strategies examined were all significantly more likely to achieve an initial AUC within the target range compared to traditional vancomycin dosing in obese patients. Clinicians should strongly consider one of these alternative dosing strategies for obese patients as opposed to traditional vancomycin dosing.
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Affiliation(s)
- Lauren Wright
- Baptist Medical Center South, 22378Montgomery, AL, USA
| | | | | | | | | | - Spencer H Durham
- Auburn University Harrison School of Pharmacy, 14374Auburn, AL, USA
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Leung E, Crass RL, Jorgensen SCJ, Raybardhan S, Langford BJ, Moore WJ, Rhodes NJ. Pharmacokinetic/Pharmacodynamic Considerations of Alternate Dosing Strategies of Tocilizumab in COVID-19. Clin Pharmacokinet 2022; 61:155-165. [PMID: 34894345 PMCID: PMC8665708 DOI: 10.1007/s40262-021-01092-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/09/2021] [Indexed: 12/29/2022]
Abstract
Tocilizumab is one of few treatments that have been shown to improve mortality in patients with coronavirus disease 2019 (COVID-19), but increased demand has led to relative global shortages. Recently, it has been suggested that lower doses, or fixed doses, of tocilizumab could be a potential solution to conserve the limited global supply while conferring equivalent therapeutic benefit to the dosing regimens studied in major trials. The relationship between tocilizumab dose, exposure, and response in COVID-19 has not been adequately characterized. There are a number of pharmacokinetic (PK) parameters that likely differ between patients with severe COVID-19 and patients in whom tocilizumab was studied during the US FDA approval process. Likewise, it is unclear whether a threshold exposure is necessary for tocilizumab efficacy. The safety and efficacy of fixed versus weight-based dosing of tocilizumab has been evaluated outside of COVID-19, but it is uncertain if these observations are generalizable to severe or critical COVID-19. In the current review, we consider the potential advantages and limitations of alternative tocilizumab dosing strategies. Leveraging PK models and simulation analyses, we demonstrate that a fixed single dose of tocilizumab 400 mg is unlikely to produce PK exposures equivalent to those achieved in the REMAP-CAP trial, although weight-stratified dosing appears to produce more uniform exposure distribution. Data from current and future trials could provide PK/pharmacodynamic insight to better inform dosing strategies at the bedside. Ultimately, rational dosing strategies that balance available limited supply with patient needs are required.
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Affiliation(s)
- Elizabeth Leung
- Department of Pharmacy, St. Michael's Hospital/Unity Health Toronto, Toronto, ON, Canada.
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
- Li Ka Shing Knowledge Institute, Toronto, ON, Canada.
| | - Ryan L Crass
- Ann Arbor Pharmacometrics Group, Ann Arbor, MI, USA
| | - Sarah C J Jorgensen
- Department of Pharmacy, Mount Sinai Hospital, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | | | | | - W Justin Moore
- Department of Pharmacy, Northwestern Medicine, Chicago, IL, USA
| | - Nathaniel J Rhodes
- Department of Pharmacy, Northwestern Medicine, Chicago, IL, USA
- Department of Pharmacy Practice, College of Pharmacy Downers Grove Campus, Midwestern University, Downers Grove, IL, USA
- Pharmacometrics Center of Excellence, College of Pharmacy Downers Grove Campus, Midwestern University, Downers Grove, IL, USA
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Sezgin EA, Ali AK, Ataoğlu MB, Orhan Ö, Odluyurt M, Esen E. Novel radiographic hip fat thickness ratio correlates with early re-operation following total hip arthroplasty. Hip Int 2022; 32:62-66. [PMID: 33682484 DOI: 10.1177/1120700021991783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Obesity is thought to lead to increased failure rates following total hip arthroplasty (THA). Site-specific fat distribution has been suggested to be a better indicator of risk, compared to body mass index. Fat thickness measurement methods were developed for total knee arthroplasty, however, there is limited data on the methods for THA. The aim of this study was to assess the interobserver and intraobserver reliability of a newly defined radiographic subcutaneous fat thickness ratio and investigate the correlation of this ratio with early failure following THA. METHODS 321 patients who underwent primary THA at a single institution between 2014 and 2017, with at least 1-year of follow-up and a preoperative pelvis anteroposterior x-ray radiograph were included in this study. A high hip fat thickness ratio (HFTR) was arbitrarily defined as ⩾2. Early failure was defined as revision or re-operation for any reason and death related to operation first year following THA. RESULTS The HFTR was shown to have excellent intraobserver and interobserver reliability. High HFTR was associated with higher risk of early failure following THA (odds ratio 3.8, [95% confidence interval, 1.2-12.1], p < 0.05). The same association persisted when HFTR was analysed as a continuous variable (p < 0.01) and in multivariate analysis (p < 0.05). CONCLUSIONS HFTR can be used to assess periarticular soft tissue distribution and may be regarded as a useful and reproducible tool for assessing risk of early failure following THA.
