title: Confirming model-predicted pharmacokinetic interactions between bedaquiline and lopinavir/ritonavir or nevirapine in patients with HIV and drug-resistant tuberculosis.
abstract: Bedaquiline and its metabolite M2 are metabolised by CYP3A4. The antiretrovirals ritonavir-boosted lopinavir (LPV/r) and nevirapine inhibit and induce CYP3A4, respectively. Here we aimed to quantify nevirapine and LPV/r drug-drug interaction effects on bedaquiline and M2 in patients co-infected with HIV and multidrug-resistant tuberculosis (MDR-TB) using population pharmacokinetic (PK) analysis and compare these with model-based predictions from single-dose studies in subjects without TB. An observational PK study was performed in three groups of MDR-TB patients during bedaquiline maintenance dosing: HIV-seronegative patients (n = 17); and HIV-infected patients using antiretroviral therapy including nevirapine (n = 17) or LPV/r (n = 14). Bedaquiline and M2 samples were collected over 48 h post-dose. A previously developed PK model of MDR-TB patients was used as prior information to inform parameter estimation using NONMEM. The model was able to describe bedaquiline and M2 concentrations well, with estimates close to their priors and earlier model-based interaction effects from single-dose studies. Nevirapine changed bedaquiline clearance to 82% (95% CI 67-99%) and M2 clearance to 119% (92-156%) of their original values, indicating no clinically significant interaction. LPV/r substantially reduced bedaquiline clearance to 25% (17-35%) and M2 clearance to 59% (44-69%) of original values. This work confirms earlier model-based predictions of nevirapine and LPV/r interaction effects on bedaquiline and M2 clearance from subjects without TB in single-dose studies, in MDR-TB/HIV co-infected patients studied here. To normalise bedaquiline exposure in patients with concomitant LPV/r therapy, an adjusted bedaquiline dosing regimen is proposed for further study.
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Margreke J E
authors.initials: MJ
authors.lastname: Brill
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Elin M
authors.initials: EM
authors.lastname: Svensson
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Mishal
authors.initials: M
authors.lastname: Pandie
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Gary
authors.initials: G
authors.lastname: Maartens
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. Electronic address: Mats.Karlsson@farmbio.uu.se.
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D000995:Antitubercular Agents / Q000493:pharmacokinetics*; D064687:Diarylquinolines / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D061466:Lopinavir / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000493:pharmacokinetics; D019438:Ritonavir / Q000493:pharmacokinetics; D018088:Tuberculosis, Multidrug-Resistant / Q000150:complications* / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D064687:Diarylquinolines; D061466:Lopinavir; C493870:bedaquiline; D019829:Nevirapine; D019438:Ritonavir
keywords: Bedaquiline; Drug–drug interactions; Nevirapine; Population pharmacokinetic modelling; Prior information; Ritonavir-boosted lopinavir