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We used advanced model-based methods to characterize the relationship between individual rifampicin exposure and antituberculosis treatment response. With data from a trial investigating high-dose rifampicin, a significant relation could be derived, and the clinical impact of increased doses was predicted.

ObjectivesBedaquiline is the first drug of a new class approved for the treatment of TB in decades. Bedaquiline is metabolized by cytochrome P450 (CYP) 3A4 to a less-active M2 metabolite. Its terminal half-life is extremely long (5–6 months), complicating evaluations of drug–drug interactions. Rifampicin and rifapentine, two anti-TB drugs now being optimized to shorten TB treatment duration, are potent inducers of CYP3A4. This analysis aimed to predict the effect of repeated doses of rifampicin or rifapentine on the steady-state pharmacokinetics of bedaquiline and its M2 metabolite from single-dose data using a model-based approach.MethodsPharmacokinetic data for bedaquiline and M2 were obtained from a Phase I study involving 32 individuals each receiving two doses of bedaquiline, alone or together with multiple-dose rifampicin or rifapentine. Sampling was performed over 14 days following each bedaquiline dose. Pharmacokinetic analyses were performed using non-linear mixed-effects modelling. Models were used to simulate potential dose adjustments.ResultsRifamycin co-administration increased bedaquiline clearance substantially: 4.78-fold [relative standard error (RSE) 9.10%] with rifampicin and 3.96-fold (RSE 5.00%) with rifapentine. Induction of M2 clearance was equally strong. Average steady-state concentrations of bedaquiline and M2 are predicted to decrease by 79% and 75% when given with rifampicin or rifapentine, respectively. Simulations indicated that increasing the bedaquiline dosage to mitigate the interaction would yield elevated M2 concentrations during the first treatment weeks.ConclusionsRifamycin antibiotics reduce bedaquiline concentrations substantially. In line with current treatment guidelines for drug-susceptible TB, concomitant use is not recommended, even with dose adjustment.

Albumin concentration and body weight are altered in patients with multidrug‐resistant tuberculosis (MDR‐TB) and change during the long treatment period, potentially affecting drug disposition. We here describe the pharmacokinetics (PKs) of the novel anti‐TB drug bedaquiline and its metabolite M2 in 335 patients with MDR‐TB receiving 24 weeks of bedaquiline on top of a longer individualized background regimen. Semiphysiological models were developed to characterize the changes in weight and albumin over time. Bedaquiline and M2 disposition were well described by three and one‐compartment models, respectively. Weight and albumin were correlated, typically increasing after the start of treatment, and significantly affected bedaquiline and M2 plasma disposition. Additionally, age and race were significant covariates, whereas concomitant human immunodeficiency virus (HIV) infection, sex, or having extensively drug‐resistant TB was not. This is the first population model simultaneously characterizing bedaquiline and M2 PKs in its intended use population. The developed model will be used for efficacy and safety exposure‐response analyses.