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

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 artmether-lumefantrine (AL) or artesunate-amodiaquine (AS-AQ) given with 50mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artmether-lumefantrine or artesunate-amodiaquine and DTG. The DTG/artmether-lumefantrine interaction was evaluated in a two-way cross-over study and measured artemether (ARM), dihydroartemisinin (DHA), lumefantrine (LF), desbutyl-lumefantrine (DBL) over 264h. The DTG/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine (DEAQ) and measured artesunate (ARS), amodiaquine (AQ), DEAQ over 624h. Non-compartmental analysis was performed, and geometric mean ratios and 90% confidence intervals generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, time to maximum concentration and area under the concentration-time curve (AUC) for ARM, DHA, LF and DBL nor significantly alter AUC for ARS, DHA, AQ and DEAQ. Co-administration of dolutegravir with AL resulted in a 37% decrease in DTG trough concentrations. Co-administration of dolutegravir with AS-AQ resulted in a decrease of approximately 42% and 24% in DTG trough concentrations and AUC respectively. Study drugs were well-tolerated with no serious adverse events. Standard doses of artmether-lumefantrine and artesunate-amodiaquine should be used in patients receiving DTG. The significant decreases in DTG trough concentrations with artemether-lumefantrine and artesunate-amodiaquine and DTG exposure with artesunate-amodiaquine are unlikely to be of clinical significance as DTG trough concentrations were above DTG target concentrations of 64ng/mL.