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Developmental toxicity studies of lumefantrine and artemether in rats and rabbits

Clark, Robert and Delise, Anthony and Youreneff, Maureen (2016) Developmental toxicity studies of lumefantrine and artemether in rats and rabbits. Birth defects research. Part B: developmental and reproductive toxicology, 107. pp. 243-257. ISSN 1542-9741; 1542-9733

Abstract

The combination of artemether plus lumefantrine (AL) is a type of artemisinin-based combination therapy (ACT) recommended since 2001 by the World Health Organization (WHO) for uncomplicated falciparum malaria except in the first trimester of pregnancy. The first trimester restriction was based on the marked embryotoxicity (including embryo death and cardiac and skeletal malformations) of artemisinins such as artesunate, dihydroartemisinin and artemether in animals. . Before recommending ACTs for use in the first trimester, the WHO has requested that all information relevant to the assessment of risk of ACTs to the embryo be made available to the public. This report describes the results of embryo-fetal development studies of artemether alone, lumefantrine alone and the combination in rats and rabbits as well as toxicokinetic studies of lumefantrine in pregnant rabbits. The developmental no effect levels (dNOELs) for lumefantrine were 500 mg/kg/day in rats and 1000 mg/kg/day in rabbits and the calculated safety margins based on human equivalent dose (HED) and plasma Cmax and AUC values were in the range of 3-fold to 12-fold. The dNOELs for artemether were 3 mg/kg/day in rats and 25 mg/kg/day in rabbits. No teratogenicity was observed in these studies with either compound. There were no unexpected findings with artemether or AL. The results with lumefantrine indicate that it is not a potent embryotoxin in rats and rabbits. There were no findings in pregnant rats and rabbits that would cause increased concern for the use of artemether-lumefantrine in the first trimester compared to other ACTs.

Item Type: Article
Keywords: artemether, lumefantrine, embryotoxicity, malaria
Date Deposited: 23 Feb 2017 00:45
Last Modified: 23 Feb 2017 00:45
URI: https://oak.novartis.com/id/eprint/31046

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