Concerta Mechanism of Action

Pharmacotherapeutic group: centrally acting sympathomimetics. ATC code: N06BA04.
Pharmacology: Pharmacodynamics: Mechanism of action: Methylphenidate hydrochloride is a 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.
Clinical Studies: CONCERTA was demonstrated to be effective in the treatment of ADHD in 4 randomized, double-blind, placebo-controlled studies in children and adolescents and 2 double-blind placebo-controlled studies in adults who met the Diagnostic and Statistical Manual 4th edition (DSM-IV) criteria for ADHD.
Children: Three double-blind, active- and placebo-controlled studies were conducted in 416 children aged 6 to 12 years. The controlled studies compared CONCERTA given once daily (18, 36, or 54 mg), methylphenidate given three times daily over 12 hours (15, 30, or 45 mg total daily dose), and placebo in two single-center, 3-week crossover studies (Studies 1 and 2) and in a multicenter, 4-week, parallel-group comparison (Study 3). The primary comparison of interest in all three trials was CONCERTA versus placebo.
In Studies 1, 2 and 3, symptoms of ADHD were evaluated by community schoolteachers using the Inattention/Overactivity with Aggression (IOWA) Conners scale. Statistically significant reduction in the Inattention/Overactivity subscale versus placebo was shown consistently across all three controlled studies for CONCERTA. The scores for CONCERTA and placebo for the three studies are presented in Figure 1. (See Figure 1.)

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In Studies 1 and 2, symptoms of ADHD were evaluated by laboratory schoolteachers using the SKAMP (Swanson, Kotkin, Agler, M-Flynn, and Pelham) laboratory school rating scale. The combined results from these two studies demonstrated statistically significant improvements in attention and behavior in patients treated with CONCERTA versus placebo that were maintained through 12 hours after dosing.
Figure 2 presents the laboratory schoolteacher SKAMP ratings for CONCERTA and placebo. (See Figure 2.)

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Adolescents: In a randomized, double-blind, multicenter, placebo-controlled trial (Study 4) involving 177 patients, CONCERTA was demonstrated to be effective in the treatment of ADHD in adolescents aged 13 to 18 years at doses up to 72 mg/day (1.4 mg/kg/day). Of 220 patients who entered an open 4-week titration phase, 177 were titrated to an individualized dose (maximum of 72 mg/day) based on meeting specific improvement criteria on the ADHD Rating Scale and the Global Assessment of Effectiveness with acceptable tolerability. Patients who met these criteria were then randomized to receive either their individualized dose of CONCERTA (18-72 mg/day, n=87) or placebo (n=90) during a two-week double-blind phase. At the end of this phase, mean scores for the investigator rating on the ADHD Rating Scale demonstrated that CONCERTA was statistically significantly superior to placebo.
Adults: Two double-blind, placebo-controlled studies were conducted in 627 adults aged 18 to 65 years. The controlled studies compared CONCERTA, administered once daily and placebo in a multicenter, parallel-group, 7-week dose-titration study (Study 5) (36 to 108 mg/day) and in a multicenter, parallel-group, 5-week, fixed-dose study (Study 6) (18, 36, and 72 mg/day).
Study 5 demonstrated the effectiveness of CONCERTA in the treatment of ADHD in adults aged 18 to 65 years at doses from 36 mg/day to 108 mg/day based on the change from baseline to final study visit on the Adult ADHD Investigator Rating Scale (AISRS). Of 226 patients who entered the 7-week trial, 110 were randomized to CONCERTA and 116 were randomized to placebo. Treatment was initiated at 36 mg/day and patients continued with incremental increases of 18 mg/day (36 to 108 mg/day) based on meeting specific improvement criteria with acceptable tolerability. At the final study visit, mean change scores (LS Mean, SEM) for the investigator rating on the AISRS demonstrated that CONCERTA was statistically significantly superior to placebo.
Study 6 was a multicenter, double-blind, randomized, placebo-controlled, parallel-group, dose-response study (5-week duration) with 3 fixed-dose groups (18, 36, and 72 mg). Patients were randomized to receive CONCERTA administered at doses of 18 mg (n=101), 36 mg (n=102), 72 mg/day (n=102), or placebo (n=96). All three doses of CONCERTA were statistically significantly more effective than placebo in improving CAARS (Conners' Adult ADHD Rating Scale) total scores at double-blind end point in adult subjects with ADHD.
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 between peak and trough concentrations associated with immediate-release methylphenidate three times daily – see mean plasma concentration versus time profiles in Figure 3. The relative bioavailability of CONCERTA once daily and methylphenidate three times daily in adults is comparable. (See Figure 3.)

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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 t _½ 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 healthy adults, C_max and AUC_inf of d-methylphenidate were proportional to dose, whereas l-methylphenidate C_max and AUC_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 C_max and AUC_inf 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 C_max and AUC during a dosing interval of the d-isomer 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 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 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 strengths.
Special populations: Gender: In healthy adults, the mean dose-adjusted AUC_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_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: NON-CLINICAL INFORMATION: 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 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 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.