Forecasting Clinical Dose-Response From Preclinical Studies in Tuberculosis Research: Translational Predictions With Rifampicin.
Clin Pharmacol Ther
; 104(6): 1208-1218, 2018 12.
Article
de En
| MEDLINE
| ID: mdl-29700814
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Rifampicine
/
Tuberculose pulmonaire
/
Simulation numérique
/
/
Antibiotiques antituberculeux
/
Modèles biologiques
/
Mycobacterium tuberculosis
Type d'étude:
Diagnostic_studies
/
Prognostic_studies
/
Risk_factors_studies
Limites:
Animals
/
Humans
Langue:
En
Journal:
Clin Pharmacol Ther
Année:
2018
Type de document:
Article
Pays d'affiliation:
Suède