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

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 2x2 cross-over design in 24 healthy volunteers.
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.
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.
Both combinations were well tolerated and had comparable pharmacokinetic profiles; differences are unlikely to be clinically relevant.
AuthorsVisweswaran Navaratnam, Surash Ramanathan, Mohd Suhaimi Ab Wahab, Gan Siew Hua, Sharif Mahsufi Mansor, Jean-René Kiechel, Michel Vaillant, Walter R J Taylor, Piero Olliaro
JournalEuropean journal of clinical pharmacology (Eur J Clin Pharmacol) Vol. 65 Issue 8 Pg. 809-21 (Aug 2009) ISSN: 1432-1041 [Electronic] Germany
PMID19404632 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
Chemical References
  • Antimalarials
  • Artemisinins
  • Biomarkers
  • Drug Combinations
  • Amodiaquine
  • artesunate
  • Adult
  • Amodiaquine (adverse effects, blood, pharmacokinetics)
  • Analysis of Variance
  • Antimalarials (administration & dosage, blood, pharmacokinetics)
  • Area Under Curve
  • Artemisinins (administration & dosage, blood, pharmacokinetics)
  • Asian Continental Ancestry Group (statistics & numerical data)
  • Biological Availability
  • Biomarkers (blood)
  • Chi-Square Distribution
  • Cross-Over Studies
  • Drug Combinations
  • Drug Therapy, Combination
  • Female
  • Humans
  • Malaysia
  • Male
  • Reference Values
  • Time Factors

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