Forecasting clinical dose-response from pre-clinical studies in tuberculosis research - translational predictions with rifampicin

Sebastian G. Wicha, Oskar Clewe, Robin J. Svensson, Stephen H. Gillespie, Yanmin Hu, Anthony R.m. Coates, Ulrika S.h. Simonsson

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Abstract

A crucial step for accelerating tuberculosis drug development is bridging the gap between pre‐clinical and clinical trials. In this study, we developed a pre‐clinical model‐informed translational approach to predict drug effects across pre‐clinical 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 (i) a hollow‐fiber infection model, (ii) a murine study to determine PK/PD indices, and (iii) 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.
Original languageEnglish
JournalClinical Pharmacology & Therapeutics
VolumeEarly View
Early online date19 Jun 2018
DOIs
Publication statusE-pub ahead of print - 19 Jun 2018

Keywords

  • Forward translational
  • Tuberculosis
  • Rifampicin

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