Extrapolation of lung pharmacokinetics of bedaquiline across species using physiologically-based pharmacokinetic modelling.

AIMS: Bedaquiline (BDQ) is a first-in-class diarylquinoline (DARQ) and a potent anti-tuberculosis drug, vital in combating multi-drug resistant tuberculosis (TB). Understanding its lung pharmacokinetics (PK) across species is crucial for effective clinical translation. This study aimed to extrapolate BDQ's lung PK from preclinical species to humans, focusing on healthy and TB-infected lung tissue.

METHODS

Physiologically-based PK (PBPK) modelling was employed to simulate BDQ's lung distribution in various pulmonary micro-compartments, including cellular lesions and caseous granulomas, using data from mice, rats and dogs. Complex interactions, such as lysosomal trapping within macrophages and anomalous diffusion within the caseum, utilising a catenary model and a time-dependent rate, were incorporated into the models to accurately represent BDQ's unique PK profile.

RESULTS

The study revealed intricate dynamics of BDQ's lung distribution, with only free concentrations in lysosomes of macrophages surpassing the MIC of Mycobacterium tuberculosis in both mice and humans, indicating intracellular accumulation which may further explain the proven drug's efficacy. Moreover, during the course of treatment in humans, adequate drug levels were achieved near the cellular rim but penetration into the inner caseous core was predicted to be limited.

CONCLUSIONS

Understanding BDQ's lung PK is essential for optimising dosing strategies with new companion drugs. The findings underscore the need to characterise BDQ distribution within the caseum, as it shows extensive caseum binding. Moreover, the developed PBPK model can be applied to new promising DARQ analogues, facilitating their development as effective TB treatments.