Pharmacokinetics and tolerability of artesunate and amodiaquine alone and in combination in healthy volunteers

OBJECTIVES: The WHO recommends artemisinin-based combination therapies for treatment of uncomplicated falciparum malaria. At least 15 African countries have adopted artesunate plus amodiaquine as treatment policy. As no pharmacokinetic data on this combination have been published to date, we investigated its pharmacokinetic interactions and tolerability in healthy volunteers in Africa. METHODS: In a randomized, three-phase, cross-over study, amodiaquine (10 mg/kg) and artesunate (4 mg/kg) were given as single oral doses to 15 healthy volunteers. Artesunate was given to all volunteers on day 0. On day 7 they received either amodiaquine or amodiaquine plus artesunate and the alternative regimen on day 28. The pharmacokinetics of artesunate and amodiaquine and their main active metabolites dihydroartemisinin and desethylamodiaquine were compared following monotherapy and combination therapy using analysis of variance. RESULTS: Thirteen volunteers completed the study, and pharmacokinetic parameters could be determined for twelve volunteers. When given in combination, the mean AUC was lower for dihydroartemisinin [ratio 67% (95% CI 51–88%); P = 0.008] and desethylamodiaquine [ratio 65% (95% CI 46–90%); P = 0.015] when compared with monotherapy. Adverse events of concern occurred in four volunteers (27%): grade 3 transaminitis (n = 1), neutropaenia (n = 2), and hypersensitivity (n = 1). CONCLUSION: The total drug exposure to both drugs was reduced significantly when they were given in combination. The clinical significance of these interactions is unclear and must be studied in malaria patients. The frequency and nature of adverse events among the healthy volunteers were of concern, and suggest laboratory monitoring would be needed in malaria patients treated with artesunate plus amodiaquine.