Tolerability and pharmacokinetics of non-fixed and fixed combinations of artesunate and amodiaquine in Malaysian healthy normal volunteers

Objective: There is limited pharmacokinetic data available for the combination artesunate + amodiaquine, which is used widely to treat uncomplicated malaria. This study examines the bioavailability and tolerability of a fixed (200 mg artesunate + 540 mg amodiaquine) and loose (200 mg∈+∈612 mg) combination with a 2×2 cross-over design in 24 healthy volunteers. Methods: Parent compounds and metabolites [dihydroartemisinin (DHA) and desethylamodiaquine (DEAQ)] were measured by high-performance liquid chromatography-electrochemical detection, and the area under the curve (AUC)_0-t and C_max were compared by an analysis of variance (ANOVA) based on geometric least square means using the Schuirmann two one-sided test. Results: The AUC_0-t for total DHA and DEAQ were 1522 ± 633 and 30021 ± 14211 ng h/ml for the fixed products and 1688 ± 767 and 40261 ± 19824 ng h/ml (mean ± standard deviation) for the loose products. The ANOVA showed no statistical differences except for sequence effect for DHA. The values obtained with the fixed product were within the 125% bioequivalent limits but extend below the 80% bioequivalence limits. Conclusion: Both combinations were well tolerated and had comparable pharmacokinetic profiles; differences are unlikely to be clinically relevant.