The multistate tuberculosis pharmacometric model: a semi-mechanistic pharmacokinetic-pharmacodynamic model for studying drug effects in an acute tuberculosis mouse model

AbstractThe Multistate Tuberculosis Pharmacometric (MTP) model, a pharmacokinetic-pharmacodynamic disease model, has been used to describe the effects of rifampicin onMycobacterium tuberculosis (M. tuberculosis) in vitro. The aim of this work was to investigate if the MTP model could be used to describe the rifampicin treatment response in an acute tuberculosis mouse model. Sixty C57BL/6 mice were intratracheally infected withM. tuberculosis H37Rv strain on Day 0. Fifteen mice received no treatment and were sacrificed on Days 1, 9 and 18 (5 each day). Twenty-five mice received oral rifampicin (1, 3, 9, 26 or 98  mg·kg−1·day−1; Days 1 –8; 5 each dose level) and were sacrificed on Day 9. Twenty mice received oral rifampicin (30 mg·kg−1·day−1; up to 8  days) and were sacrificed on Days 2, 3, 4 and 9 (5 each day). The MTP model was linked to a rifampicin population pharmacokinetic model to describe the change in colony forming units (CFU) in the lungs over time. The transfer rates between the different bacterial states were fixed to estimates fro m in vitro data. The MTP model described well the change in CFU over time after different exposure levels of rifampicin in an acute tuberculosis mouse model. Rifampicin significantly inhibited the growth of fast-multiplying bacteria and stimulated the death of fast- and slow-multiplying bacteria. Th e data did not support an effect of rifampicin on non-multiplying bacteria possibly due to the short duration of the study....
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research