Concerta Mechanism of Action



Johnson & Johnson
Full Prescribing Info
Pharmacotherapeutic group: Centrally-acting sympathomimetics. ATC code: N06BA04.
Pharmacology: Pharmacodynamics: Mechanism of Action: Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. The mode of therapeutic action in 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 to adults, plasma methylphenidate concentrations increase rapidly reaching an initial maximum at about 1 to 2 hours, then increase gradually over the next several hours. Peak plasma concentrations are achieved at about 6 to 8 hours after which a gradual decrease in plasma levels of methylphenidate begins. CONCERTA once daily minimizes the fluctuations betvveen peak and trough concentrations associated with immediate-release methylphenidate three times daily. The relative bioavailability of CONCERTA once daily and methylphenidate three times daily in adults is comparable.
The mean pharmacokinetic parameters in 36 adults following the administration of CONCERTA 18 mg once daily and methylphenidate hydrochloride 5 mg three times daily are summarized in Table 1. (See Table 1.)

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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.
Dose proportionality: Following administration of CONCERTA in single doses of 18, 36, and 54 mg/day to adults, C-max 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, (alpha)-phenyl-piperidine acetic acid (PPAA). The single dose and steady state (Day 4) clearance and half-life parameters were similar, indicating that 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.
In a multiple-dose study in adolescent ADHD patients aged 13 to 16 years administered 18 to 72 mg/day of CONCERTA, mean Cmax and AUCTAU of d- and total methylphenidate increased proportionally with respect to dose.
Distribution: Plasma methylphenidate concentrations in adults decline biexponentially following oral administration. The half-life of methylphenidate in adults following oral administration of CONCERTA was approximately 3.5 h.
Metabolism: In humans, methylphenidate is metabolized primarily by deesterification to (alpha)-phenyl-piperidine acetic acid (PPAA) which has little or no pharmacologic activity. In adults, the metabolism of CONCERTA once daily as evaluated by metabolism to PPAA is similar to that of methylphenidate three times daily. The metabolism of single and repeated once daily doses of CONCERTA is similar.
Elimination: After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPAA, accounting for approximately 80% of the dose.
Food effects: In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of CONCERTA when administered after a high fat breakfast. There is no evidence of dose dumping in the presence or absence of food.
Alcohol effect: An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the CONCERTA 18 mg tablet dosage form. At an alcohol concentration up to 40% there was no increased release of methylphenidate in the first hour. The results with the 18 mg tablet strength are considered representative of the other available tablet strength.
Special populations: Gender: In healthy adults, the mean dose-adjusted AUC(0-inf) values for CONCERTA 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 adults receiving CONCERTA, dose-adjusted AUC(0-inf) was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics.
Age: The pharmacokinetics of CONCERTA has not been studied in children less than 6 years of age.
Renal Insufficiency: There is no experience with the use of CONCERTA in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of PPAA. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of CONCERTA.
Hepatic Insufficiency: There is no experience with the use of CONCERTA in patients with hepatic insufficiency.
Toxicology: In a lifetime carcinogenicity study carried out in mice, methylphenidate hydrochloride caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas at a daily dose of 60 mg/kg/day. This is considerably higher than the recommended human dose on a mg/kg basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown.
A similar lifetime study in the rat at a methylphenidate hydrochloride dose of up to 45 mg/kg/day showed no evidence of carcinogenicity.
In a 24-week study in the transgenic mouse strain p53+/-, there was no evidence of carcinogenicity at methylphenidate hydrochloride doses of up to 74 mg/kg/day.
No adverse toxicologic effects were seen in two separate 30-day oral dosing studies in dogs with CONCERTA at doses up to 72 mg/day (up to 8.6 mg/kg/day) and 144 mg/day (up to 22 mg/kg/day), respectively.
Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchange and chromosome aberrations were increased in an in vitro test on cultured ovary cells of Chinese Hamster. Methylphenidate was negative in vivo in the mouse bone marrow micronucleus assay.
All other safety data relevant to the prescriber have been included in the appropriate section.
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