Artesunate: developmental toxicity and toxicokinetics in monkeys

Area of Science:

• Pharmacology
• Toxicology
• Reproductive Science

Background:

• Previous studies investigated artesunate's developmental toxicity, toxicokinetics, and hematological effects in rats and rabbits.
• This study extends these investigations to cynomolgus monkeys.

Purpose of the Study:

• To assess the developmental toxicity of the antimalarial drug artesunate in pregnant cynomolgus monkeys.
• To evaluate the influence of dosing duration on artesunate's embryotoxic effects.

Main Methods:

• Pregnant cynomolgus monkeys were administered artesunate at various doses (e.g., 4, 12, 30 mg/kg/day) during specific gestational periods (Gestation Days 20-50 or 3-7 day intervals).
• Embryo and fetal development were monitored, including examination for malformations and assessment of embryonic erythroblasts and maternal plasma concentrations (AUC).

Main Results:

• Artesunate induced embryolethality at doses greater than or equal to 12 mg/kg/day when administered for at least 12 days, with observed effects including embryo death, reduced erythroblasts, and cardiomyopathy.
• No developmental toxicity was observed when artesunate was administered for shorter durations (3 or 7 days) at 12 mg/kg/day.
• Embryotoxic exposures in monkeys were lower than human therapeutic exposures, but differences in volume of distribution (Vss) complicate direct risk assessment based on AUC alone.

Conclusions:

• Artesunate exhibits dose-dependent and duration-dependent embryolethality in cynomolgus monkeys.
• The duration of artesunate exposure is a critical factor in its developmental toxicity.
• Findings suggest careful consideration of dosing regimens is necessary when using artesunate during pregnancy.