RELEXXII (Page 6 of 9)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Methylphenidate HCl is a CNS stimulant. The mode of therapeutic action in ADHD is not known.

12.2 Pharmacodynamics

Methylphenidate is a racemic mixture comprised of the d- and l-threo entantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

12.3 Pharmacokinetics

In a relative bioavailability study in healthy adults under fasted conditions, plasma exposures of 72 mg RELEXXII and 72 mg (2 x 36 mg) methylphenidate extended-release tablets were compared. The peak plasma concentration (Cmax ) of RELEXXII and methylphenidate extended-release tablets is 19.7 ng/mL and 19.3 ng/mL, respectively. The area under the plasma concentration-time curve (AUC0-inf ) of RELEXXII and methylphenidate extended-release tablets is 206.1 ng∙h/mL and 200.9 ng∙h/mL, respectively.

Absorption

Methylphenidate is readily absorbed. Following oral administration of RELEXXII plasma methylphenidate concentrations increase rapidly, reaching an initial maximum at about 1.5 hour, followed by gradual ascending concentrations over the next 5 to 6 hours, after which a gradual decrease begins. Mean time to reach peak plasma concentrations of RELEXXII occurs at 5.5 hours.

Methylphenidate hydrochloride extended-release tablets once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily. Figure 1 displays mean plasma exposures of methylphenidate hydrochloride extended-release tablets once daily and methylphenidate three times daily (administered every 4 hours) in adults.

Figure 1: Mean Methylphenidate Plasma Concentration-Time Profiles

Figure 1
(click image for full-size original)

The mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of methylphenidate hydrochloride extended-release tablets 18 mg once daily and methylphenidate 5 mg three times daily are summarized in Table 7.

Table 7. Methylphenidate Pharmacokinetic Parameters (Mean ± SD) After Single Dose in Healthy Adults

Parameters

Methylphenidate Hydrochloride Extended-release Tablets (18 mg once daily) (n=36)

Methylphenidate (5 mg three times daily) (n=35)

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 methylphenidate hydrochloride extended-release tablets were evaluated in healthy adults following single- and multiple-dose administration (steady state) of doses up to 144 mg per day (2 times the maximum recommended daily dosage of methylphenidate hydrochloride extended-release tablets). The mean half-life was about 3.6 hours. No differences in the pharmacokinetics of methylphenidate hydrochloride extended-release tablets 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 methylphenidate hydrochloride extended-release tablets in a dose range of 18 mg to 144 mg.

Effect of Food

There were no differences in either the pharmacokinetics or the pharmacodynamic performance of methylphenidate hydrochloride extended-release tablets when administered after a high-fat breakfast. There is no evidence of dose dumping in the presence or absence of food.

Effect of Alcohol

In-vitr o studies were conducted to explore the effect of alcohol on the release characteristics of methylphenidate from RELEXXII. At alcohol concentrations up to 40%, there was no increased release of methylphenidate in the first two hours.

Dose Proportionality

Following administration methylphenidate hydrochloride extended-release tablets in single doses of 18 mg, 36 mg, and 54 mg per 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 methylphenidate hydrochloride extended-release tablets, 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 methylphenidate hydrochloride extended-release tablets doses from 54 mg to 144 mg per 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 mg to 144 mg per day, both after single dose and upon multiple dosing.

In a multiple-dose study in ADHD with pediatric patients 13 to 16 years administered their prescribed dose (18 mg to 72 mg per day) of methylphenidate hydrochloride extended-release tablets, mean Cmax and AUCTAU of d- and total methylphenidate increased proportionally with respect to dose.

Distribution

Plasma methylphenidate concentrations in adults and pediatric patients 13 to 17 years decline biexponentially following oral administration. The half-life of methylphenidate in adults and adolescents following oral administration of methylphenidate hydrochloride extended-release tablets was approximately 3.5 hours.

Elimination

Metabolism

In humans, methylphenidate is metabolized primarily by de-esterification to PPAA, which has little or no pharmacologic activity. In adults the metabolism of methylphenidate hydrochloride extended-release tablets 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 methylphenidate hydrochloride extended-release tablets is similar.

Excretion

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.

Specific Populations

Male and Female Patients

In healthy adults, the mean dose-adjusted AUC (0–inf) values for methylphenidate hydrochloride extended-release tablets were 36.7 ng∙h/mL in men and 37.1 ng∙h/mL in women, with no differences noted between the two groups.

Racial or Ethnic Groups

In adults receiving methylphenidate hydrochloride extended-release tablets, dose-adjusted AUC (0–inf) was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics.

Pediatric Patients

Increase in age resulted in increased apparent oral clearance (CL/F) (58% increase in pediatric patients 13 to 17 years compared to pediatric patients 6 to 12 years). 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 methylphenidate hydrochloride extended-release tablets have not been studied in pediatric patients less than 6 years of age.

Patients with Renal Impairment

There is no experience with the use of methylphenidate hydrochloride extended-release tablets 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 methylphenidate hydrochloride extended-release tablets.

Patients with Hepatic Impairment

There is no experience with the use of methylphenidate hydrochloride extended-release tablets in patients with hepatic insufficiency.

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