An Individual Participant Data Population Pharmacokinetic Meta-analysis of Drug-Drug Interactions between Lumefantrine and Commonly Used Antiretroviral Treatment
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Date
2020
Journal Title
Journal ISSN
Volume Title
Publisher
Antimicrobial agents and chemotherapy
Abstract
Treating malaria in HIV-coinfected individuals should consider potential drug-drug interactions. Artemether-lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an
enzyme that commonly used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from 10 studies with 6,100 lumefantrine concentrations from 793 nonpregnant adult participants (41% HIV-malaria-coinfected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers). Lumefantrine exposure increased 3.4-fold with coadministration of lopinavirritonavir- based antiretroviral therapy (ART), while it decreased by 47% with efavirenzbased ART and by 59% in the patients with rifampin-based antituberculosis treatment. Nevirapine- or dolutegravir-based ART and malaria or HIV infection were not associated with significant effects. Monte Carlo simulations showed that those on concomitant efavirenz or rifampin have 49% and 80% probability of day 7 concentrations 200 ng/ml, respectively, a threshold associated with an increased risk of treatment failure. The risk of achieving subtherapeutic concentrations increases with larger body weight. An extended 5-day and 6-day artemether-lumefantrine regimen is predicted to overcome these drug-drug interactions with efavirenz and rifampin, respectively.
Description
Keywords
Uncomplicated malaria, Lumefantrine, Human immunodeficiency virus, Drug-drug interactions, Population pharmacokinetics
Citation
Citation Francis J, Barnes KI, Workman L, Kredo T, Vestergaard LS, Hoglund RM, Byakika-Kibwika P, Lamorde M, Walimbwa SI, Chijioke-Nwauche I, Sutherland CJ, Merry C, Scarsi KK, Nyagonde N, Lemnge MM, Khoo SH, Bygbjerg IC, Parikh S, Aweeka FT, Tarning J, Denti P. 2020. An individual participant data population pharmacokinetic meta-analysis of drug-drug interactions between lumefantrine and commonly used antiretroviral treatment. Antimicrob Agents Chemother 64:e02394-19. https://doi.org/10.1128/AAC.02394-19.