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Attention deficit hyperactivity disorder (ADHD) in children is effectively treated by racemic oral methylphenidate (dl-MPH). The d-isomer (d-MPH) has been developed as an improved treatment for ADHD since only half the racemic dose is used. This study, performed in healthy subjects, assessed the effect of food on the pharmacokinetics of dexmethylphenidate hydrochloride (d-MPH HCl) in a single dose (2 x 10-mg tablets), two-way crossover with d-MPH administered to subjects in both a fasting state or after a high-fat breakfast. There were no serious or unexpected adverse events during the course of this study, with most events reported in comparable numbers of fed and fasted subjects. The bioequivalence of d-MPH was similar with or without food, with 90% confidence intervals of 88.2% to 104.6% and 105.9% to 118.2% for ln(C(max)) and ln[(AUC(0-infinity))], respectively. There was a marginal but statistically significant 1-hour increase in t(max) in the fed versus fasted state, reflecting an absorption delay. The rate of formation of the major metabolite, d-ritalinic acid (d-RA), was marginally decreased ( approximately 14%) after food. The extent of exposure to d-RA was similar (within 1.2%) between both treatments. There was a marginal but statistically significant difference in mean t(max) for d-RA between fed and fasted conditions, with peak concentration occurring 1.5 hours later after d-MPH administration with food. There was no measurable in vivo chiral inversion of d-MPH to l-MPH in plasma. In addition, the metabolism of d-MPH was stereospecific as d-MPH only produced d-RA. In summary, food had no substantial effect on the bioavailability of d-MPH, with an equivalent rate and extent of exposure obtained. Therefore, d-MPH can be administered without regard to food intake.

D-Methylphenidate (dexmethylphenidate; D-MPH) and its racemate D,L-methylphenidate (D,L-MPH) are currently prescribed for the chronic treatment of attention deficit hyperactivity disorder (ADHD) in children. Studies have shown that D-MPH is the pharmacologically active enantiomer for ADHD and is therefore the preferred drug for the treatment of ADHD symptoms. Although studies on the mutagenicity of D,L-MPH have been conducted, similar data for D-MPH are lacking. Therefore, D-MPH was evaluated in the bacterial reverse mutation and mouse lymphoma assays with and without S9 and in a bone marrow micronucleus test in male and female CD-1 mice. As a comparison, the L-enantiomer and racemate were also included in the assessments. While MPH-associated toxicity was observed in the mammalian tests, none of the three compounds tested induced mutagenic or clastogenic effects. Our present results along with published epidemiological data from patient populations are consistent with the conclusion that D-MPH and D,L-MPH do not present a carcinogenic risk to humans.

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.

D,L-methylphenidate (Ritalin) is used to treat attention deficit hyperactivity disorder (ADHD) in children. The therapeutic effect is predominantly due to the d enantiomer. Dexmethylphenidate (D-MPH; Focalin) was therefore developed for its better therapeutic index. The present study determined and compared the acute behavioral toxicity of D,L-MPH, D-MPH and L-MPH in rats after oral dosing. Comprehensive functional observational battery (FOB) evaluations and rota-rod tests were performed 30, 60 and 120 min after dosing. Ten rats/sex/dose were administered a single dose of vehicle, 2, 20, 100 mg/kg D,L-MPH and 1, 10, 50 mg/kg D-MPH or 1, 100, 500 mg/kg L-MPH. There was no mortality. Certain FOB evaluations were statistically significant from vehicle control at any of the time points with most occurring at 60 and 120 min in the high D,L-MPH dose. These included increases in rearing, difficulty in removal from box, arousal, click, tail-pinch and decreases in hind-limb splay distance, hind-limb grip strength and handling reactivity. Behavioral responses were also present at the mid-dose D,L-MPH and high dose D- and L-MPH. Responses in female were significantly different from males in D,L- and L-MPH groups suggesting a sex difference in sensitivity. In the rota-rod test, mean latency to remain on the rod was significantly less for males compared to control given high dose D-MPH and D,L-MPH. In females, latency times were significantly less for high doses of all three compounds. In summary, fewer significant FOBs were seen with D- and L-MPH compared to equimolar doses of D,L-MPH. L-MPH was the least potent in producing FOBs. These results were supported by rota-rod studies.