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Affiliation(s)
- Erdem A Sezgin
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Gazi University, Ankara, Turkey.,Department of Orthopaedics and Traumatology, Aksaray University Training and Research Hospital, Aksaray, Turkey
| | - Ali K Ali
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Kirkuk University, Kirkuk, Iraq
| | - M Baybars Ataoğlu
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Özlem Orhan
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Gazi University, Ankara, Turkey.,Şanlıurfa Training and Research Hospital, Department of Orthopaedics and Traumatology, Şanlıurfa, Turkey
| | - Mustafa Odluyurt
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Erdinç Esen
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Gazi University, Ankara, Turkey
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Grøndahl MFG, Lund A, Bagger JI, Petersen TS, Wewer Albrechtsen NJ, Holst JJ, Vilsbøll T, Christensen MB, Knop FK. Glucagon Clearance is Preserved in Type 2 Diabetes. Diabetes 2021; 71:db210024. [PMID: 34957488 DOI: 10.2337/db21-0024] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 10/18/2021] [Indexed: 11/13/2022]
Abstract
Hyperglucagonemia is a common observation in both obesity and type 2 diabetes, and the etiology is primarily thought to be hypersecretion of glucagon. We investigated whether altered elimination kinetics of glucagon could contribute to the hyperglucagonemia in type 2 diabetes and obesity. Individuals with type 2 diabetes and preserved kidney function (8 with and 8 without obesity) and matched control individuals (8 with and 8 without obesity) were recruited. Each participant underwent a 1-hour glucagon infusion (4 ng/kg/min), achieving steady-state plasma glucagon concentrations, followed by a 1-hour wash-out period. Plasma levels, the metabolic clearance rate (MCR), half-life (T½) and volume of distribution of glucagon were evaluated and a pharmacokinetic model was constructed. Glucagon MCR and volume of distribution were significantly higher in the type 2 diabetes group compared to the control group, while no significant differences between the groups were found in glucagon T½. Individuals with obesity had neither a significantly decreased MCR, T½, nor volume of distribution of glucagon. In our pharmacokinetic model, glucagon MCR associated positively with fasting plasma glucose and negatively with body weight. In conclusion, our results suggest that impaired glucagon clearance is not a fundamental part of the hyperglucagonemia observed in obesity and type 2 diabetes.
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Affiliation(s)
- Magnus F G Grøndahl
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
| | - Asger Lund
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
| | - Jonatan I Bagger
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
| | - Tonny S Petersen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nicolai J Wewer Albrechtsen
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Mikkel B Christensen
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Pharmacology, Bispebjerg University Hospital, Copenhagen, Denmark
- Copenhagen Center for Translational Research, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
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Xie YL, Liu JJ, Peng JF, Li YQ, Lin YQ, Pei Q, Zuo XC. The pharmacokinetic challenge of polymyxin B in critically ill patients with morbid obesity. J Glob Antimicrob Resist 2021; 27:172-174. [PMID: 34562657 DOI: 10.1016/j.jgar.2021.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 08/28/2021] [Accepted: 09/03/2021] [Indexed: 10/20/2022] Open
Affiliation(s)
- Yue-Liang Xie
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China; Department of Pharmacy and Center of Clinical Pharmacology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China
| | - Jing-Jing Liu
- Department of ICU, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China
| | - Jin-Fu Peng
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China; Department of Pharmacy and Center of Clinical Pharmacology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China
| | - Ya-Qian Li
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China
| | - Ya-Qi Lin
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China
| | - Qi Pei
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China; Department of Pharmacy and Center of Clinical Pharmacology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China.
| | - Xiao-Cong Zuo
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China; Department of Pharmacy and Center of Clinical Pharmacology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China.
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Hartinger JM, Šíma M, Hronová K, Halouzková BA, Szonowská B, Polakovič V, Bednářová V, Hladinová Z, Tesař V, Slanař O. Vancomycin pharmacokinetics in patients treated with intermittent haemodialysis based on therapeutic drug monitoring. J Chemother 2021; 34:149-156. [PMID: 34551680 DOI: 10.1080/1120009x.2021.1979747] [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] [Indexed: 10/20/2022]
Abstract
Vancomycin is frequently used in haemodialysis (HD) patients but generally accepted target serum ranges and dosing strategy are still lacking in this group. Based on retrospective analysis of data from 118 HD patients treated with vancomycin the interdialytic elimination constant (Ke), apparent volume of distribution (Vd) and dialysis efficacy were calculated. The influence of possible clinical variables on the pharmacokinetic parameters of vancomycin have been tested. The median of Ke in interdialytic periods, corresponding half-life and Vd were 0.0073 h-1, 95.0 h and 0.87 L/kg, respectively. We found significant positive correlation between time in dialysis program and Ke. The Vd correlated best with lean body mass (LBM). For high- and low flux membrane HD of 4 hours duration the decline in vancomycin levels was 20.88% and 12.86%, respectively. Based on these data loading dose for vancomycin in HD patient should be calculated as 24.483 × LBM (kg) + 455 mg. The utility of this equation for entire HD population should be also verified prospectively.
