Impact of Postural Restrictions on Tetrabenazine Pharmacokinetics in Healthy Volunteers: A Randomized Crossover Study Emphasizing Variance Minimization Strategies in Good Clinical Practice-Guided Bioequivalence Research

IF 2.7

Future pharmacology Pub Date : 2025-11-10 DOI:10.3390/futurepharmacol5040067

Nirav Chandegara, Shrikalp Deshpande, Bhupendra G. Prajapati, Anup K. Singh, Dignesh Khunt

{"title":"Impact of Postural Restrictions on Tetrabenazine Pharmacokinetics in Healthy Volunteers: A Randomized Crossover Study Emphasizing Variance Minimization Strategies in Good Clinical Practice-Guided Bioequivalence Research","authors":"Nirav Chandegara, Shrikalp Deshpande, Bhupendra G. Prajapati, Anup K. Singh, Dignesh Khunt","doi":"10.3390/futurepharmacol5040067","DOIUrl":null,"url":null,"abstract":"Background: Tetrabenazine, a VMAT2 inhibitor used for hyperkinetic disorders, shows considerable pharmacokinetic variability due to extensive first-pass metabolism. Standardization of clinical trial conditions, including posture, may reduce variability and improve bioequivalence assessments. Objective: The aim of this study was to determine the impact of postural restriction on the pharmacokinetics of tetrabenazine and its active metabolite, dihydrotetrabenazine (HTBZ), under controlled conditions. Methods: A randomized, open-label, four-period replicate crossover study enrolled 72 healthy fasted adults who received a single 25 mg tetrabenazine dose under two conditions: 4 h semirecumbent posture versus unrestricted movement. Plasma drug concentrations were measured across 36 h using validated LC–MS/MS method. Pharmacokinetic parameters were estimated via non-compartmental analysis and compared with Wilcoxon signed-rank tests. Results: Postural restriction significantly increased tetrabenazine exposure (AUC0–t: +16.4%, p < 0.0001) and half-life (p = 0.002), with a nonsignificant rise in Cmax. For HTBZ, Cmax decreased (−16.2%, p = 0.018), whereas AUC was unchanged. Parent-to-metabolite ratios increased by 24–29%. Replicate design analyses showed reduced intra-subject variability for tetrabenazine AUC with posture control (~24% vs. >28%). Simulation suggested that posture restriction could lower sample size requirements by 15–30% in two-period average bioequivalence trials. Conclusions: Maintaining a semirecumbent posture after dosing enhances tetrabenazine’s bioavailability, attenuates early metabolite formation, and reduces pharmacokinetic variability. Incorporating posture control into bioequivalence trial protocols may optimize study design, reduce participant exposure, and align with ICH-GCP ethical principles.","PeriodicalId":520944,"journal":{"name":"Future pharmacology","volume":"5 4","pages":"67-67"},"PeriodicalIF":2.7000,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Future pharmacology","FirstCategoryId":"0","ListUrlMain":"https://doi.org/10.3390/futurepharmacol5040067","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Tetrabenazine, a VMAT2 inhibitor used for hyperkinetic disorders, shows considerable pharmacokinetic variability due to extensive first-pass metabolism. Standardization of clinical trial conditions, including posture, may reduce variability and improve bioequivalence assessments. Objective: The aim of this study was to determine the impact of postural restriction on the pharmacokinetics of tetrabenazine and its active metabolite, dihydrotetrabenazine (HTBZ), under controlled conditions. Methods: A randomized, open-label, four-period replicate crossover study enrolled 72 healthy fasted adults who received a single 25 mg tetrabenazine dose under two conditions: 4 h semirecumbent posture versus unrestricted movement. Plasma drug concentrations were measured across 36 h using validated LC–MS/MS method. Pharmacokinetic parameters were estimated via non-compartmental analysis and compared with Wilcoxon signed-rank tests. Results: Postural restriction significantly increased tetrabenazine exposure (AUC0–t: +16.4%, p < 0.0001) and half-life (p = 0.002), with a nonsignificant rise in Cmax. For HTBZ, Cmax decreased (−16.2%, p = 0.018), whereas AUC was unchanged. Parent-to-metabolite ratios increased by 24–29%. Replicate design analyses showed reduced intra-subject variability for tetrabenazine AUC with posture control (~24% vs. >28%). Simulation suggested that posture restriction could lower sample size requirements by 15–30% in two-period average bioequivalence trials. Conclusions: Maintaining a semirecumbent posture after dosing enhances tetrabenazine’s bioavailability, attenuates early metabolite formation, and reduces pharmacokinetic variability. Incorporating posture control into bioequivalence trial protocols may optimize study design, reduce participant exposure, and align with ICH-GCP ethical principles.

查看原文本刊更多论文

体位限制对健康志愿者四苯那嗪药代动力学的影响：一项强调良好临床实践指导下生物等效性研究中方差最小化策略的随机交叉研究

背景：Tetrabenazine是一种用于多运动障碍的VMAT2抑制剂，由于广泛的首过代谢，显示出相当大的药代动力学变异性。临床试验条件（包括姿势）的标准化可以减少可变性并改善生物等效性评估。目的：在控制条件下，研究体位限制对丁苯那嗪及其活性代谢物二氢丁苯那嗪（HTBZ）药代动力学的影响。方法：一项随机、开放标签、四期重复交叉研究纳入了72名健康禁食的成年人，他们在两种情况下接受单剂量25 mg丁苯那嗪：半卧位姿势4小时和无限制运动。采用经验证的LC-MS /MS方法测定36 h内的血浆药物浓度。通过非区室分析估计药代动力学参数，并与Wilcoxon符号秩检验进行比较。结果：体位限制显著增加了丁苯那嗪暴露量（AUC0-t: +16.4%, p < 0.0001）和半衰期（p = 0.002）， Cmax无显著升高。对于HTBZ， Cmax降低（- 16.2%,p = 0.018），而AUC不变。母体与代谢物之比增加了24-29%。重复设计分析显示，在姿势控制的情况下，丁苯那嗪AUC的受试者内部变异性降低（~24% vs >28%）。模拟表明，在两期平均生物等效性试验中，姿势限制可以将样本量要求降低15-30%。结论：给药后保持半卧位可提高丁苯那嗪的生物利用度，减少早期代谢物的形成，并降低药代动力学变异性。将姿势控制纳入生物等效性试验方案可以优化研究设计，减少受试者暴露，并符合ICH-GCP伦理原则。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