Pharmacokinetics and tolerability of artesunate and amodiaquine alone and in combination in healthy volunteers |
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Authors: | Catherine Orrell Francesca Little Peter Smith Peter Folb Walter Taylor Piero Olliaro Karen I Barnes |
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Institution: | Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Anzio Road, Observatory, Cape Town, 7925, South Africa. |
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Abstract: | 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. |
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Keywords: | Amodiaquine Artesunate Pharmacokinetics Tolerability Healthy normal volunteers |
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