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Affiliation(s)
- Jan Miroslav Hartinger
- Department of Clinical Pharmacology and Pharmacy, Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Martin Šíma
- Department of Clinical Pharmacology and Pharmacy, Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Karolína Hronová
- Department of Clinical Pharmacology and Pharmacy, Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Barbora Agátha Halouzková
- Department of Clinical Pharmacology and Pharmacy, Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Barbora Szonowská
- Internal Department of Strahov, General University Hospital in Prague, Prague, Czech Republic
| | - Vladimír Polakovič
- Internal Department of Strahov, General University Hospital in Prague, Prague, Czech Republic
| | - Vladimíra Bednářová
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Zuzana Hladinová
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Vladimír Tesař
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Ondřej Slanař
- Department of Clinical Pharmacology and Pharmacy, Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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Falcone M, Menichetti F, Cattaneo D, Tiseo G, Baldelli S, Galfo V, Leonildi A, Tagliaferri E, Di Paolo A, Pai MP. Pragmatic options for dose optimization of ceftazidime/avibactam with aztreonam in complex patients. J Antimicrob Chemother 2021; 76:1025-1031. [PMID: 33378458 DOI: 10.1093/jac/dkaa549] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 12/04/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Avibactam is a β-lactamase inhibitor that is combined with aztreonam against Enterobacterales co-expressing serine- and metallo-β-lactamases (MBL). Optimal dosing of aztreonam with avibactam is not well-defined in critically ill patients and contingent on ceftazidime/avibactam product labelling. OBJECTIVES To identify a pragmatic dosing strategy for aztreonam with avibactam to maximize the probability of target attainment (PTA). METHODS We conducted a prospective observational pharmacokinetic study. Five blood samples were collected around the fourth dose of aztreonam or ceftazidime/avibactam and assayed for all three drugs. Population pharmacokinetic (PK) analysis coupled with Monte Carlo simulations were used to create a dosing nomogram for aztreonam and ceftazidime/avibactam based on drug-specific pharmacodynamic (PD) targets. RESULTS A total of 41 participants (59% male) median age of 75 years (IQR 63-79 years) were enrolled. They were critically ill (46%) with multiple comorbidities and complications including burns (20%). Population PK analysis identified higher volume of distribution and lower clearance (CL) compared with typical value expectations for aztreonam and ceftazidime/avibactam. Estimated glomerular filtration (eGFR) rate using the CKD-EPI equation predicted CL for all three drugs. The need for high doses of aztreonam and ceftazidime/avibactam above those in the existing product labels are not predicted by this analysis with the exception of ceftazidime/avibactam for patients with eGFR of 6-15 mL/min, in whom suboptimal PTA of ≤71% is predicted. CONCLUSIONS Pragmatic and lower daily-dose options are predicted for aztreonam and ceftazidime/avibactam when the eGFR is <90 mL/min. These options should be tested prospectively.
