Single-dose pharmacokinetic interaction between artesunate and amodiaquine: assembling the clues for the purported interaction

Abstract

To the Editor – Due to the rampant development of resistance to most of the commonly used antimalarial drugs, the use of combination drug regimens is now strongly recommended. One of the interesting combination treatment includes the use of artesunate and amodiaquine as a first-line treatment option in several African countries [1, 2]. Whereas the safety, tolerability, and efficacy data have been gathered for this combination use, the pharmacokinetic data have been hitherto elusive. However, a recent paper published by Orrell and coworkers captures the pharmacokinetic data of the individually administered oral doses of artesunate/ amodiaquine as well as the combined entity in healthy African subjects in a well-planned and executed single-dose crossover design [3]. Generally, it appeared to be a well controlled study that ensured, among other things: rigorous study entry criteria, robust plasma sampling scheme, employment of sound bioanalytical assays, and reasonably adequate washout time between periods to remove any drug/metabolite(s) residues [3]. However, the single-dose data of the combined entity revealed the existence of pharmacokinetic interaction such that the total exposure of the two agents in combination treatment (parent and respective metabolites) were significantly reduced when compared with exposure data from the individual drug administrations [3]. As these new findings had not been published before, it would definitely add a new twist in trying to understand the pharmacokinetic play(s) when such combinations are being used to control the spread of the resistant malarial disease. More importantly, it brings into question the rationale in combining two agents that in combination may render it unsuitable in a combination situation from a clinical efficacy point of view due to loss of total drug exposure as a result of a very pronounced interaction. The intent of this note is to build some speculative clues by which to understand the nature of the observed pharmacokinetic interaction reported by Orrell and coworkers [3]. Typically, the loss of exposure of both agents following a mere single oral dose coadministration of the two agents is not a commonly observed pharmacokinetic interaction. However, opportunities do exist for single dose interaction in situations such as: (a) when there is a physicochemical interaction via chelation and/or degradation after oral ingestion; (b) when one and/or the combined entity can significantly alter gastrointestinal motility; (c) when one and/or the combined entity can hinder absorption by causing permeability issues and/or via efflux phenomenon. Although increased metabolism in the gut and/or autoinduction phenomenon may cause lowered exposure, it may be associated with increased exposure to one or more metabolite(s). It is interesting to note from limited pharmacokinetic reports available that artesunate did not alter the kinetics of compounds such as artemisinin [4], atovaquone–proguanil combination [5], and/or sulfadoxine/pyrimethamine combination [6] upon single/multiple dose coadministration. Mefloquine, another commonly used antimalarial, did not alter the pharmacokinetics of artesunate [7]. Similarly, amodiaquine did not alter the kinetics of halofantrine following pretreatment, although pharmacodynamically there appeared to be QTc prolongation attributable to the combination treatment [8]. Therefore, it appears that via documented pharmacokinetic data, neither artesunate nor Eur J Clin Pharmacol (2008) 64:1231–1233 DOI 10.1007/s00228-008-0539-x