ACTs: counterfeit and/or unstable
L'instabilité des ACT
The problem of ACTs: counterfeit or unstable? A recent paper Kristel Van Acker, Marc Mommaerts, Stijn Vanermen, Jolien Meskens, Yvan Vander Heyden, and Jacqueline Plaizier-Vercammen. Chemical stability of artemisinin derivatives Malar J. 2012; 11(Suppl 1): P99 doi: 10.1186/1475-2875-11. 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 a hydrophobic agent. Finally, stability could be achieved in experimental batches by separating artesunate and amodiaquine in a bilayer co-formulation Catherine Lacaze, Tina KaussEmail author, Jean-René Kiechel, Antonella Caminiti, Fawaz Fawaz, Laurent Terrassin, Sylvie Cuart, Luc Grislain, Visweswaran Navaratnam, Bellabes Ghezzoul, Karen Gaudin, Nick J White, Piero L Olliaro and Pascal Millet. The initial pharmaceutical development of an artesunate/amodiaquine oral formulation for the treatment of malaria: a public-private partnership. Malaria Journal201110:142 DOI: 10.1186/1475-2875-10-142 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 Sandrine Houzé, Aline Munier, Xavier Paoletti, Halima Kaddouri, Pascal Ringwald and Jacques Le Bras. Shelf Life of Predosed Plates Containing Mefloquine, Artemisinin, Dihydroartemisinin, and Artesunate as Used for In Vitro Plasmodium falciparum Susceptibility Assessmen. J Clin Microbiol. Aug 2007, 2734-2736. Zoe Hall, Elizabeth Louise Allan, Donelly Andrew van Schalkwyk, Albert van Wyk, and Harparkash Kaur. Degradation of Artemisinin-Based Combination Therapies under Tropical Conditions Am J Trop Med Hyg. 2016 May 4; 94(5): 993–1001.doi: 10.4269/ajtmh.15-0665 Artesunate in sodium chloride solutions for injection was stable only for 4h at 30°C Kevin T Batty, Le Thi Anh Thu, Timothy M E Davis, Kenneth F Ilett, Truong Xuan Mai, Nguyen Canh Hung, Nguyen Phuc Tien, Shane M Powell, Huynh Van Thien, Tran Quang Binh, and Nguyen Van Kim. A pharmacokinetic and pharmacodynamic study of intravenous vs oral artesunate in uncomplicated falciparum malaria. Br J Clin Pharmacol. 1998 Feb; 45(2): 123–129. doi: 10.1046/j.1365-2125 In 0.1 N NaOH aqueous solutions the degradation of artesunate is 100 % after 2 hours. János Pogány, pharmacist, Ph.D. consultant to WHO. Guilin, China, 10 January 2006 The University of Bordeaux Gaudin K, Langlois MH, Barbaud A, Boyer C, Millet P, Fawaz F, Dubost JP. Stability of artesunate in pharmaceutical solvents. J Pharm Biomed Anal. 2007 Feb 19;43(3):1019-24. studied the stability of artesunate in different solvents. Unfortunately, none prevented artesunate from degradation longer than 3 months. It is now recommended by the manufacturer Cayman Chemicals “For long term storage, we suggest that artesunate be stored as crystalline solid at – 20°C.” How many villages in Africa do have storage facilities at minus 20 degrees? In 1996. the high recrudescence after intravenous injection was related to the short half-lives of artesunate. Artesunate in water after one hour has disintegrated and/or precipitated as insoluble DHA. Artemisinin in aqueous solutions at 37°C for at least 24 hours. In the leaves of the plant for years. In a similar study involving the Hongkong University and WHO Haynes RK, Chan HW, Lung CM, Ng NC, Wong HN, Shek LY, Williams ID, Cartwright A, Gomes MF. Artesunate and dihydroartemisinin (DHA): unusual decomposition products formed under mild conditions and comments on the fitness of DHA as an antimalarial drug. ChemMedChem. 2007 Oct;2(10):1448-63. 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-Kwaky, Y Asantewaa and O Gaye. Quality of Artesunate Tablets Sold in Pharmacies in Kumasi, Ghana. Tropical Journal of Pharmaceutical Research, December 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. OO Odunfa, OA Adegoke and IC Onaga. Pharmaceutical Equivalence of Some Commercial Samples of Artesunate and Amodiaquine Tablets Sold in Southwestern Nigeria. Tropical Journal of Pharmaceutical Research, December 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 Teddy Ehianeta, Bidemi Williams, Jadesola Surakat, Nura Mohammed and Chimezie Anyakora, Quality survey of some brands of artesunate-amodiaquine in Lagos drug market. African Journal of Pharmacy and Pharmacology Vol. 6(9), pp. 636-642, 8 March, 2012, DOI: 10.5897/AJPP11.841 Another paper from the same Malaria Journal S. Suleman, K. Vandercruyssen, E. Wynendaele, M. D’Hondt, L. Duchateau and B. De Spiegeleer. A rapid stability-indicating fused core HPLC method for simultaneous determination of β-artemether and lumefantrine in