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Forecasting Clinical Dose–Response From Preclinical Studies in Tuberculosis Research: Translational Predictions With Rifampicin
Author(s) -
Wicha Sebastian G.,
Clewe Oskar,
Svensson Robin J.,
Gillespie Stephen H.,
Hu Yanmin,
Coates Anthony R.M.,
Simonsson Ulrika S.H.
Publication year - 2018
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1102
Subject(s) - rifampicin , medicine , biomarker , pharmacodynamics , tuberculosis , clinical trial , pharmacology , pharmacokinetics , phases of clinical research , drug development , drug , oncology , pathology , biology , biochemistry
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 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.