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Affiliation(s)
- Marco Falcone
- Infectious Diseases Unit, Department of Clinical and Experimental Medicine, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy
| | - Francesco Menichetti
- Infectious Diseases Unit, Department of Clinical and Experimental Medicine, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy
| | - Dario Cattaneo
- Unit of Clinical Pharmacology, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy
| | - Giusy Tiseo
- Infectious Diseases Unit, Department of Clinical and Experimental Medicine, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy
| | - Sara Baldelli
- Unit of Clinical Pharmacology, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy
| | - Valentina Galfo
- Infectious Diseases Unit, Department of Clinical and Experimental Medicine, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy
| | - Alessandro Leonildi
- Infectious Diseases Unit, Department of Clinical and Experimental Medicine, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy.,Microbiology Unit, Azienda Ospedaliera Universitaria Pisana., Pisa, Italy
| | - Enrico Tagliaferri
- Infectious Diseases Unit, Department of Clinical and Experimental Medicine, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy
| | - Antonello Di Paolo
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Manjunath P Pai
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
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Arshad U, Taubert M, Seeger-Nukpezah T, Ullah S, Spindeldreier KC, Jaehde U, Hallek M, Fuhr U, Vehreschild JJ, Jakob C. Evaluation of body-surface-area adjusted dosing of high-dose methotrexate by population pharmacokinetics in a large cohort of cancer patients. BMC Cancer 2021; 21:719. [PMID: 34147089 PMCID: PMC8214796 DOI: 10.1186/s12885-021-08443-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 06/02/2021] [Indexed: 12/03/2022] Open
Abstract
Background The aim of this study was to identify sources of variability including patient gender and body surface area (BSA) in pharmacokinetic (PK) exposure for high-dose methotrexate (MTX) continuous infusion in a large cohort of patients with hematological and solid malignancies. Methods We conducted a retrospective PK analysis of MTX plasma concentration data from hematological/oncological patients treated at the University Hospital of Cologne between 2005 and 2018. Nonlinear mixed effects modeling was performed. Covariate data on patient demographics and clinical chemistry parameters was incorporated to assess relationships with PK parameters. Simulations were conducted to compare exposure and probability of target attainment (PTA) under BSA adjusted, flat and stratified dosing regimens. Results Plasma concentration over time data (2182 measurements) from therapeutic drug monitoring from 229 patients was available. PK of MTX were best described by a three-compartment model. Values for clearance (CL) of 4.33 [2.95–5.92] L h− 1 and central volume of distribution of 4.29 [1.81–7.33] L were estimated. An inter-occasion variability of 23.1% (coefficient of variation) and an inter-individual variability of 29.7% were associated to CL, which was 16 [7–25] % lower in women. Serum creatinine, patient age, sex and BSA were significantly related to CL of MTX. Simulations suggested that differences in PTA between flat and BSA-based dosing were marginal, with stratified dosing performing best overall. Conclusion A dosing scheme with doses stratified across BSA quartiles is suggested to optimize target exposure attainment. Influence of patient sex on CL of MTX is present but small in magnitude. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08443-x.
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Affiliation(s)
- Usman Arshad
- Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Str 24, 50931, Cologne, Germany. .,Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Bonn, Germany.
| | - Max Taubert
- Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Str 24, 50931, Cologne, Germany
| | - Tamina Seeger-Nukpezah
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Sami Ullah
- Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Str 24, 50931, Cologne, Germany.,Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Bonn, Germany
| | | | - Ulrich Jaehde
- Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Bonn, Germany
| | - Michael Hallek
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Uwe Fuhr
- Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Str 24, 50931, Cologne, Germany
| | - Jörg Janne Vehreschild
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.,German Center for Infection Research (DZIF), Partner site Bonn-Cologne, Cologne, Germany.,Department of Internal Medicine, Hematology and Oncology, Faculty of Medicine and University Hospital of Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Carolin Jakob
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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Serum Metabolites Responding in a Dose-Dependent Manner to the Intake of a High-Fat Meal in Normal Weight Healthy Men Are Associated with Obesity. Metabolites 2021; 11:metabo11060392. [PMID: 34208710 PMCID: PMC8233812 DOI: 10.3390/metabo11060392] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/11/2021] [Accepted: 06/15/2021] [Indexed: 12/28/2022] Open
Abstract
Although the composition of the human blood metabolome is influenced both by the health status of the organism and its dietary behavior, the interaction between these two factors has been poorly characterized. This study makes use of a previously published randomized controlled crossover acute intervention to investigate whether the blood metabolome of 15 healthy normal weight (NW) and 17 obese (OB) men having ingested three doses (500, 1000, 1500 kcal) of a high-fat (HF) meal can be used to identify metabolites differentiating these two groups. Among the 1024 features showing a postprandial response, measured between 0 h and 6 h, in the NW group, 135 were dose-dependent. Among these 135 features, 52 had fasting values that were significantly different between NW and OB men, and, strikingly, they were all significantly higher in OB men. A subset of the 52 features was identified as amino acids (e.g., branched-chain amino acids) and amino acid derivatives. As the fasting concentration of most of these metabolites has already been associated with metabolic dysfunction, we propose that challenging normal weight healthy subjects with increasing caloric doses of test meals might allow for the identification of new fasting markers associated with obesity.
