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Clin Pharmacol Ther. 2018 Dec;104(6):1208-1218. doi: 10.1002/cpt.1102. Epub 2018 Jun 19.

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

Author information

1
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
2
Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany.
3
School of Medicine, University of St Andrews, St Andrews, UK.
4
Institute for Infection and Immunity, St George's University of London, London, UK.

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 EBA0-2 days (90% prediction interval) of 0.513 log CFU/mL/day (0.310; 0.701) compared to the standard dose of 10 mg/kg of 0.181 log/CFU/mL/day (0.076; 0.483). These results suggest that the translational approach could assist in the selection of drugs and doses in early-phase clinical tuberculosis trials.

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