Journal
CLINICAL PHARMACOLOGY & THERAPEUTICS
Volume 104, Issue 6, Pages 1208-1218Publisher
WILEY
DOI: 10.1002/cpt.1102
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Funding
- Swedish Research Council [521-2011-3442]
- Innovative Medicines Initiative Joint Undertaking from the European Union's Seventh Framework Programme (FP7/2007-2013) [115337]
- EFPIA
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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.
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