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Silvestris N, Argentiero A, Natalicchio A, D'Oronzo S, Beretta GD, Acquati S, Adinolfi V, Di Bartolo P, Danesi R, Faggiano A, Ferrari P, Gallo M, Gori S, Morviducci L, Russo A, Tuveri E, Zatelli MC, Montagnani M, Giorgino F. Antineoplastic dosing in overweight and obese cancer patients: an Associazione Italiana Oncologia Medica (AIOM)/Associazione Medici Diabetologi (AMD)/Società Italiana Endocrinologia (SIE)/Società Italiana Farmacologia (SIF) multidisciplinary consensus position paper. ESMO Open 2021; 6:100153. [PMID: 33984679 PMCID: PMC8134762 DOI: 10.1016/j.esmoop.2021.100153] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 03/23/2021] [Accepted: 04/14/2021] [Indexed: 01/22/2023] Open
Abstract
Most anticancer molecules are administered in body-size-based dosing schedules, bringing up unsolved issues regarding pharmacokinetic data in heavy patients. The worldwide spread of obesity has not been matched by improved methods and strategies for tailored drug dosage in this population. The weight or body surface area (BSA)-based approaches may fail to fully reflect the complexity of the anthropometric features besides obesity in cancer patients suffering from sarcopenia. Likewise, there is a lack of pharmacokinetic data on obese patients for the majority of chemotherapeutic agents as well as for new target drugs and immunotherapy. Therefore, although the available findings point to the role of dose intensity in cancer treatment, and support full weight-based dosing, empirical dose capping often occurs in clinical practice in order to avoid toxicity. Thus a panel of experts of the Associazione Italiana Oncologia Medica (AIOM), Associazione Medici Diabetologi (AMD), Società Italiana Endocrinologia (SIE), and Società Italiana Farmacologia (SIF), provides here a consensus statement for appropriate cytotoxic chemotherapy and new biological cancer drug dosing in obese patients.
The worldwide spread of obesity is an emerging challenge also in cancer patients Weight or BSA-based approaches do not adequately address the critical issue of optimal dosing for cancer drugs under obesity Empirical dose capping is often employed in clinical practice to avoid toxicities among overweight and obese patients There is a lack of clinical and pharmacokinetic studies in this population Clinical practice recommendations should guide suitable dosing of cytotoxic and biological cancer drugs in obese patients
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Affiliation(s)
- N Silvestris
- Medical Oncology Unit, IRCCS Istituto Tumori 'Giovanni Paolo II', Bari, Italy; Department of Biomedical Sciences and Human Oncology, Division of Medical Oncology, University of Bari Aldo Moro, Bari, Italy.
| | - A Argentiero
- Medical Oncology Unit, IRCCS Istituto Tumori 'Giovanni Paolo II', Bari, Italy
| | - A Natalicchio
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - S D'Oronzo
- Department of Biomedical Sciences and Human Oncology, Division of Medical Oncology, University of Bari Aldo Moro, Bari, Italy; Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, UK
| | - G D Beretta
- Medical Oncology Department, Humanitas Gavazzeni, Bergamo, Italy
| | - S Acquati
- Endocrinology Unit, Ospedale Pierantoni-Morgagni, Forlì, Italy
| | - V Adinolfi
- Endocrinology and Diabetology Unit, ASL Verbano Cusio Ossola, Domodossola, Italy
| | - P Di Bartolo
- Diabetology Clinic, Rete Clinica di Diabetologia Aziendale - Dipartimento, Internistico di Ravenna - AUSL Romagna, Ravenna, Italy
| | - R Danesi
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - A Faggiano
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - P Ferrari
- Palliative Care Unit, Istituti Clinici Scientifici Maugeri SPA SB, IRCCS (PV), Pavia PV, Italy
| | - M Gallo
- Endocrinology and Metabolic Diseases Unit of AO SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
| | - S Gori
- Oncologia Medica, IRCCS Ospedale Don Calabria-Sacro Cuore di Negrar, Verona, Italy
| | - L Morviducci
- Diabetology and Nutrition Unit, Department of Medical Specialities, ASL Roma 1 - S. Spirito Hospital, Rome, Italy
| | - A Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - E Tuveri
- Diabetology, Endocrinology and Metabolic Diseases Service, ATS Sardegna - ASSL Carbonia-Iglesias, Italy
| | - M C Zatelli
- Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - M Montagnani
- Department of Biomedical Sciences and Human Oncology, Division of Medical Oncology, University of Bari Aldo Moro, Bari, Italy
| | - F Giorgino
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
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Rybak MJ, Le J, Lodise TP, Levine DP, Bradley JS, Liu C, Mueller BA, Pai MP, Wong-Beringer A, Rotschafer JC, Rodvold KA, Maples HD, Lomaestro BM. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2021; 77:835-864. [PMID: 32191793 DOI: 10.1093/ajhp/zxaa036] [Citation(s) in RCA: 713] [Impact Index Per Article: 178.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
- Michael J Rybak
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, MI, School of Medicine, Wayne State University, Detroit, MI, and Detroit Receiving Hospital, Detroit, MI
