Bacterial growth dynamics and pharmacokinetic-pharmacodynamic relationships of rifampicin and bedaquiline in BALB/c mice.

Abstract

Background and PurposeTranslational efforts in the evaluation of novel anti‐tubercular 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 that allows distinction between drug‐ and system‐specific properties.Experimental ApproachGiven their clinical relevance, rifampicin and bedaquiline were used as test 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 characterised in terms of potency (EC50‐F and EC50‐S) and maximum killing rate.Key ResultsThe doubling time of the fast‐ and slow‐growing population was estimated to be 25 h and 42 days, respectively. Rifampicin was more potent against the fast‐growing (EC50‐F = 4.8 mg·L−1), as compared with the slow‐growing population (EC50‐S = 60.2 mg·L−1). Bedaquiline showed higher potency than rifampicin (EC50‐F = 0.19 mg·L−1; EC50‐S = 3.04 mg·L−1). External validation procedures revealed an effect of infection route on the apparent potency of rifampicin.Conclusion and ImplicationsModel 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 anti‐tubercular drugs in humans.