Clark Robert L, Youreneff Maureen, DeLise Anthony M
Artemis Pharmaceutical Research, Jacksonville, FL, USA.
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Birth Defects Res B Dev Reprod Toxicol. 2016 Dec;107(6):243-257. doi: 10.1002/bdrb.21189.
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.
蒿甲醚加本芴醇的组合是一种基于青蒿素的联合疗法（ACT），世界卫生组织推荐其用于治疗非复杂性恶性疟，孕期头三个月除外。孕期头三个月的限制是基于青蒿素类药物（如青蒿琥酯、双氢青蒿素和蒿甲醚）在动物身上具有明显的胚胎毒性（包括胚胎死亡以及心脏和骨骼畸形）。在推荐ACT用于孕期头三个月之前，世界卫生组织要求将所有与评估ACT对胚胎风险相关的信息向公众公开。本报告描述了蒿甲醚单独使用、本芴醇单独使用以及二者在大鼠和兔子体内联合使用的胚胎-胎儿发育研究结果，以及本芴醇在怀孕兔子体内的毒代动力学研究结果。本芴醇的发育无影响剂量在大鼠中为300毫克/千克/天（基于1000毫克/千克/天时有25%的窝仔数减少），在兔子中为1000毫克/千克/天。根据人体等效剂量以及血浆C和AUC值计算得出的安全系数在2.5至17倍的范围内。蒿甲醚的发育无影响剂量在大鼠中为3毫克/千克/天，在兔子中为25毫克/千克/天。本芴醇在大鼠和兔子中未导致致畸性，也不是强效胚胎毒素。单独使用蒿甲醚以及蒿甲醚/本芴醇联合使用时，观察到了预期的类似青蒿素的结果，只是未观察到畸形。与其他ACT相比，怀孕大鼠和兔子中未发现会增加对孕期头三个月使用蒿甲醚-本芴醇担忧的情况。
