Richard M. Hoglund (1,2), Pauline Byakika-Kibwika (3,4), Mohammed Lamorde (4), Concepta Merry (4), Michael Ashton (5), Warunee Hanpithakpong (1), Nicholas P. J. Day (1,2), Nicholas J. White (1,2), Angela Äbelö (5), Joel Tarning (1,2)
(1) Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand,(2) Centre for Tropical Medicine & Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK, (3) Department of Medicine, School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda, (4) Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda, (5) Unit for Pharmacokinetics and Drug Metabolism, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Objectives: Drug-drug interactions between antimalarial and antiretroviral drugs may influence antimalarial treatment outcomes. The aim of this study was to investigate the potential drug-drug interactions between the anti-malarial drugs; lumefantrine, artemether and their respective metabolites desbutyl-lumefantrine and dihydroartemisinin, and the HIV-drugs efavirenz, nevirapine and lopinavir/ritonavir.
Methods: Data from two clinical studies, investigating the influence of the HIV-drugs efavirenz, nevirapine and lopinavir/ritonavir on the pharmacokinetics of the antimalarial drugs lumefantrine, artemether and their respective metabolites, in HIV infected patients were pooled and analysed using a nonlinear mixed-effects modelling approach.
Results: Efavirenz and nevirapine significantly decreased the terminal exposure to lumefantrine (decrease of 70% and 25%, respectively) while ritonavir/lopinavir substantially increased the exposure with 440%. All antiretroviral drugs decreased the total exposure to dihydroartemisinin (decrease of 72%, 41% and 60% for efavirenz, nevirapine and ritonavir/lopinavir, respectively). Simulations suggest that a substantially increased artemether-lumefantrine dose is required to achieve equivalent exposures when co-administered with efavirenz (250% dose increase) and nevirapine (75% dose increase). When co-administered with ritonavir/lopinavir it is unclear if the increased lumefantrine exposure compensates adequately for the reduced dihydroartemisinin exposure and thus whether dose adjustment is required. The pharmacokinetics of efavirenz were not affected by concomitant administration of artemether-lumefantrine while the elimination clearance of nevirapine was increased by 65%.
Conclusions: There are substantial drug interactions between artemether-lumefantrine and efavirenz, nevirapine and ritonavir/lopinavir. Especially the antimalarial drugs are affected. Given the readily saturable absorption of lumefantrine, the dose adjustments predicted to be necessary will need to be evaluated prospectively in malaria-HIV coinfected patients.
Reference: PAGE 24 () Abstr 3498 [www.page-meeting.org/?abstract=3498]
Poster: Drug/Disease modeling - Infection