Teo Steve K, Stirling David I, Hoberman Alan M, Christian Mildred S, Thomas Steve D, Khetani Vikram D
Celgene Corporation, Warren, New Jersey 07059, USA.
Birth Defects Res B Dev Reprod Toxicol. 2003 Apr;68(2):162-71. doi: 10.1002/bdrb.10018.
D,L-threo-Methylphenidate (D,L-MPH) is marketed currently for attention deficit hyperactivity disorder in children. D-threo-methylphenidate (dexmethylphenidate; D-MPH) is a refined formulation of D,L-methylphenidate containing only the active enantiomer and was recently approved in the U.S. for the same condition. D-Methylphenidate has been shown to be efficacious in patients at half the dose of D,L-MPH with a potentially improved therapeutic profile. The developmental toxicity of both compounds was determined and compared in rats and rabbits according to current International Conference on Harmonization (ICH) guidelines.
Groups of pregnant rats were orally dosed twice daily 6 hr apart from Days 7 to 17 of presumed gestation (DG 7-17) for total daily doses of 2, 6 and 20 mg/kg D-MPH and 40 mg/kg D,L-MPH. Groups of presumed pregnant rabbits were similarly dosed from DG 6 to 18 for total daily doses of 4, 20 and 100 mg/kg D-MPH and 200 mg/kg D,L-MPH. Control groups for both studies were given water vehicle. Comprehensive clinical and developmental measurements were made. Satellite groups of animals were included in the main rat and rabbit studies for toxicokinetic assessment.
No drug-related mortality was seen in the F0 rats and rabbits. The number of rats with repetitive pawing, dilated pupil and aggression was significantly greater for the 40 mg/kg D,L-MPH compared to the 20 mg/kg D-MPH dosed rats. Maternal body weight and body weight gain were significantly reduced for both D-MPH and D,L-MPH groups compared to control. Maternal reproductive and litter parameters were unaffected by both drugs. No gross external, soft tissue, or skeletal alterations related to both compounds were seen in the fetuses. In rabbits, head-bobbing and hyperpnea were significantly greater for the 200 mg/kg D,L-MPH compared to 100 mg/kg D-MPH. No other maternal or fetal effects related to both compounds were seen. Exposure to D-MPH (as assessed by AUC) showed no teratogenic effects at exposures of up to 5.6 and 1.7 times for the rat and rabbit respectively compared to children taking the maximum therapeutic dose of 20 mg/day (10 mg twice a day). No teratogenic effects were seen for D,L-MPH in rat and rabbit at exposures of up to 3.7 to 11.7 times that of the maximum therapeutic pediatric dose of 60 mg/ day.
Rats and rabbits dosed with D,L-MPH exhibited significantly greater incidence of maternal clinical observations at twice the dose of D-MPH. Both D-MPH and D,L-MPH were not teratogenic in rats and rabbits at higher exposure levels compared to humans.
消旋甲基苯丙胺（D,L-MPH）目前用于治疗儿童注意力缺陷多动障碍。右旋甲基苯丙胺（右旋安非他明；D-MPH）是D,L-甲基苯丙胺的精制制剂，仅含有活性对映体，最近在美国被批准用于相同病症。已证明D-甲基苯丙胺在剂量仅为D,L-MPH一半时对患者有效，且可能具有更好的治疗效果。根据当前国际协调会议（ICH）指南，在大鼠和兔子中测定并比较了这两种化合物的发育毒性。
在假定的妊娠期（DG 7-17）的第7至17天，对怀孕大鼠组每天口服给药两次，间隔6小时，D-MPH的总日剂量为2、6和20 mg/kg，D,L-MPH为40 mg/kg。假定怀孕的兔子组在DG 6至18天以类似方式给药，D-MPH的总日剂量为4、20和100 mg/kg，D,L-MPH为200 mg/kg。两项研究的对照组均给予溶剂。进行了全面的临床和发育测量。在大鼠和兔子的主要研究中纳入了卫星动物组进行毒代动力学评估。
在F0代大鼠和兔子中未观察到与药物相关的死亡。与给予20 mg/kg D-MPH的大鼠相比，给予40 mg/kg D,L-MPH的大鼠出现反复抓挠、瞳孔散大和攻击行为的数量明显更多。与对照组相比，D-MPH和D,L-MPH组的母体体重和体重增加均显著降低。两种药物均未影响母体生殖和产仔参数。在胎儿中未观察到与这两种化合物相关的明显外部、软组织或骨骼改变。在兔子中，与给予100 mg/kg D-MPH相比，给予200 mg/kg D,L-MPH时头部摆动和呼吸急促明显更严重。未观察到与这两种化合物相关的其他母体或胎儿影响。与服用最大治疗剂量20 mg/天（每天两次，每次10 mg）的儿童相比，大鼠和兔子暴露于D-MPH（通过AUC评估）分别在高达5.6倍和1.7倍的暴露水平下未显示致畸作用。在大鼠和兔子中，当D,L-MPH的暴露水平高达儿科最大治疗剂量60 mg/天的3.7至11.7倍时，未观察到致畸作用。
给予D,L-MPH的大鼠和兔子在D-MPH剂量两倍时母体临床观察的发生率显著更高。与人类相比，在更高暴露水平下，D-MPH和D,L-MPH在大鼠和兔子中均无致畸性。
