Drug Interactions between Dolutegravir and Artemether-Lumefantrine or Artesunate-Amodiaquine

Walimbwa, Stephen I, Lamorde, Mohammed, Waitt, Catriona ORCID: 0000-0003-0134-5855, Kaboggoza, Julian ORCID: 0000-0001-9510-0474, Else, Laura, Byakika-Kibwika, Pauline, Amara, Alieu ORCID: 0000-0002-1137-2948, Gini, Joshua, Winterberg, Markus, Chiong, Justin ORCID: 0000-0001-8063-6399
et al (show 2 more authors) (2019) Drug Interactions between Dolutegravir and Artemether-Lumefantrine or Artesunate-Amodiaquine. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 63 (2). e01310-e01318.

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Across sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need cotreatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artemether-lumefantrine or artesunate-amodiaquine given with 50 mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artemether-lumefantrine or artesunate-amodiaquine and dolutegravir. The dolutegravir/artemether-lumefantrine interaction was evaluated in a two-way crossover study and measured artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine over 264 h. The dolutegravir/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine and measured artesunate, amodiaquine, and desethylamodiaquine over 624 h. Noncompartmental analysis was performed, and geometric mean ratios and 90% confidence intervals were generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, the time to maximum concentration, and the area under the concentration-time curve (AUC) for artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine, nor did it significantly alter the AUC for artesunate, dihydroartemisinin, amodiaquine, and desethylamodiaquine. Coadministration of dolutegravir with artemether-lumefantrine resulted in a 37% decrease in DTG trough concentrations. Coadministration of dolutegravir with artesunate-amodiaquine resulted in 42 and 24% approximate decreases in the DTG trough concentrations and the AUC, respectively. The significant decreases in DTG trough concentrations with artemether-lumefantrine and artesunate-amodiaquine and dolutegravir exposure with artesunate-amodiaquine are unlikely to be of clinical significance since the DTG trough concentrations were above dolutegravir target concentrations of 300 ng/ml. Study drugs were well tolerated with no serious adverse events. Standard doses of artemether-lumefantrine and artesunate-amodiaquine should be used in patients receiving dolutegravir. (This study has been registered at ClinicalTrials.gov under identifier NCT02242799.).

Item Type: Article
Uncontrolled Keywords: dolutegravir, malaria, artemether, artesunate, lumefantrine, amodiaquine, drug-drug interactions
Depositing User: Symplectic Admin
Date Deposited: 06 Dec 2018 10:42
Last Modified: 19 Jan 2023 01:09
DOI: 10.1128/AAC.01310-18
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3029621