title: Drug-drug interactions between bedaquiline and the antiretrovirals lopinavir/ritonavir and nevirapine in HIV-infected patients with drug-resistant TB.
abstract: OBJECTIVE
  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 t1/2. We evaluated the effect of nevirapine and lopinavir/ritonavir on bedaquiline exposure.
  
  
  METHODS
  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.
  
  
  RESULTS
  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) (67 002 versus 34 730 ng · h/mL; P = 0.003); Tmax (6 versus 4 h; P = 0.003); and t1/2 (55 versus 31 h; P = 0.004). 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.
  
  
  CONCLUSIONS
  Lopinavir/ritonavir significantly increased bedaquiline exposure. The clinical significance of this interaction remains to be determined.
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: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
authors.affiliation: Brooklyn Chest Hospital, Cape Town, South Africa.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hughes
authors.affiliation: Médecins sans Frontières, Khayelitsha, Cape Town, South Africa.
authors.forename: Sweetness
authors.initials: S
authors.lastname: Siwendu
authors.affiliation: Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa Right to Care, Johannesburg, South Africa.
authors.forename: Francesca
authors.initials: F
authors.lastname: Conradie
authors.affiliation: Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Ebrahim
authors.initials: E
authors.lastname: Variava
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa gary.maartens@uct.ac.za.
authors.forename: Gary
authors.initials: G
authors.lastname: Maartens
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D064687:Diarylquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D004338:Drug Combinations; D004347:Drug Interactions; D016903:Drug Monitoring; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D061466:Lopinavir / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D019829:Nevirapine / Q000494:pharmacology / Q000627:therapeutic use*; D019438:Ritonavir / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; D004338:Drug Combinations; C558899:lopinavir-ritonavir drug combination; D061466:Lopinavir; C493870:bedaquiline; D019829:Nevirapine; D019438:Ritonavir