Mechanism of Action

Methylphenidate HCl is a 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 norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

Pharmacodynamics

Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer.

Pharmacokinetics

Absorption

Methylphenidate is readily absorbed. Following oral administration of CONCERTA® , plasma methylphenidate concentrations increase rapidly reaching an initial maximum at about 1 hour, followed by gradual ascending concentrations over the next 5 to 9 hours after which a gradual decrease begins. Mean times to reach peak plasma concentrations across all doses of CONCERTA® occurred between 6 to 10 hours.

CONCERTA® once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily (see Figure 1). The relative bioavailability of CONCERTA® once daily and methylphenidate three times daily in adults is comparable.

Figure 1. Mean methylphenidate plasma concentrations in 36 adults, following a single dose of CONCERTA® 18 mg once daily and immediate-release methylphenidate 5 mg three times daily administered every 4 hours.

The mean single dose pharmacokinetic parameters in 36 healthy adults following the administration of CONCERTA® 18 mg once daily and methylphenidate 5 mg three times daily are summarized in Table 6.

TABLE 6. Pharmacokinetic Parameters (Mean ± SD)

The pharmacokinetics of CONCERTA® were evaluated in healthy adults following single and multiple dose administration (steady-state) of doses up to 144 mg/day. The mean half-life was about 3.6 hours. No differences in the pharmacokinetics of CONCERTA® were noted following single and repeated once-daily dosing indicating no significant drug accumulation. The AUC and t½ following repeated once-daily dosing are similar to those following the first dose of CONCERTA® in a dose range of 18 to 144 mg.

Dose Proportionality

Following administration of CONCERTA® in single doses of 18, 36, and 54 mg/day to healthy adults, Cmax and AUC (0-inf) of d-methylphenidate were proportional to dose, whereas l-methylphenidate Cmax and AUC (0-inf) increased disproportionately with respect to dose. Following administration of CONCERTA® , plasma concentrations of the l-isomer were approximately 1/40th the plasma concentrations of the d-isomer.

In healthy adults, single and multiple dosing of once daily CONCERTA® doses from 54 to 144 mg/day resulted in linear and dose proportional increases in Cmax and AUCinf for total methylphenidate (MPH) and its major metabolite, -phenyl-piperidine acetic acid (PPAA). There was no time dependency in the pharmacokinetics of methylphenidate. The ratio of metabolite (PPAA) to parent drug (MPH) was constant across doses from 54 to 144 mg/day, both after single dose and upon multiple dosing.

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