Improved power for TB phase IIa trials using a model-based pharmacokinetic-pharmacodynamic approach compared with commonly used analysis methods

Abstract

Background : The demand for new anti-TB drugs is high, but development programmes are long and costly. Consequently there is a need for new strategies capable of accelerating this process. Objectives : To explore the power to find statistically significant drug effects using a model-based pharmacokinetic–pharmacodynamic approach in comparison with the methods commonly used for analysing TB Phase IIa trials. Methods : Phase IIa studies of four hypothetical anti-TB drugs (labelled A, B, C and D), each with a different mechanism of action, were simulated using the multistate TB pharmacometric (MTP) model. cfu data were simulated over 14 days for patients taking once-daily monotherapy at four different doses per drug and a reference (10 mg/kg rifampicin). The simulated data were analysed using t-test, ANOVA, mono- and bi-exponential models and a pharmacokinetic–pharmacodynamic model approach (MTP model) to establish their respective power to find a drug effect at the 5% significance level. Results : For the pharmacokinetic–pharmacodynamic model approach, t-test, ANOVA, mono-exponential model and bi-exponential model, the sample sizes needed to achieve 90% power were: 10, 30, 75, 20 and 30 (drug A); 30, 75, 245, 75 and 105 (drug B); 70, >1250, 315, >1250 and >1250 (drug C); and 30, 110, 710, 170 and 185 (drug D), respectively. Conclusions : A model-based design and analysis using a pharmacokinetic–pharmacodynamic approach can reduce the number of patients required to determine a drug effect at least 2-fold compared with current methodologies. This could significantly accelerate early-phase TB drug development.