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9. A 90-Day Oral Gavage Toxicity Study of d -Methylphenidate and d , l -Methylphenidate in Beagle Dogs.

Author

Teo, Steve K., Stirling, David I., Thomas, Steve D., Evans, Mark G., and Khetani, Vikram D.

Subjects
TOXICITY testing, TREATMENT of attention-deficit hyperactivity disorder, BODY weight, WEIGHT loss, CLINICAL pathology
Abstract

d-Methylphenidate (d-MPH) was approved as a treatment for attention deficit hyperactivity disorder (ADHD) in children. The repeated-dose toxicity of the d enantiomer of d,l-methylphenidate (d,l-MPH) was assessed in male and female Beagle dogs. Dogs were orally dosed twice a day in equally divided doses 6 hours apart for total daily doses of 1, 3, and 10 mg/kg/day d-MPH or 20 mg/kg/day d,l-MPH for 90 days, followed by a 30-day recovery period. The top d-MPH dose of 10 mg/kg was equimolar to 20 mg/kg d,l-MPH in d-MPH content. The 10-mg/kg d-MPH and d,l-MPH doses were at least 13 times the maximum therapeutic dose giving rise to systemic exposures that were equivalent to or at least 2 times greater than those at the maximum therapeutic doses in children. The 10-mg/kg d-MPH and 20-mg/kg d,l-MPH doses had systemic exposures that were equivalent to or two to five times greater than the maximum therapeutic plasma levels in children respectively. There was no treatment-related mortality in all doses tested. Reversible salivation, hyperactivity, and diarrhea were seen in the high-dose d-MPH and d,l-MPH groups. Significant body weight loss and reduction in food consumption were observed in males for both high-dose groups with weights comparable to control values by the end of the recovery period. There were no abnormal clinical pathology or macroscopic or microscopic findings. Based on body weight changes, the no-observed-adverse-effect level (NOAEL) of d-MPH in beagle dogs was 3 mg/kg/day. [ABSTRACT FROM AUTHOR]

Published
2003
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10. D‐methylphenidate and D,L‐methylphenidate are not developmental toxicants in rats and rabbits

Author

Teo, Steve K., Stirling, David I., Hoberman, Alan M., Christian, Mildred S., Thomas, Steve D., and Khetani, Vikram D.

Abstract

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.

Published
2003
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15. A 90-day oral gavage toxicity study of d-methylphenidate and d,l-methylphenidate in beagle dogs.

Author

Teo SK, Stirling DI, Thomas SD, Evans MG, and Khetani VD

Subjects
Administration, Oral, Animals, Behavior, Animal drug effects, Behavior, Animal physiology, Body Weight drug effects, Central Nervous System Stimulants administration & dosage, Central Nervous System Stimulants pharmacokinetics, Dogs, Dose-Response Relationship, Drug, Drug Administration Schedule, Eating drug effects, Female, Male, Methylphenidate administration & dosage, Methylphenidate pharmacokinetics, No-Observed-Adverse-Effect Level, Recovery of Function, Stereoisomerism, Central Nervous System Stimulants toxicity, Methylphenidate toxicity
Abstract

d-Methylphenidate (d-MPH) was approved as a treatment for attention deficit hyperactivity disorder (ADHD) in children. The repeated-dose toxicity of the d enantiomer of d,l-methylphenidate (d,l-MPH) was assessed in male and female Beagle dogs. Dogs were orally dosed twice a day in equally divided doses 6 hours apart for total daily doses of 1, 3, and 10 mg/kg/day d-MPH or 20 mg/kg/day d,l-MPH for 90 days, followed by a 30-day recovery period. The top d-MPH dose of 10 mg/kg was equimolar to 20 mg/kg d,l-MPH in d-MPH content. The 10-mg/kg d-MPH and d,l-MPH doses were at least 13 times the maximum therapeutic dose giving rise to systemic exposures that were equivalent to or at least 2 times greater than those at the maximum therapeutic doses in children. The 10-mg/kg d-MPH and 20-mg/kg d,l-MPH doses had systemic exposures that were equivalent to or two to five times greater than the maximum therapeutic plasma levels in children respectively. There was no treatment-related mortality in all doses tested. Reversible salivation, hyperactivity, and diarrhea were seen in the high-dose d-MPH and d,l-MPH groups. Significant body weight loss and reduction in food consumption were observed in males for both high-dose groups with weights comparable to control values by the end of the recovery period. There were no abnormal clinical pathology or macroscopic or microscopic findings. Based on body weight changes, the no-observed-adverse-effect level (NOAEL) of d-MPH in beagle dogs was 3 mg/kg/day.

Published
2003
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