TY - JOUR
T1 - An individual participant data population pharmacokinetic meta-analysis of drug-drug interactions between lumefantrine and commonly used antiretroviral treatment
AU - Francis, Jose
AU - Barnes, Karen I.
AU - Workman, Lesley
AU - Kredo, Tamara
AU - Vestergaard, Lasse S.
AU - Hoglund, Richard M.
AU - Byakika-Kibwika, Pauline
AU - Lamorde, Mohammed
AU - Walimbwa, Stephen I.
AU - Chijioke-Nwauche, Ifeyinwa
AU - Sutherland, Colin J.
AU - Merry, Concepta
AU - Scarsi, Kimberley K.
AU - Nyagonde, Nyagonde
AU - Lemnge, Martha M.
AU - Khoo, Saye H.
AU - Bygbjerg, Ib C.
AU - Parikh, Sunil
AU - Aweeka, Francesca T.
AU - Tarning, Joel
AU - Denti, Paolo
N1 - Funding Information:
We thank all patients, family, and staff who participated in these studies at all the institutions/sites. We also thank WWARN for curating the data and facilitating the data-sharing initiative that made this research possible. We all declare no conflict of interest (if not stated elsewhere). The Worldwide Antimalarial Resistance Network (WWARN) is partly funded by the Bill and Melinda Gates Foundation. The SEACAT and InterACT studies were funded by the Bill and Melinda Gates Foundation through the ACT Consortium (http://actconsortium.org). P.D. is supported by the South African National Research Foundation (IFR170227223728). The funding bodies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. K.I.B. and P.D. designed the research. J.F. and P.D. performed the research and analyzed the data. J.F., P.D., and K.I.B. wrote the manuscript. L.W. managed the collation and curation of data. T.K., L.S.V., R.M.H., P.B.K., M.L., S.I.W., I.C.N., C.J.S., C.M., K.K.S., N.N., M.M.L., S.H.K., I.C.B., S.P., F.T.A., and J.T. contributed individual participant data for the pooled analysis. All authors reviewed the manuscript critically for important intellectual content and approved the final version submitted. Computations were performed using facilities provided by the University of Cape Town’s High-Performance Computing team (http://hpc.uct.ac.za).
Publisher Copyright:
Copyright © 2020 Francis et al.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - 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.
AB - 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.
KW - Drug-drug interactions
KW - Human immunodeficiency virus
KW - Lumefantrine
KW - Population pharmacokinetics
KW - Uncomplicated malaria
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U2 - 10.1128/AAC.02394-19
DO - 10.1128/AAC.02394-19
M3 - Article
C2 - 32071050
AN - SCOPUS:85083651265
VL - 64
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 5
M1 - e02394-19
ER -