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
(18 mg once daily)
(5 mg three times daily)
||3.7 ± 1.0
||4.2 ± 1.0
||6.8 ± 1.8
||6.5 ± 1.8
||41.8 ± 13.9
||38.0 ± 11.0
||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.
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.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
In a lifetime carcinogenicity study carried out in B6C3F1 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 dose is approximately 30 times and 4 times the maximum recommended human dose of CONCERTA® on a mg/kg and mg/m2 basis, respectively. 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.
Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and 5 times the maximum recommended human dose of CONCERTA® on a mg/kg and mg/m2 basis, respectively.
In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate.
Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay.
Impairment of Fertility
Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 80-fold and 8-fold the highest recommended human dose of CONCERTA® on a mg/kg and mg/m2 basis, respectively.