Bacterial growth dynamics and PKPD relationships of rifampicin and bedaquiline in BALB/c mice.

Abstract

BACKGROUND AND PURPOSE\nTranslational efforts in the evaluation of novel antitubercular drugs demand better integration of pharmacokinetic-pharmacodynamic data arising from preclinical protocols. However, parametric approaches that discriminate drug effect from the underlying bacterial growth dynamics have not been fully explored, making it difficult to translate and/or extrapolate preclinical findings to humans. This analysis aims to develop a drug-disease model which allows distinction between drug- and system-specific properties.\n\n\nEXPERIMENTAL APPROACH\nGiven their clinical relevance, rifampicin (RIF) and bedaquiline (BDQ) were used as paradigm compounds. A two-state model was used to describe bacterial growth dynamics. The approach assumes the existence of fast and slow-growing bacterial populations. Drug effect on the growth dynamics of each subpopulation was parameterised in terms of potency (EC50 -F and EC50 -S) and maximum killing rate.\n\n\nKEY RESULTS\nThe doubling time of the fast- and slow-growing population was estimated to be 25 h and 42 days, respectively. RIF was more potent against the fast-growing (EC50 -F = 4.8 mg/L), as compared to the slow-growing population (EC50 -S = 60.2 mg/L). BDQ showed higher potency relative to RIF (EC50 -F = 0.19 mg/L; EC50 -S = 3.04 mg/L). External validation procedures revealed an effect of infection route on the apparent potency of RIF.\n\n\nCONCLUSION AND IMPLICATIONS\nModel parameter estimates suggest that nearly maximum killing rate is achieved against fast-growing, but not against slow-growing populations at the tested doses. Evidence of differences in drug potency for each subpopulation may facilitate the translation of preclinical findings and improve the dose rationale for antitubercular drugs in humans.