Bedaquiline pharmacokinetics in drug-resistant tuberculosis: from exposure variability to individualized therapy

Bedaquiline has transformed the treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) and is now a core component of contemporary all-oral regimens. However, translating its distinctive pharmacokinetic properties into individualized clinical management remains challenging. Bedaquiline exhibits food-enhanced absorption, extensive plasma protein binding, broad but heterogeneous tissue distribution, cytochrome P450 3A4-mediated metabolism to the N-monodesmethyl metabolite M2, and prolonged persistence caused by tissue sequestration and slow redistribution. These features contribute to substantial interindividual variability, clinically important drug-drug interactions, delayed accumulation, and residual exposure long after treatment discontinuation. This narrative review synthesizes current evidence on the absorption, distribution, metabolism, and elimination of bedaquiline; population pharmacokinetic models and determinants of exposure variability; target-site penetration; pharmacokinetics in children, pregnancy, organ dysfunction, and HIV coinfection; and clinically relevant interactions with antituberculosis and antiretroviral drugs. We also critically evaluate exposure-efficacy and exposure-toxicity relationships, including evidence from bedaquiline-containing multidrug regimens, and examine the potential roles of therapeutic drug monitoring, minimum inhibitory concentration-normalized exposure indices, and model-informed precision dosing. Current evidence supports administration with food, avoidance of potent CYP3A inducers, caution during prolonged CYP3A inhibition, and intensified electrocardiographic and electrolyte monitoring when QT-prolonging agents are combined. Nevertheless, no plasma, M2, area-under-the-curve, or susceptibility-normalized exposure target has been prospectively validated for routine dose adjustment. Covariate effects identified by population models are inconsistent across cohorts, and pharmacokinetic evidence remains limited in several special populations. Individualized assessment may therefore be appropriate when clinically meaningful uncertainty exists, but empirical departure from standard dosing is not currently justified. Progress toward precision dosing will require standardized sampling and susceptibility testing, measurement of unbound and target-site exposure, externally validated pharmacokinetic-pharmacodynamic models, and prospective demonstration that exposure-guided interventions improve clinical outcomes.