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