| | - Jennifer Le
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA
| | - Thomas P Lodise
- Albany College of Pharmacy and Health Sciences, Albany, NY, and Stratton VA Medical Center, Albany, NY
| | - Donald P Levine
- School of Medicine, Wayne State University, Detroit, MI, and Detroit Receiving Hospital, Detroit, MI
| | - John S Bradley
- Department of Pediatrics, Division of Infectious Diseases, University of California at San Diego, La Jolla, CA, and Rady Children's Hospital San Diego, San Diego, CA
| | - Catherine Liu
- Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, and Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | | | | | | | | | | | - Holly D Maples
- University of Arkansas for Medical Sciences College of Pharmacy & Arkansas Children's Hospital, Little Rock, AR
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Song X, Cai C, Jin Q, Chen X, Yu C. The efficacy of Helicobacter pylori eradication in diabetics and its effect on glycemic control: A systematic review and meta-analysis. Helicobacter 2021; 26:e12781. [PMID: 33465265 DOI: 10.1111/hel.12781] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/15/2020] [Accepted: 12/15/2020] [Indexed: 01/30/2023]
Abstract
BACKGROUND AND AIMS Previous studies have revealed the association between Helicobacter pylori (H. pylori) and diabetes mellitus, but conflicts still exist. The present study tried to investigate the underlying link between these two diseases by making comprehensive analyses of the impact of diabetes on H. pylori eradication and the influence of H. pylori eradication on diabetes. METHODS We systematically searched relevant studies from PubMed, Cochrane Library, Web of Science, and Embase updated to April 23, 2020. Studies examining the association between H. pylori eradication and diabetes were included. Pooled odds ratio (OR) and weighted mean differences (WMD) were calculated for different results. RESULTS Among the 2125 retrieved studies, 36 studies were included. Patients with type 2 diabetes mellitus (T2DM) have higher risk of H. pylori eradication failure than the non-diabetic one (OR = 2.59, 95% CI 1.82-3.70). Body mass index (BMI) was identified as a major factor affecting the efficacy of H. pylori eradication in diabetics, and better glycemic control was also found in eradication succeed patients (WMD: 0.51, 95% CI 0.20-0.81). Moreover, after eradication of H. pylori, improvement of HbA1c was proved (WMD = -0.33, 95% CI -0.65 to -0.02) in T2DM. CONCLUSION A higher risk of H. pylori eradication failure in T2DM was confirmed, and it was associated with BMI and glycemic control. Moreover, we also provided evidence that H. pylori eradication could improve glycemic control in patients with T2DM, which indirectly reflect the interaction between H. pylori and the diabetes.
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Affiliation(s)
- Xin Song
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Changzhou Cai
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Qi Jin
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xueyang Chen
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Chaohui Yu
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Pai MP. Antimicrobial Dosing in Specific Populations and Novel Clinical Methodologies: Obesity. Clin Pharmacol Ther 2021; 109:942-951. [PMID: 33523485 PMCID: PMC8855475 DOI: 10.1002/cpt.2181] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 01/16/2021] [Indexed: 12/17/2022]
Abstract
Obesity and its related comorbidities can negatively influence the outcomes of certain infectious diseases. Specific dosing recommendations are often lacking in the product label for patients with obesity that leads to unclear guidance in practice. Higher rates of therapeutic failure have been reported with some fixed dose antibiotics and pragmatic approaches to dose modification are limited for orally administered agents. For i.v. antimicrobials dosed on weight, alternate body size descriptors (ABSDs) have been used to reduce the risk of overdosing. These ABSDs are mathematical transformations of height and weight that represent fat-free weight and follow the same principles as body surface area (BSA)-based dosing of cancer chemotherapy. However, ABSDs are rarely studied in pivotal phase III studies and so can risk the underdosing of antimicrobials in patients with obesity when incorrectly applied in the real-world setting. Specific case examples are presented to highlight these risks. Although general principles may be considered by clinicians, a universal approach to dose modification in obesity is unlikely. Studies that can better distinguish human body phenotypes may help reduce our reliance on height and weight to define dosing. Simple and complex technologies exist to quantify individual body composition that could improve upon our current approach. Early evidence suggests that body composition parameters repurposed from medical imaging data may improve upon height and weight as covariates of drug clearance and distribution. Clinical trials that can integrate human body phenotyping may help us identify new approaches to optimal dose selection of antimicrobials in patients with obesity.
