Concomitant nevirapine impacts pharmacokinetic exposure to the antimalarial artemether-lumefantrine in African children

• Published in: PloS one 2017-10, Vol.12 (10), p.e0186589
• Main Authors: Huang, Liusheng, Carey, Vincent, Lindsey, Jane C, Marzan, Florence, Gingrich, David, Graham, Bobbie, Barlow-Mosha, Linda, Ssemambo, Phionah K, Kamthunzi, Portia, Nachman, Sharon, Parikh, Sunil, Aweeka, Francesca T
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; Africa South of the Sahara; AIDS; Antimalarials - pharmacokinetics; Antiretroviral agents; Antiretroviral drugs; Antiretroviral therapy; Artemether; Artemisinin; Artemisinins - administration & dosage; Artemisinins - pharmacokinetics; Biology and Life Sciences; Child; Child, Preschool; Children; Clinical outcomes; Collaboration; Complications and side effects; Control methods; Cytochrome; Cytochrome P450; Dihydroartemisinin; Dosage and administration; Drug dosages; Drug therapy; Drugs; Enrollments; Ethanolamines - administration & dosage; Ethanolamines - pharmacokinetics; Exposure; Female; Fluorenes - administration & dosage; Fluorenes - pharmacokinetics; HIV; Human immunodeficiency virus; Humans; Lumefantrine; Malaria; Male; Medicine; Medicine and Health Sciences; Nevirapine; Nevirapine - therapeutic use; Parasites; People and Places; Pharmacokinetics; Pharmacology; Pharmacy; Plasmodium falciparum; Public health; Therapy; Vector-borne diseases
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0186589

The antiretroviral drug nevirapine and the antimalarial artemisinin-based combination therapy artemether-lumefantrine are commonly co-administered to treat malaria in the context of HIV. Nevirapine is a known inhibitor of cytochrome P450 3A4, which metabolizes artemether and lumefantrine. To address the concern that the antiretroviral nevirapine impacts the antimalarial artemether-lumefantrine pharmacokinetics, a prospective non-randomized controlled study in children presenting with uncomplicated malaria and HIV in sub-Saharan Africa was carried out. Participants received artemether-lumefantrine (20/120 mg weight-based BID) for 3 days during nevirapine-based antiretroviral therapy (ART) co-administration (158-266 mg/m2 QD). HIV positive participants who were not yet on ART drugs were also enrolled as the control group. The target enrollment was children aged 3-12 years (n = 24 in each group). Intensive pharmacokinetics after the last artemether-lumefantrine dose was assessed for artemether, its active metabolite dihydroartemisinin, and lumefantrine. Pharmacokinetic parameters (area under the plasma concentration vs. time curve (AUC), maximum concentration and day 7 lumefantrine concentrations) were estimated using non-compartmental methods and compared to controls. Nineteen children (16 on nevirapine and three not on ART) enrolled. Fifteen of the 16 (aged 4 to 11 years) on nevirapine-based ART were included in the pharmacokinetic analysis. Due to evolving WHO HIV treatment guidelines, insufficient children were enrolled in the control group (n = 3), so the pharmacokinetic data were compared to a historical control group of 20 HIV-uninfected children 5-12 years of age who also presented with malaria and underwent identical study procedures. Decreases of pharmacokinetic exposure [as estimated by AUC (AUC0-8hr)] were marginally significant for artemether (by -46%, p = 0.08) and dihydroartemisinin (-22%, p = 0.06) in the children on nevirapine-based ART, compared to when artemether-lumefantrine was administered alone. Similarly, peak concentration was decreased by 50% (p = 0.07) for artemether and 36% (p = 0.01) for dihydroartemisinin. In contrast, exposure to lumefantrine increased significantly in the context of nevirapine [AUC0-120hr:123% (p