Impact of lopinavir-ritonavir or nevirapine on bedaquiline exposures and potential implications for patients with tuberculosis-HIV coinfection

Abstract

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. (These studies have been registered at ClinicalTrials.gov under registration numbers NCT00828529 [study C110] and NCT00910806 [study C117].).

Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Figures

FIG 1

Prediction- and variability-corrected visual predictive check of study C117 (upper) and study C110 (lower), showing the 5th, 50th, and 95th percentiles (lines) of observed data (dots) (sampling points were before and 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 120, 168, 216, 264, and 336 h after the dose) and the 95% confidence intervals (shaded areas) of the same percentiles of bedaquiline and M2 data simulated from the model.

FIG 2

Simulated weekly average concentration (Cavg) values (means and interquartile ranges) for BDQ (upper) and M2 (lower) when BDQ is administered at standard doses alone, at standard doses with ritonavir-boosted lopinavir throughout treatment, and at recommended adjusted doses with ritonavir-boosted lopinavir.

FIG 3

Box plots showing model-derived exposures of bedaquiline (upper) and its M2 metabolite (lower) up to 336 h (AUC0–336h) (left) and in total (AUCinf) (right) for the 16 individuals participating in study C110, following a single dose of 400 mg of bedaquiline administered alone or with steady-state ritonavir-boosted lopinavir. Black squares in the left panels represent average observed AUC0–336h values during the first dosing occasion for the 8 individuals who then received bedaquiline alone and the 8 individuals who received bedaquiline and LPV/r concomitantly.