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Affiliation(s)
- Manjunath P. Pai
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
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Pai MP. Antimicrobial Dosing in Specific Populations and Novel Clinical Methodologies: Kidney Function. Clin Pharmacol Ther 2021; 109:952-957. [PMID: 33523498 DOI: 10.1002/cpt.2179] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 01/04/2021] [Indexed: 12/26/2022]
Abstract
Kidney function is a common parameter used to define antimicrobial drug dosage and frequency of administration. Several methods exist to measure kidney function but for pragmatic reasons rely on estimated kidney function equations based on the endogenous biomarker serum creatinine and common clinical variables. Current regulatory guidance on the design of studies in patients with abnormal kidney function in the United States also recommend consideration of estimated kidney function for this reason. Over the past few decades, alternate endogenous biomarkers, administration of exogenous biomarkers for noninvasive measurement, use of probe substrates to characterize individual kidney drug clearance pathways, modifications to conventional equations to account for time-varying clearance, and improved clinical trial modeling and simulation to factor in these uncertainties have occurred. Furthermore, major changes to kidney replacement therapy delivery in the outpatient, inpatient, and at-home setting are occurring. Antimicrobial drug dose adjustment in this diverse population is complex and in a state of flux due to technical innovations. Over-reliance on kidney function estimates to guide drug dosing in patients with infectious diseases can bias underdosing especially among the acutely ill. A holistic approach to drug dose adjustment in patients with abnormal kidney function is necessary to optimize clinical outcomes.
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Affiliation(s)
- Manjunath P Pai
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
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Acosta Mérida MA, Pedrianes Martín PB, Hernanz Rodríguez GM. Nutritional treatment in the critically-ill complicated patient. NUTRITION AND BARIATRIC SURGERY 2021:99-114. [DOI: 10.1016/b978-0-12-822922-4.00013-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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A randomised dose-response study of prophylactic Methoxamine infusion for preventing spinal-induced hypotension during Cesarean delivery. BMC Anesthesiol 2020; 20:198. [PMID: 32787783 PMCID: PMC7422554 DOI: 10.1186/s12871-020-01119-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 08/06/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND α-receptor agonists have been reported to be safe and effective for treating or preventing spinal-induced hypotension during cesarean delivery. As a pure α1 adrenergic agonist, methoxamine has potential advantages of reducing myocardial oxygen consumption and protecting the heart in obstetric patients compared to phenylephrine. The aim of this study was to determine the optimal prophylactic methoxamine infusion dose that would be effective for preventing spinal-induced hypotension in 50% (ED50) and 95% (ED95) of parturients. METHODS Eighty parturients with a singleton pregnancy scheduled for elective cesarean delivery were randomly allocated to receive prophylactic methoxamine infusion at one of four different fixed-rates: 1 μg/kg/min (group M1), 2 μg/kg/min (group M2), 3 μg/kg/min (group M3), or 4 μg/kg/min (group M4). An adequate response was defined as absence of hypotension (maternal SBP < 80% of baseline or SBP < 90 mmHg). The values for ED50 and ED95 of prophylactic methoxamine infusion were determined by probit regression model. The outcomes of maternal hemodynamics and fetal status were compared among the groups. RESULTS The calculated ED50 and ED95 (95% confidence interval) of prophylactic methoxamine infusion dose were 2.178 (95% CI 1.564 to 2.680) μg/kg/min and 4.821 (95% CI 3.951 to 7.017) μg/kg/min, respectively. The incidence of hypotension decreased with increasing methoxamine infusion dose (15/20, 11/20, 7/20 and 2/20 in group M1, M2, M3 and M4 respectively, P < 0.001). 1-min Apgar scores and umbilical arterial PaO2 were lower but umbilical arterial PaCO2 was higher in Group M1. No difference was found in the other incidence of adverse effects and neonatal outcomes among groups. CONCLUSIONS Under the conditions of this study, when prophylactic methoxamine infusion was given at a fixed-rate based on body weight for preventing spinal-induced hypotension in obstetric patients, the values for ED50 and ED95 were 2.178 μg/kg/min and 4.821 μg/kg/min respectively. CLINICAL TRIAL REGISTRATION Chinese Clinical Trial Registry (ChiCTR), registry number of clinical trial: ChiCTR-1,800,018,988 , date of registration: October 20, 2018.
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Pai MP, DeBacker KC. Modeling Kinetic Glomerular Filtration Rate in Adults with Stable and Unstable Kidney Function: Vancomycin as the Motivating Example. Pharmacotherapy 2020; 40:872-879. [DOI: 10.1002/phar.2442] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Manjunath P. Pai
- Department of Clinical Pharmacy College of Pharmacy University of Michigan Ann Arbor MichiganUSA
| | - Kenneth C. DeBacker
- Department of Clinical Pharmacy College of Pharmacy University of Michigan Ann Arbor MichiganUSA
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Martin-Tellez KS, van Houdt WJ, van Coevorden F, Colombo C, Fiore M. Isolated limb perfusion for soft tissue sarcoma: Current practices and future directions. A survey of experts and a review of literature. Cancer Treat Rev 2020; 88:102058. [PMID: 32619864 DOI: 10.1016/j.ctrv.2020.102058] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 06/11/2020] [Indexed: 12/15/2022]
Abstract
Soft tissue sarcomas constitute 1% of adult malignant tumors. They are a heterogeneous group of more than 50 different histologic types. Isolated limb perfusion is an established treatment strategy for locally advanced sarcomas. Since its adoption for sarcomas in 1992, after the addition of TNFα, few modifications have been done and although indications for the procedure are essentially the same across centers, technical details vary widely. The procedures mainly involves a 60 min perfusion with melphalan and TNFα under mild hyperthermia, achieving a limb preservation rate of 72-96%; with an overall response rates from 72 to 82.5% and an acceptable toxicity according to the Wieberdink scale. The local failure rate is 27% after a median follow up of 14-31 months compared to 40% of distant recurrences after a follow up of 12-22 months. Currently there is no consensus regarding the benefit of ILP per histotype, and the value of addition of radiotherapy or systemic treatment. Further developments towards individualized treatments will provide a better understanding of the population that can derive maximum benefit of ILP with the least morbidity.
