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

Visweswaran Navaratnam, Surash Ramanathan, Mohd Suhaimi Ab Wahab, Gan Siew Hua, Sharif Mahsufi Mansor, Jean René Kiechel, Michel Vaillant, Walter R.J. Taylor, Piero Olliaro*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

40 Citations (Scopus)

Abstract

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 Cmax were compared by an analysis of variance (ANOVA) based on geometric least square means using the Schuirmann two one-sided test. Results: The AUC0-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.

Original languageEnglish
Pages (from-to)809-821
Number of pages13
JournalEuropean Journal of Clinical Pharmacology
Volume65
Issue number8
DOIs
Publication statusPublished - Aug 2009

Keywords

  • Amodiaquine
  • Artesunate
  • Fixed combination treatment
  • Non-fixed combination treatment
  • Pharmacokinetics
  • Tolerability

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