Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection

Concomitant treatment of tuberculosis (TB) and HIV is recommended and improves outcomes. Bedaquiline is a novel drug for the treatment of multidrug-resistant (MDR) TB; combined use with antiretroviral drugs, nevirapine, or ritonavir-boosted lopinavir (LPV/r) is anticipated, but no clinical data from coinfected patients are available. Plasma concentrations of bedaquiline and its M2 metabolite after single doses were obtained from interaction studies with nevirapine or LPV/r in healthy volunteers. The antiretrovirals' effects on bedaquiline and M2 pharmacokinetics were assessed by nonlinear mixed-effects modeling. Potential dose adjustments were evaluated with simulations. No significant effects of nevirapine on bedaquiline pharmacokinetics were identified. LPV/r decreased bedaquiline and M2 clearances to 35% (relative standard error [RSE], 9.2%) and 58% (RSE, 8.4%), respectively, of those without comedication. As almost 3-fold (bedaquiline) and 2-fold (M2) increases in exposures during chronic treatment with LPV/r are expected, dose adjustments are suggested for evaluation. Efficacious, safe bedaquiline dosing for MDR-TB patients receiving antiretrovirals is important. Modeling results suggest that bedaquiline can be coadministered with nevirapine without dose adjustments. The predicted elevation of bedaquiline and M2 levels during LPV/r coadministration may be a safety concern, and careful monitoring is recommended. Further data are being collected in coinfected patients to determine whether dose adjustments are needed.