Abstract
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. 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. 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. 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); a...Continue Reading
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