Methylphenidate

Methylphenidate HCl is a mild central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate is thought to block the reuptake of noradrenaline and dopamine into the presynaptic neurone and increase the release of these monoamines into the extraneuronal space. Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer.

Absorption

Methylphenidate is readily absorbed. Following oral administration of methylphenidate prolonged-release tablet to adults the drug overcoat dissolves, providing an initial maximum drug concentration at about 1 to 2 hours. The methylphenidate contained in the internal drug layer is gradually released over the next several hours. Peak plasma concentrations are achieved at about 6 to 8 hours, after which plasma levels of methylphenidate gradually decrease. Methylphenidate prolonged-release tablet taken once daily minimises the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily. The extent of absorption of methylphenidate prolonged-release tablet once daily is generally comparable to conventional immediate release preparations.

Following the administration of methylphenidate prolonged-release tablet 18 mg once daily in 36 adults, the mean pharmacokinetic parameters were: C_max 3.7 ± 1.0 (ng/mL), T_max 6.8 ± 1.8 (h), AUC_inf 41.8 ± 13.9 (ng.h/mL), and t_½ 3.5 ± 0.4 (h).

No differences in the pharmacokinetics of methylphenidate prolonged-release tablet were noted following single and repeated once daily dosing, indicating no significant drug accumulation. The AUC and t_1/2 following repeated once daily dosing are similar to those following the first dose of methylphenidate prolonged-release tablet 18 mg.

Following administration of methylphenidate prolonged-release tablet in single doses of 18, 36, and 54 mg/day to adults, C_max and AUC_(0-inf) of methylphenidate were proportional to dose.

Distribution

Plasma methylphenidate concentrations in adults decline biexponentially following oral administration. The half-life of methylphenidate in adults following oral administration of methylphenidate prolonged-release tablet was approximately 3.5 h. The rate of protein binding of methylphenidate and of its metabolites is approximately 15%. The apparent volume of distribution of methylphenidate is approximately 13 litres/kg.

Biotransformation

In humans, methylphenidate is metabolised primarily by de-esterification to alpha-phenyl-piperidine acetic acid (PPA, approximately 50 fold the level of the unchanged substance) which has little or no pharmacologic activity. In adults the metabolism of methylphenidate prolonged-release tablet once daily as evaluated by metabolism to PPA is similar to that of methylphenidate three times daily. The metabolism of single and repeated once daily doses of methylphenidate prolonged-release tablet is similar.

Elimination

The elimination half-life of methylphenidate in adults following administration of methylphenidate prolonged-release tablet was approximately 3.5 hours. After oral administration, about 90% of the dose is excreted in urine and 1 to 3% in faeces, as metabolites within 48 to 96 hours. Small quantities of unchanged methylphenidate are recovered in urine (less than 1%). The main urinary metabolite is alpha-phenyl-piperidine acetic acid (60-90%).

After oral dosing of radiolabelled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPA, accounting for approximately 80% of the dose.

Food Effects

In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of methylphenidate prolonged-release tablet when administered after a high fat breakfast on an empty stomach.

Special Populations

Gender

In healthy adults, the mean dose-adjusted AUC_(0-inf) values for methylphenidate prolonged-release tablet were 36.7 ng.h/mL in men and 37.1 ng.h/mL in women, with no differences noted between the two groups.

Race

In healthy adults receiving methylphenidate prolonged release tablets, dose-adjusted AUC was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics.

Age

The pharmacokinetics of methylphenidate prolonged-release tablet has not been studied in children younger than 6 years of age. In children 7-12 years of age, the pharmacokinetics of methylphenidate prolonged-release tablet after 18, 36 and 54 mg were (mean±SD): C_max 6.0±1.3, 11.3±2.6, and 15.0±3.8 ng/mL, respectively, Tmax 9.4±0.02, 8.1±1.1, 9.1±2.5 h, respectively, and AUC_0-11.5 50.4±7.8, 87.7±18.2, 121.5±37.3 ng.h/mL, respectively.

Renal insufficiency

There is no experience with the use of methylphenidate prolonged-release tablet in patients with renal insufficiency. After oral administration of radiolabelled methylphenidate in humans, methylphenidate was extensively metabolised and approximately 80% of the radioactivity was excreted in the urine in the form of PPA. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of methylphenidate prolonged-release tablets.

Hepatic insufficiency

There is no experience with the use of methylphenidate prolonged-release tablet in patients with hepatic insufficiency.

Carcinogenicity

In life-time rat and mouse carcinogenicity studies, increased numbers of malignant liver tumours were noted in male mice only. The significance of this finding to humans is unknown.

Methylphenidate did not affect reproductive performance or fertility at low multiples of the clinical dose.

Pregnancy-embryonal / foetal development

Methylphenidate is not considered to be teratogenic in rats and rabbits. Foetal toxicity (i.e. total litter loss) and maternal toxicity was noted in rats at maternally toxic doses.