Concerta Mechanism of Action





DCH Auriga - Healthcare
Full Prescribing Info
Pharmacology: Pharmacodynamics: Methylphenidate HCl is a central nervous system 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 1-2 hrs, then increase gradually over the next several hours. Peak plasma concentrations are achieved at about 6-8 hrs after which a gradual decrease in plasma levels of methylphenidate begins. Concerta once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate 3 times daily. The relative bioavailability of Concerta once daily and methylphenidate 3 times daily in adults is comparable.
The mean pharmacokinetic parameters in 36 adults following the administration of Concerta 18 mg once daily and methylphenidate 5 mg 3 times daily are summarized in Table 1. (See Table 1.)

Click on icon to see table/diagram/image

No differences in the pharmacokinetics of Concerta were noted following single and repeated once daily dosing indicating no significant drug accumulation. The AUC and t1/2 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 healthy adults, Cmax and AUC(0-∞) of d-methylphenidate were proportional to dose, whereas 1-methylphenidate Cmax and AUC(0-∞) increased disproportionately with respect to dose. Following administration of Concerta, plasma concentration 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 54-144 mg/day resulted in linear and dose proportional increases in Cmax and AUC(0-∞) for total methylphenidate (MPH) and its major metabolite, (α)-phenyl-piperidine acetic acid (PPAA). The single dose and steady state (Day 4) clearance and t½ 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 54-144 mg/day, both after single dose and upon multiple dosing.
In a multiple-dose study in adolescent ADHD patients 13-16 years of age administered 18-72 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 t1/2 of methylphenidate in adults following oral administration of Concerta was approximately 3.5 hrs.
Metabolism and Excretion: In humans, methylphenidate is metabolized primarily by de-esterification to 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 3 times daily. The metabolism of single and repeated once-daily doses of Concerta is similar.
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.
Special Populations: Gender: In healthy adults, the mean dose-adjusted AUC(0-∞) values for Concerta were 36.7 ng·hr/mL in men and 37.1 ng·hr/mL in women, with no differences noted between the 2 groups.
Race: In adults receiving Concerta, dose-adjusted AUC(0-∞) 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 <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: Preclinical Safety Data: In a lifetime carcinogenicity study carried out in mice, methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas at a daily dose of approximately 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 HCl dose of up to 45 mg/kg/day showed no evidence of carcinogenicity.
In a 24-week study in transgenic mouse strain p53+/-, there was no evidence of carcinogenicity at methylphenidate doses of up to 74 mg/kg/day.
No adverse toxicologic effects were seen in 2 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.
Exclusive offer for doctors
Register for a MIMS account and receive free medical publications worth $768 a year.
Sign up for free
Already a member? Sign in