Artesunate: developmental toxicity and toxicokinetics in monkeys.
BACKGROUND
The developmental toxicity, toxicokinetics, and hematological effects of the antimalarial drug, artesunate, were previously studied in rats and rabbits and have now been studied in cynomolgus monkeys.


METHODS
Groups of up to 15 pregnant females were dosed on Gestation Days (GD) 20-50 or for 3-7-day intervals.


RESULTS
At 30 mg/kg/day, 6 embryos died between GD30 and GD40. Histologic examination of 3 live embryos (GD26-GD36) revealed a marked reduction in embryonic erythroblasts and cardiomyopathy. At 12 mg/kg/day, 6 embryos died between GD30 and GD45. Four surviving fetuses examined on GD100 had no malformations, but long bone lengths were slightly decreased. At the developmental no-adverse-effect-level (4 mg/kg/day), maternal plasma AUC was 3.68 ng.h/mL for artesunate and 6.93 ng.h/ml for its active metabolite, dihydroartemisinin (DHA). No developmental toxicity occurred with administration of 12 mg/kg/day for 3 or 7 days, GD29-31 or GD27-33 (maternal plasma AUC of 9.84 ng.h/mL artesunate and 16.4 ng.h/mL DHA). Exposures at embryotoxic doses were substantially lower than human therapeutic exposures. However, differences in monkey and human Vss for artesunate (0.5 L/kg vs. 0.18 L/kg) confound relying solely on AUC for assessing human risk. Decreases in reticulocyte count occur at therapeutic doses in humans. Changes to reticulocyte counts at embryotoxic doses in monkeys (> or =12 mg/kg/day) were variable and generally minor.


CONCLUSIONS
Artesunate was embryolethal at > or =12 mg/kg/day when dosed for at least 12 days at the beginning of organogenesis, but not when dosed for 3 or 7 days, indicating that developmental toxicity of artesunate is dependent upon duration of dosing in cynomologus monkeys.
Clark
Robert L
RL
GlaxoSmithKline, Upper Merion, Pennsylvania 19406-0939, USA.
Arima
Akihiro
A
Makori
Norbert
N
Nakata
Yasuto
Y
Bernard
Frederic
F
Gristwood
William
W
Harrell
Andrew
A
White
Tacey E K
TE
Wier
Patrick J
PJ
D000818:Animals; D037621:Artemisinins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D000077332:Artesunate; D001772:Blood Cell Count; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000196:embryology; D000882:Haplorhini; D006439:Hemodynamics / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000097:blood* / Q000139:chemically induced / Q000503:physiopathology
D037621:Artemisinins; D000077332:Artesunate; C039060:artenimol