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.

Multidrug-resistant tuberculosis and beyond: an updated analysis of the current evidence on bedaquiline

“…This CYP P450-mediated metabolism opens the issue of DDIs with ARVs [39]. BRILL et al [39] observed that bedaquiline clearance was reduced by NVP to 82% and M2 clearance increased to 119% of their original values, underpinning no clinically significant interactions. Conversely, LPV/r significantly reduced both bedaquiline and M2 clearance, increasing their concentrations.…”

“…Information about cardiac safety of bedaquiline in association with clofazimine or fluoroquinolones is still scanty [37]. The GUGLIELMETTI et al [35] study suggests that co-administration of clofazimine is not associated with QTc prolongation, while the administration of both high-dose moxifloxacin and methadone was associated with QTcF values >500 ms. New information on drug-drug interactions (DDIs) with antiretrovirals (ARVs) like lopinavir/ritonavir (LPV/r) and nevirapine (NVP) can be retrieved from pharmacokinetic (PK) studies [38,39]. The PK profile of bedaquiline is characterised by extensive tissue distribution and an extremely long terminal half-life, exceeding 5 months [40].…”

“…Bedaquiline primarily undergoes N-demethylation catalysed by the cytochrome P450 (CYP) 3A4 enzyme, forming a three-to six-fold less active metabolite called M2 [41]. This CYP P450-mediated metabolism opens the issue of DDIs with ARVs [39]. BRILL et al [39] observed that bedaquiline clearance was reduced by NVP to 82% and M2 clearance increased to 119% of their original values, underpinning no clinically significant interactions.…”

State‐of‐the‐Art Review of HIV‐TB Coinfection in Special Populations

“…Bedaquiline, which is metabolized by CYP 3A4, can be used with nevirapine (and presumably with raltegravir or dolutegravir). Efavirenz reduces and ritonavir‐boosted lopinavir increases bedaquiline concentrations, yet the clinical relevance of these interactions and the effectiveness of potential dose modifications in mitigating the DDIs has not been explored in patients . Dosing for bedaquiline in children is still being established; the magnitude of DDIs with this drug and efavirenz or ritonavir‐boosted lopinavir for children cannot be extrapolated directly from adult studies, particularly for children aged <5 years, in whom expression of CYP3A isoforms is different from adults and varies by age.…”

“…Efavirenz reduces and ritonavir-boosted lopinavir increases bedaquiline concentrations, yet the clinical relevance of these interactions and the effectiveness of potential dose modifications in mitigating the DDIs has not been explored in patients. [59][60][61] Dosing for bedaquiline in children is still being established; the magnitude of DDIs with this drug and efavirenz or ritonavir-boosted lopinavir for children cannot be extrapolated directly from adult studies, particularly for children aged <5 years, in whom expression of CYP3A isoforms is different from adults and varies by age. Mechanistic models or models that consider CYP3A maturation function are available to predict drug PKs in children but not to predict the effects of inducers or inhibitors of CYP3A on substrates of that enzyme.…”