Pharmacodynamics

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

FIGURE 1

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

The mean pharmacokinetic parameters in 36 adults following the administration of CONCERT A® 18 mg qd and methylphenidate 5 mg tid are summarized in Table 1.

TABLE 1: Mean ± SD Pharmacokinetic Parameters

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® 18 mg.

Dose Proportionality

Following administration of CONCERTA® in single doses of 18, 36, and 54 mg/day to 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 a multiple-dose study in adolescent ADHD patients aged 13 to 16 administered their prescribed dose (18 to 72 mg/day) of CONCERTA®, mean Cmax and AUC_TAU of d- and total methylphenidate increased proportionally with respect to dose.

Distribution

Plasma methylphenidate concentrations in adults and adolescents decline biexponentially following oral administration. The half-life of methylphenidate in adults and adolescents following oral administration of CONCERTA® was approximately 3.5 h.

Metabolism and Excretion

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