Le problème des « artemisinin combined therapy »: contrefaits ou obsolètes?

Les résistances contre l’artemisinine sous forme d’ACT se développent en Asie, mais également en Afrique et en Amérique latine seraient dues non seulement aux contrefaçons mais également aux pilules où les principes actifs se sont détériorés sous climat tropical.

A recent paper (K van Acker, J Plaizier, Malaria Journal, 2012-11 Suppl.1) confirms the concern raised by previous publications: “Stability of artemisinin derivatives has so far only been partially investigated and it is unclear how much this contributes to the reports of bad quality or substandard antimalarials” One of the conclusions of this study is that” Artesunate and amodiaquine can only be used in a fixed dose combination if they are physically separated”.
Artesunate and amodiaquine are indeed incompatible, in presence of each other. Artesunate is sensitive to the acidity brought by HCl molecules present in the amodiaquine, effect which is enhanced by temperature and humidity. The chemical incompatibility of the two drugs causes mutual decomposition and leads to stability problems.
The attempt to combine these two incompatible active principles while preventing artesunate degradation under tropical conditions was difficult. It required three years of development by WHO and DNDi) Several options failed: incorporating artesunate in the external phase of the tablets, adding a pH regulator, alcoholic wet granulation, dry granulation, addition of an hydrophobic agent. Finally stability could be achieved in experimental batches by separating artesunate and amodiaquine in a bilayer co-formulation ( C Lacaze et al., Malaria Journal, 2011, 10:142)
Already in 2007 a paper published jointly by the Université Paris Descartes and WHO Geneva found that the shelf life of artesunate was 24 weeks only when stored at 4°C, 12 weeks at 25°C and less than one week at 37°C, The packaging had no influence on shelf life ( S Houzé et al., J Clin Microbiol. Aug 2007, 2734-2736.) In 1996 the high recrudescence after intravenous injection was related to the short half-lives of artesunate. Artesunate in sodium chloride solutions for injection was stable only for 4h at 30°C ( KT Batty et al., J Pharm Pharmacol 1996, 48-1, 22-26).
In a similar study involving the Hongkong University and WHO (RK Haynes, MG Gomes et al., ChemMedChem 2007. 2, 1448-1463) the authors conclude that the thermal lability of the clinically used artemisinins is incompatible with ICH/WHO requirements for formulated drugs destined for use in climatic zone III and IV countries. And that in fixed formulations it is critically important that the amount of active artimisinin does not fall below the designated effective therapeutic dose before the expiry date.
A study carried out in Ghana (K Ofori-Kwakye et al., Trop J Pharmac Res. 2008, 7:4) 1179-1184) on 17 artesunate tablets purchased from pharmacies revealed a lower than specified artesunate content. Only 3 of the samples met the European Pharmacopoeia content requirements. None of the tablets sampled was found to be a counterfeit.
A similar study from Nigeria showed that on 13 generic brands of artesunate tables 66.7% failed the drug content assay test (O Odunfa et al., Trop J Pharmac Res, 2009, 8:6, 491-499). In another study on amodiaquine and artesunate tablets , only 15.4% of the sample had both amodiaquine and artesunate within the USP specification. 53,8 % failed the active content test for both amodiaquine and artesunate (T Ehianeta et al., African J of Pharmacy and Pharmacology, 6-9, 2012, 636-642).
Another recent paper from the same Malaria Journal ( S Suleman, et al. Malaria J. 2013, 212:145) describes a similar problem of stability in artemether-lumefantrine combinations, indicating that they are inherently unstable and require controlled distribution and storage conditions, which are not always available in resource-limited settings.
Sometimes ACTs are compared with a combination of two leaking buckets
WHO recognizes the problem of instability in the document PROCUREMENT OF ARTEMETHER-LUMEFANTRINE(COARTEM®) THROUGH WHO . “The commercial pack has a three-day supply of 16 or 24 tablets in individual blister. After the tablets are removed from this single blister, they will begin to degrade within 24 hours” . Stability is one of the reasons the manufacturer recommends that Coartem should not be stored above 30o C (Andrea Bosman WHO-RBM)
In a document published in 2011 (ISBN 9789241500838) WHO confirms that widespread use of these and other subtherapeutic antimalarial regimens is likely to play a major role in the emergence of drug resistance.

Pierre Lutgen
lutgenp@gms.lu

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