Forecasting Clinical Dose-Response From Preclinical Studies in Tuberculosis Research: Translational Predictions With Rifampicin.

ABSTRACT: A crucial step for accelerating tuberculosis drug development is bridging the gap between preclinical and clinical trials. In this study, we developed a preclinical model-informed translational approach to predict drug effects across preclinical systems and early clinical trials using the in vitro-based Multistate Tuberculosis Pharmacometric (MTP) model using rifampicin as an example. The MTP model predicted rifampicin biomarker response observed in 1) a hollow-fiber infection model, 2) a murine study to determine pharmacokinetic/pharmacodynamic indices, and 3) several clinical phase IIa early bactericidal activity (EBA) studies. In addition, we predicted rifampicin biomarker response at high doses of up to 50 mg/kg, leading to an increased median EBA_{0-2 days} (90% prediction int

SUBMITTER: Wicha SG 

PROVIDER: S-EPMC6282494 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature