An individual participant data population pharmacokinetic meta-analysis of drug-drug interactions between lumefantrine and commonly used antiretroviral treatment

• Main Authors: Jose Francis, Karen I. Barnes, Lesley Workman, Tamara Kredo, Lasse S. Vestergaard, Richard M. Hoglund, Pauline Byakika-Kibwika, Mohammed Lamorde, Stephen I. Walimbwa, Ifeyinwa Chijioke-Nwauche, Colin J. Sutherland, Concepta Merry, Kimberley K. Scarsi, Nyagonde Nyagonde, Martha M. Lemnge, Saye H. Khoo, Ib C. Bygbjerg, Sunil Parikh, Francesca T. Aweeka, Joel Tarning, Paolo Denti
• Other Authors: Makerere University
• Format: Article
• Published: 2020
• Subjects: Medicine; Pharmacology, Toxicology and Pharmaceutics
• Online Access: https://repository.li.mahidol.ac.th/handle/123456789/54599
• Institution: Mahidol University

Copyright © 2020 Francis et al. 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.