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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 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.

SUBMITTER: Wicha SG 

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

REPOSITORIES: biostudies-literature

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

Wicha Sebastian G SG   Clewe Oskar O   Svensson Robin J RJ   Gillespie Stephen H SH   Hu Yanmin Y   Coates Anthony R M ARM   Simonsson Ulrika S H USH  

Clinical pharmacology and therapeutics 20180619 6


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  ...[more]

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