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Artemether-lumefantrine coadministration with antiretrovirals; population pharmacokinetics and dosing implications

Artikel i vetenskaplig tidskrift
Författare Richard Höglund
Pauline Byakika‐Kibwika
Mohammed Lamorde
Concepta Merry
Michael Ashton
Nicholas Philip John Day
Nicholas J White
Angela Abelö
Joel Tärning
Publicerad i British Journal of Clinical Pharmacology
Volym 79
Nummer/häfte 4
Sidor 636–649
ISSN 0306-5251
Publiceringsår 2015
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi
Sidor 636–649
Språk en
Länkar dx.doi.org/10.1111/bcp.12529
Ämneskategorier Farmaceutisk vetenskap

Sammanfattning

AimDrug-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.Method 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.ResultsEfavirenz and nevirapine significantly decreased the terminal exposure to lumefantrine (decrease of 69.9% and 25.2%, respectively) while lopinavir/ritonavir substantially increased the exposure (increase of 439%). All antiretroviral drugs decreased the total exposure to dihydroartemisinin (decrease of 71.7%, 41.3% and 59.7% 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% increase) and nevirapine (75% increase). When co-administered with lopinavir/ritonavir it is unclear if the increased lumefantrine exposure compensates adequately for the reduced dihydroartemisinin exposure and thus whether dose adjustment is required.Conclusion There are substantial drug interactions between artemether-lumefantrine and efavirenz, nevirapine and ritonavir/lopinavir. 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.

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