Drug-drug interactions between bedaquiline and the antiretrovirals lopinavir/ritonavir and nevirapine in HIV-infected patients with drug-resistant TB

Bedaquiline is a new anti-TB drug, which is metabolized by cytochrome P450 (CYP) 3A4. Concomitant ART is important for all HIV-infected patients treated for TB, but several antiretrovirals inhibit or induce CYP3A4. Single-dose drug-drug interaction studies found no significant interactions with nevirapine or lopinavir/ritonavir, but these findings could be misleading, especially because of bedaquiline's long terminal t(1/2). We evaluated the effect of nevirapine and lopinavir/ritonavir on bedaquiline exposure. We conducted a parallel-group pharmacokinetic study of three groups of participants who were on bedaquiline as part of therapy for drug-resistant TB: no ART (HIV seronegative); nevirapine-based ART; and lopinavir/ritonavir-based ART. Non-compartmental analyses were done and exposure of bedaquiline and its M2 metabolite compared between the no-ART group and the two ART groups. We enrolled 48 participants: 17 in the no-ART group, 17 in the nevirapine group and 14 in the lopinavir/ritonavir group. The following median bedaquiline pharmacokinetic parameters were significantly higher in the lopinavir/ritonavir group than in the no-ART group: AUC(0-48) (67aEuroS002 versus 34aEuroS730 ngaEuroS center dot aEuroSh/mL; PaEuroS=aEuroS0.003); T-max (6 versus 4 h; PaEuroS=aEuroS0.003); and t(1/2) (55 versus 31 h; PaEuroS=aEuroS0.004). On multivariate analysis, bedaquiline exposure was increased by lopinavir/ritonavir, male sex and time on bedaquiline. Bedaquiline exposure was not significantly different between the nevirapine group and the no-ART group. M2 metabolite exposure was not significantly different in either of the antiretroviral groups compared with the no-ART group. Lopinavir/ritonavir significantly increased bedaquiline exposure. The clinical significance of this interaction remains to be determined.