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BACKGROUND: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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. © 2003 Wiley‐Liss, Inc.