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Affiliation(s)
- K S Martin-Tellez
- Fellow of the European School of Soft Tissue Sarcoma, Department of Surgical Oncology, The American British Cowdray Medical Center ABC, Mexico city, Mexico.
| | - W J van Houdt
- Sarcoma Unit, Department of Surgical Oncology, The Netherlands Cancer Institute Antoni van Leeuwenhoek, Amsterdam, the Netherlands
| | - F van Coevorden
- Sarcoma Unit, Department of Surgical Oncology, The Netherlands Cancer Institute Antoni van Leeuwenhoek, Amsterdam, the Netherlands
| | - C Colombo
- Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - M Fiore
- Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
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Drug dosing in the critically ill obese patient-a focus on sedation, analgesia, and delirium. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2020; 24:315. [PMID: 32513237 PMCID: PMC7282067 DOI: 10.1186/s13054-020-03040-z] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 05/27/2020] [Indexed: 12/12/2022]
Abstract
Practice guidelines provide clear evidence-based recommendations for the use of drug therapy to manage pain, agitation, and delirium associated with critical illness. Dosing recommendations however are often based on strategies used in patients with normal body habitus. Recommendations specific to critically ill patients with extreme obesity are lacking. Nonetheless, clinicians must craft dosing regimens for this population. This paper is intended to help clinicians design initial dosing regimens for medications commonly used in the management of pain, agitation, and delirium in critically ill patients with extreme obesity. A detailed literature search was conducted with an emphasis on obesity, pharmacokinetics, and dosing. Relevant manuscripts were reviewed and strategies for dosing are provided.
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50
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Levin G, Meyer R, Dior U, Gilad R, Benshushan A, Shushan A, Rottenstreich A. Outcome of methotrexate treatment for ectopic pregnancies among obese women. J Gynecol Obstet Hum Reprod 2020; 49:101790. [PMID: 32413523 DOI: 10.1016/j.jogoh.2020.101790] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 04/28/2020] [Accepted: 04/29/2020] [Indexed: 10/24/2022]
Abstract
OBJECTIVE Single dose administration of methotrexate (MTX) is considered the first line of treatment in selected patients with an ectopic pregnancy (EP). However, data regarding MTX efficacy among obese patients is limited. We sought to investigate the efficacy of MTX single dose regimen among obese patients MATERIAL AND METHODS: A retrospective cohort study conducted at a gynecology department in a tertiary teaching hospital, between January 2010 and December 2018, including women diagnosed with an EP and treated by a single-dose regimen of MTX. We compared success rate and gestation characteristics between obese and non-obese women. RESULTS Overall, 195 women were treated with single-dose intramuscular MTX for EP during the study period. Of those, 31 women (15.9%) were obese (BMI ≥ 30 kg/m2) and the rest 164 (84.1%) were of normal body weight. Median MTX dosage for the obese group was 95 milligrams (IQR 91-104) vs. 83 milligrams (IQR 78-87) for the non-obese group. Treatment success rate of the overall cohort was 66.6% (130/195) and treatment success rate of single-dose MTX was comparable between the obese and non-obese groups (64.5% vs. 67.0%, p = 0.78). Obese patients were older as compared to non-obese (median age 33 vs. 29, p = 0.03). In multivariate logistic regression analysis, percentage hCG change from day 1 to day 4 was the only factor associated with treatment success (aOR 1.02; 95%CI 1.01, 1.04, p < 0.001). CONCLUSION Single-dose MTX treatment among obese patients diagnosed with ectopic pregnancy led to similar success rates as compared to non-obese patients.
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Affiliation(s)
- Gabriel Levin
- The Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Raanan Meyer
- The Department of Obstetrics and Gynecology, the Chaim Sheba Medical Center, Ramat-Gan, Israel.
| | - Uri Dior
- The Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Ronit Gilad
- The Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Avi Benshushan
- The Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Asher Shushan
- The Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Amihai Rottenstreich
- The Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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