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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.
Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer.
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 and 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) After Single Dose in Healthy Adults
|Parameters||CONCERTA® (18 mg once daily)
|Methylphenidate (5 mg three times daily)
|Cmax (ng/mL)||3.7 ± 1.0||4.2 ± 1.0|
|Tmax (h)||6.8 ± 1.8||6.5 ± 1.8|
|AUCinf (ng•h/mL)||41.8 ± 13.9||38.0 ± 11.0|
|t½ (h)||3.5 ± 0.4||3.0 ± 0.5|
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 t1/2 following repeated once-daily dosing are similar to those following the first dose of CONCERTA® in a dose range of 18 to 144 mg.
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 1/40 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, α-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.
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 AUCTAU of d- and total methylphenidate increased proportionally with respect to dose.
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 hours.
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 three 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.
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.
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.
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.
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.
Increase in age resulted in increased apparent oral clearance (CL/F) (58% increase in adolescents compared to children). Some of these differences could be explained by body-weight differences among these populations. This suggests that subjects with higher body weight may have lower exposures of total methylphenidate at similar doses.
The pharmacokinetics of CONCERTA® have not been studied in children less than 6 years of age.
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® .
There is no experience with the use of CONCERTA® in patients with hepatic insufficiency.
CONCERTA® was demonstrated to be effective in the treatment of Attention Deficit Hyperactivity Disorder (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.
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.
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 2.
Figure 2: Mean Community School Teacher IOWA
Conners Inattention/Overactivity Scores with CONCERTA® once
daily (18, 36, or 54 mg) and placebo. Studies 1 and 2 involved a 3-way crossover
of 1 week per treatment arm. Study 3 involved 4 weeks of parallel-group
treatments with a Last Observation Carried Forward analysis at week 4. Error
bars represent the mean plus standard error of the mean.
In Studies 1 and 2, symptoms of ADHD were evaluated by laboratory schoolteachers using the SKAMP* 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 3 presents the laboratory schoolteacher SKAMP ratings for CONCERTA® and placebo.
*Swanson, Kotkin, Agler, M-Fynn, and Pelham
Figure 3: Laboratory School Teacher SKAMP Ratings: Mean (SEM) of
Combined Attention (Studies 1 and 2)
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.
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.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994.
Last reviewed on RxList: 5/20/2013
This monograph has been modified to include the generic and brand name in many instances.
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