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

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 TarningPaolo Denti

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere02394-19
JournalAntimicrobial Agents and Chemotherapy
Volume64
Issue number5
DOIs
StatePublished - May 1 2020

Keywords

  • Drug-drug interactions
  • Human immunodeficiency virus
  • Lumefantrine
  • Population pharmacokinetics
  • Uncomplicated malaria

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Francis, J., Barnes, K. I., Workman, L., Kredo, T., Vestergaard, L. S., Hoglund, R. M., Byakika-Kibwika, P., Lamorde, M., Walimbwa, S. I., Chijioke-Nwauche, I., Sutherland, C. J., Merry, C., Scarsi, K. K., Nyagonde, N., Lemnge, M. M., Khoo, S. H., Bygbjerg, I. C., Parikh, S., Aweeka, F. T., ... Denti, P. (2020). An individual participant data population pharmacokinetic meta-analysis of drug-drug interactions between lumefantrine and commonly used antiretroviral treatment. Antimicrobial Agents and Chemotherapy, 64(5), [e02394-19]. https://doi.org/10.1128/AAC.02394-19