anti-malarial fixed dose combination products. Malaria Journal 2013, 12:145. describe 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. A recent study of WHO and UNICEF examined the behaviour of DHA in plasma and erythrocyte lysate at different temperatures and pH ranges. A significant reduction in the antimalarial activity of DHA was seen after incubation in plasma and to a lesser extent in erythrocyte lysate. Activity was reduced by half after 3h and almost completely abolished after 24 h. In vivo disorders such as fever, hemolysis or acidosis associated with malaria severity may contribute to instability and clinical efficacy. S Parapini, P Olliaro, V Navaratnam, N Basilico. Stability of the antimalarial drug dihydroartemisinin under physiologically relevant conditions: implications for clinical treatment. Antimicrob Agents and Chemotherapy, 2015, 59, 7.4046-4056 Artemisinin-derivative formulations are now widely used to treat falciparum malaria. However, the dry powder suspensions developed for children are few and/or are of poor quality. In addition to the active compound, the presence of a suitable preservative in these medicines is essential. In a study of the Vrije Universiteit Brussel, an evaluation of the preservative content and efficacy in some dry suspensions available on the Kenyan market was performed. Magnus A Atemnkeng, Katelijne De Cock and Jacqueline Plaizier-Vercammen Post-marketing assessment of content and efficacy of preservatives in artemisinin-derived antimalarial dry suspensions for paediatric use. Malaria Journal 2007, 6:12 doi:10.1186/1475-2875-6-12 UV spectrophotometry was used to identify the preservatives in each sample while HPLC-UV was used for quantification. After reconstitution of the powders in water, the dissolution of the preservatives was followed for 7 days. Antimicrobial efficacy of the preservatives was assessed by conducting a preservative efficacy test (PET) following the European pharmacopoeia standards. Four different preservatives were identified namely methylparahydroxybenzoate (MP), propylparahydroxybenzoate (PP), benzoic acid and sorbic acid. MP and PP were identified in Artesiane® (artemether 300 mg/100 ml), Alaxin® (dihydroartemisinin 160 mg/80 ml) respectively. Sorbic acid was present in Artenam® (artemether 180 mg/60 ml) while benzoic acid was identified in Santecxin® (dihydroartemisinin 160 mg/80 ml) and Artexin® (dihydroartemisinin 160 mg/80 ml) respectively. Cotecxin® (dihydroartemisinin 160 mg/80 ml) did not contain any of the above preservatives. After reconstitution in water, preservatives in 50% (3/6) of the products did not completely dissolve and the PET results revealed that only Artenam® and Gvither® met the requirements for antimicrobial efficacy. The other products did not conform. These results show that paediatric antimalarial dry powder formulations on the market may contain ineffective or incorrect amounts of preservatives. This is a potential risk to the patient. Studies conducted on the dry powder suspensions should include the analysis of both the active ingredient and the preservative, including the efficacy of the latter Sometimes ACTs are compared with a combination of two leaking buckets. On the other hand, instability of artemisinin in water or plasma has evolved from a rumour to a dogma. Several papers show that artemisinin can be extracted up to 90 % in tea infusions and stays stable for at least 24 hours Frank van der Kooy, Shaun Edward Sullivan. The complexity of medicinal plants: the traditional Artemisia annua formulation, current status and future perspectives. J Ethnopharmacol 2013 Oct 20;150(1):1-13. 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 30° C (Andrea Bosman WHO-RBM). We tried to obtain from the experts at the ITG (Institute for Tropical Medicine) at Antwerpen documentation on clinical trials which have been run with one year old ACT’s. They are unable to find such, because all the trials probably and only have been made with freshly made pills. In 2005 Novartis had to destroy millions of Coartem tablets, for the heat-sensitive life-saving drug wouldn’t keep for long. African governments ordered less than half of Novartis’s supply (Sonia Shah in “The Fever”. But the millions of pills which had perished in African warehouses were never returned to Europe and found their place in African drugstores. In a document published in 2011 Global plan for artemisinin resistance containment (GPARC) WHO 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.