Table 1_Bedaquiline pharmacokinetics in drug-resistant tuberculosis: from exposure variability to individualized therapy.xlsx

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.</p>