Developmental toxicity studies of lumefantrine and artemether in rats and rabbits

Abstract

The combination of artemether plus lumefantrine is a type of artemisinin-based combination therapy (ACT) recommended by the World Health Organization for uncomplicated falciparum malaria except in the first trimester of pregnancy. The first trimester restriction was based on the marked embryotoxicity in animals (including embryo death and cardiac and skeletal malformations) of artemisinins such as artesunate, dihydroartemisinin, and artemether. Before recommending ACTs for use in the first trimester, the World Health Organization 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 for lumefantrine were 300 mg/kg/day in rats (based on a 25% decrease in litter size at 1000 mg/kg/day) and 1000 mg/kg/day in rabbits. The calculated safety margins based on human equivalent dose and plasma C and AUC values were in the range of 2.5- to 17-fold. The developmental no-effect levels for artemether were 3 mg/kg/day in rats and 25 mg/kg/day in rabbits. Lumefantrine caused no teratogenicity and was not a potent embryotoxin in rats and rabbits. Expected artemisinin-like findings were seen with artemether alone and with artemether/lumefantrine combined except that no malformations were observed. 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.

Animal Embryotoxicity Studies of Key Non‐Artemisinin Antimalarials and Use in Women in the First Trimester

“…It is an unusual feature of thalidomide that it caused high incidences of unusual malformations at nonmaternally toxic doses in rabbits and primates (e.g., Christian et al, ). Artesunate, artemether, and DHA have also caused embryo deaths and/or malformations at nonmaternally toxic doses when tested in rats, rabbits, and/or monkeys (Clark et al, , , ).…”

“…In the second pharmacokinetic study (Tarning et al, ), blood sampling started at the first dose and extended to 168 hr after the last dose. The C max and AUC 48‐72h values for lumefantrine were estimated to be 9.2 μg/ml and 170 μg.h/ml, respectively (Clark et al, ).…”

“…ICH‐ and GLP‐compliant EFD studies of lumefantrine, artemether, and 1:6 combinations of artemether and lumefantrine were conducted in rats and rabbits with treatment throughout organogenesis (Clark et al, ). Study details for the studies involving lumefantrine are provided in Table .…”

Safety of Artemisinin Derivatives in the First Trimester of Pregnancy: A Controversial Story

“…The authors concluded that artesunate caused embryo-lethality at doses ≥12 mg/kg/day administered for more than 12 days at the beginning of organogenesis, but not when administered for shorter treatment period [ 53 ]. It is interesting to note that although ACT and not artemisinin monotherapy, is the recommended treatment against uncomplicated malaria, the developmental toxicity of ACTs, compared to artemisinin derivatives alone, has been scarcely studied in vitro [ 54 , 55 ].…”

Teratogen update: Malaria in pregnancy and the use of antimalarial drugs in the first trimester

“…In the rat EFD study of artemether (Clark, Youreneff, & DeLise, 2016), there was no maternal toxicity at any dose tested (1, 3, and 10 mg/kg/day) but developmental effects seen at the high dose consisted of 16 total litter resorptions among 25 pregnant females, increased early resorptions in the remaining litters, a 13% decrease in mean fetal weight, and an increased incidence of fetuses with wavy/angulated rib (Clark et al, 2016). The middle dose group (3 mg/kg/day) was the dNOEL.…”