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Pharmacokinetics and pharmacodynamics of a new ACT formulation: Artesunate/Amodiaquine (TRIMALACT®) following oral administration in African malaria patients

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Summary

A new fixed-dose combination of artesunate (AS) plus amodiaquine (AQ) (TRIMALACT®) was recently developed for the treatment of uncomplicatedfalciparum malaria. The originality of this combination lies in its galenic formulation which consists of a threelayer tablet with two layers containing each of the active ingredients, i.e. AS and AQ, and these are separated by a middle layer containing an antioxidant compound. To evaluate the efficacy and tolerability of this combination, adults with uncomplicated malaria received three administrations of two tablets (100:300 mg AS/AQ) in a 24-h interval, in Democratic Republic of Congo. Parasitemia and fever were measured and the plasma levels of parent compounds and metabolites [dihydroartemisinin (DHA) and monodeselhylamodiaquine (MdAQ)] were determined by high-performance liquid chromatography. In addition, we determined the prevalence of molecular markers of resistance to chloroquine (CQ) and sulfadoxine/pyrimethamine (SP). The AS/AQ combination TRIMALACT® demonstrated a good efficacy resulting in an excellent clinical and parasitological response rate of 100% after correction for PCR results. Treatment regimen was well tolerated. The main disposition parameters to AS+AQ were: for DHA, AUC = 632 + 475 ng h/ml and Cmax= 432 ± 325 ng/ml, and for MdAQ = 14268 ± 4114 ng h/ml and Cmax= 336 ± 225 ng/ml (mean ± standard deviation). Parasite genotyping show high frequencies of molecular SP- and CQ-resistance markers with more 80% of the samples showing more than three mutations linked to SP resistance and 93.48% carrying parasite with the CQ-resistant haplotype. This study shows that the AS/AQ combination TRIMALACT® is safe and effective in the treatment of highly drug-resistantfalciparum malaria.

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Authors and Affiliations

  1. 1UMR-MD3, Faculty of Pharmacy, University of Méditerranée, Institute of Tropical Medicine of the French Army Forces, Marseille, France

    V. Sinou, N. Taudon, L. Bert Aux & D. Parzy

  2. Monkole Hospital Center, Kinshasa, Democratic Republic of Congo

    L. Tshilolo Muepu Maladca, R. Lwango & S. Sese Alegre

  3. Sugnaux Scientific, Blonay, Switzerland

    F. Sugnaux

  4. Pharmacology Department, Faculty of Medicine, Geneva University, Geneva, Switzerland

    A. Benakis

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  1. V. Sinou
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Note: Parts of these results have been already presented as a Poster at the European Congress on Tropical Medicine and International Health, May 2007, Amsterdam, The Netherlands

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Sinou, V., Maladca, L.T.M., Taudon, N. et al. Pharmacokinetics and pharmacodynamics of a new ACT formulation: Artesunate/Amodiaquine (TRIMALACT®) following oral administration in African malaria patients. Eur. J. Drug Metabol. Pharmacokinet. 34, 133–142 (2009). https://doi.org/10.1007/BF03191163

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