Mockeliunas Laurynas, Faraj Alan, van Wijk Rob C, Upton Caryn M, van den Hoogen Gerben, Diacon Andreas H, Simonsson Ulrika S H
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
TASK, Cape Town, South Africa.
Front Pharmacol. 2023 Apr 13;14:1150243. doi: 10.3389/fphar.2023.1150243. eCollection 2023.
A critical step in tuberculosis (TB) drug development is the Phase 2a early bactericidal activity (EBA) study which informs if a new drug or treatment has short-term activity in humans. The aim of this work was to present a standardized pharmacometric model-based early bactericidal activity analysis workflow and determine sample sizes needed to detect early bactericidal activity or a difference between treatment arms. Seven different steps were identified and developed for a standardized pharmacometric model-based early bactericidal activity analysis approach. Non-linear mixed effects modeling was applied and different scenarios were explored for the sample size calculations. The sample sizes needed to detect early bactericidal activity given different TTP slopes and associated variability was assessed. In addition, the sample sizes needed to detect effect differences between two treatments given the impact of different TTP slopes, variability in TTP slope and effect differences were evaluated. The presented early bactericidal activity analysis approach incorporates estimate of early bactericidal activity with uncertainty through the model-based estimate of TTP slope, variability in TTP slope, impact of covariates and pharmacokinetics on drug efficacy. Further it allows for treatment comparison or dose optimization in Phase 2a. To detect early bactericidal activity with 80% power and at a 5% significance level, 13 and 8 participants/arm were required for a treatment with a TTP-EBA as low as 11 h when accounting for variability in pharmacokinetics and when variability in TTP slope was 104% [coefficient of variation (CV)] and 22%, respectively. Higher sample sizes are required for smaller early bactericidal activity and when pharmacokinetics is not accounted for. Based on sample size determinations to detect a difference between two groups, TTP slope, variability in TTP slope and effect difference between two treatment arms needs to be considered. In conclusion, a robust standardized pharmacometric model-based EBA analysis approach was established in close collaboration between microbiologists, clinicians and pharmacometricians. The work illustrates the importance of accounting for covariates and drug exposure in EBA analysis in order to increase the power of detecting early bactericidal activity for a single treatment arm as well as differences in EBA between treatments arms in Phase 2a trials of TB drug development.
结核病（TB）药物研发中的关键一步是2a期早期杀菌活性（EBA）研究，该研究可确定一种新药或治疗方法在人体中是否具有短期活性。这项工作的目的是提出一种基于标准化药代动力学模型的早期杀菌活性分析工作流程，并确定检测早期杀菌活性或治疗组间差异所需的样本量。针对基于标准化药代动力学模型的早期杀菌活性分析方法，确定并制定了七个不同步骤。应用了非线性混合效应建模，并针对样本量计算探索了不同场景。评估了在给定不同TTP斜率和相关变异性的情况下检测早期杀菌活性所需的样本量。此外，还评估了在考虑不同TTP斜率、TTP斜率变异性和效应差异影响的情况下，检测两种治疗方法之间效应差异所需的样本量。所提出的早期杀菌活性分析方法通过基于模型的TTP斜率估计、TTP斜率变异性、协变量和药代动力学对药物疗效的影响，将早期杀菌活性估计与不确定性结合起来。此外，它还允许在2a期进行治疗比较或剂量优化。为了在80%的检验效能和5%的显著性水平下检测早期杀菌活性，当考虑药代动力学变异性且TTP斜率变异性分别为104%[变异系数（CV）]和22%时，对于TTP-EBA低至11小时的治疗，每组需要13名和8名参与者。早期杀菌活性越小且不考虑药代动力学时，所需样本量越大。基于检测两组间差异的样本量确定，需要考虑TTP斜率、TTP斜率变异性和两个治疗组间的效应差异。总之，微生物学家、临床医生和药代动力学家密切合作，建立了一种强大的基于标准化药代动力学模型的EBA分析方法。这项工作说明了在EBA分析中考虑协变量和药物暴露的重要性，以便在结核病药物研发的2a期试验中提高检测单个治疗组早期杀菌活性以及治疗组间EBA差异的效能。
