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

Background and purpose: Translational 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 approach: Given 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 results: The 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 implications: Model 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.