Methylphenidate Hydrochloride (CD) (Page 5 of 8)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Methylphenidate hydrochloride is a central nervous system (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 lthreo enantiomers. 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 increases the release of these monoamines into the extraneuronal space.

12.3 Pharmacokinetics

Following one week of once-daily doses of 20 mg or 40 mg methylphenidate hydrochloride extended-release capsules (CD) to children aged 7 to12 years old with ADHD, Cmax and AUC of methylphenidate were approximately proportional to the administered doses.

Absorption
Following administration of methylphenidate hydrochloride extended-release capsules (CD) in children aged 7 to 12 years old with ADHD, the plasma concentration time profile of methylphenidate showed two phases of drug release with a sharp, initial slope similar to a methylphenidate immediate-release tablet (median Tmax1 about 1.5 hours post dose), and a second rising portion approximately three hours later (median Tmax2 about 4.5 hours post dose)*, followed by a gradual decline (Figure 1). The means for Cmax and area under the curve (AUC) following a dose of 20 mg were slightly lower than those seen with 10 mg of the immediate-release formulation, dosed at 0 and 4 hours.

*25% to 30% of the subjects had only one observed peak (Cmax ) concentration of methylphenidate.

Figure 1: Comparison of Immediate Release (IR) and Methylphenidate Hydrochloride Extended-Release Capsule (CD) Formulations After Repeated Doses of Methylphenidate Hydrochloride in Pediatric Patients 7 to 12 Years of Age with ADHD

Figure 1
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Effect of Food
Ingestion of a high-fat meal with methylphenidate hydrochloride extended-release capsules (CD) increased the mean Cmax and AUC of methylphenidate by about 30% and 17%, respectively. The presence of food delayed the early peak by approximately 1 hour (range -2 to 5 hours delay) [see Dosage and Administration (2.1)].

The bioavailability (Cmax and AUC) of methylphenidate was unaffected by sprinkling the methylphenidate hydrochloride extended-release capsule (CD) contents on applesauce as compared to the intact capsule.

Effect of Alcohol
At an alcohol concentration of 40%, there was an increase in the release rate of methylphenidate in the first hour, resulting in 84% of the methylphenidate being released. The results with the 60 mg capsule are considered to be representative of the other available capsule strengths [see Drug Interactions (7)].

Distribution
Plasma protein binding is 10% to 33%. The volume of distribution was 2.65 ± 1.11 L/kg for d-methylphenidate and 1.80 ± 0.91 L/kg for l-methylphenidate.

Elimination
The mean terminal half-life (t½) of methylphenidate following administration of methylphenidate hydrochloride extended-release capsules (CD) (t½ =6.8 hours) is longer than the mean terminal t½ following administration of methylphenidate hydrochloride immediate-release tablets (t½ =2.9 hours) and methylphenidate hydrochloride extended-release tablets (t½ =3.4 hours) in healthy adult volunteers.

Metabolism
In vitro studies showed that methylphenidate was not metabolized by cytochrome P450 isoenzymes. Methylphenidate is metabolized primarily by deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity.

Excretion
After oral administration of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was ritalinic acid, accounting for approximately 80% of the dose.

Specific Populations
Male and Female Patients
The pharmacokinetics of methylphenidate after a single dose of methylphenidate hydrochloride extended-release capsules (CD) were similar between adult men and women.

Racial or Ethnic Groups
The influence of race on the pharmacokinetics of methylphenidate after methylphenidate hydrochloride extended-release capsule (CD) administration has not been studied.

Pediatric Patients
The pharmacokinetics of methylphenidate after methylphenidate hydrochloride extended-release capsule (CD) administration has not been studied in children less than 6 years of age.

Patients with Renal Impairment
Methylphenidate hydrochloride extended-release capsules (CD) have not been studied in patients with renal insufficiency. Since renal clearance is not an important route of methylphenidate clearance, and the major metabolite (ritalinic acid), has little or no pharmacologic activity, renal insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate hydrochloride extended-release capsules (CD).

Patients with Hepatic Impairment
Methylphenidate hydrochloride extended-release capsules (CD) have not been studied in patients with hepatic insufficiency. Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body

Drug Interaction Studies
In vitro studies showed that methylphenidate did not inhibit cytochrome P450 isoenzymes at clinically observed plasma drug concentrations.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
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 per day. This dose is approximately 2 times the maximum recommended human dose (MRHD) of 60 mg/day given to children on a mg/m2 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.

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 4 times the MRHD (children) on a mg/m2 basis.

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 per day of methylphenidate.

Mutagenesis
Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. 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 FertilityMethylphenidate 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 per day, approximately 10 times the maximum recommended human dose of 60 mg/day given to adolescents on a mg/m2 basis.

14 CLINICAL STUDIES

Methylphenidate hydrochloride extended-release capsules (CD) were evaluated in a double-blind, parallel-group, placebo-controlled trial in which 321 untreated or previously treated pediatric patients with a DSM-IV diagnosis of Attention Deficit Hyperactivity Disorder (ADHD), 6 to 15 years of age, received a single morning dose for up to 3 weeks. Patients were required to have the combined or predominantly hyperactive-impulsive subtype of ADHD; patients with the predominantly inattentive subtype were excluded. Patients randomized to the methylphenidate hydrochloride extended-release capsules (CD) group received 20 mg daily for the first week. Their dosage could be increased weekly to a maximum of 60 mg by the third week, depending on individual response to treatment.

The patient’s regular school teacher completed the teachers’ version of the Conners’ Global Index Scale (TCGIS), a scale for assessing ADHD symptoms, in the morning and again in the afternoon on three alternate days of each treatment week. The primary efficacy endpoint was determined by the average of the total scores for the 10-item TCGIS completed by the classroom teacher in the morning and again in the afternoon on the three observation days during the last week of double-blind therapy.

Patients treated with methylphenidate hydrochloride extended-release capsules (CD) showed a statistically significant improvement in symptom scores from baseline over patients who received placebo (See Figure 2). Separate analyses of TCGIS scores in the morning and afternoon revealed superiority in improvement with methylphenidate hydrochloride extended-release capsules (CD) over placebo during both time periods (See Figure 3).

Figure 2: Least Squares Mean Change from Baseline in TCGIS Total Score in Pediatric Patients 6 to 15 years of Age with ADHD

Figure2
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Figure 3: Least Squares Mean Change from Baseline in TCGIS Total Score in Pediatric Patients 6 to 15 years of Age with ADHD: Morning (AM) and Afternoon (PM)

figure 3
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* FIGURES 2 & 3: Last observation carried forward analysis at week 3. Error bars represent the standard error of the mean.

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