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Daytrana (Methylphenidate Transdermal) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Daytrana is an adhesive-based matrix transdermal system (patch) that is applied to intact skin. The chemical name for methylphenidate is α-phenyl-2-piperidineacetic acid methyl ester. It is a white to off-white powder and is soluble in alcohol, ethyl acetate, and ether. Methylphenidate is practically insoluble in water and petrol ether. Its molecular weight is 233.31. Its empirical formula is C14H19NO2. The structural formula of methylphenidate is:

Patch Components

Daytrana contains methylphenidate in a multipolymeric adhesive. The methylphenidate is dispersed in acrylic adhesive that is dispersed in a silicone adhesive. The composition per unit area of all dosage strengths is identical, and the total dose delivered is dependent on the patch size and wear time.

The patch consists of three layers, as seen in the figure below (cross-section of the patch).

Proceeding from the outer surface toward the surface adhering to the skin, the layers are (1) a polyester/ethylene vinyl acetate laminate film backing, (2) a proprietary adhesive formulation incorporating Noven Pharmaceuticals, Inc.'s DOT Matrix™ transdermal technology consisting of an acrylic adhesive, a silicone adhesive, and methylphenidate, and (3) a fluoropolymer-coated polyester protective liner which is attached to the adhesive surface and must be removed before the patch can be used.

The active component of the patch is methylphenidate. The remaining components are pharmacologically inactive.

CLINICAL PHARMACOLOGY

Mechanism of Action

Methylphenidate is a CNS stimulant. Its mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known, but methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and to increase the release of these monoamines into the extraneuronal space.

Pharmacodynamics

Methylphenidate is a racemic mixture comprised of the d-and l-enantiomers. The d-enantiomer is more pharmacologically active than the l-enantiomer.

Pharmacokinetics

The pharmacokinetics of Daytrana when applied to the hip for 9 hours have been studied in ADHD patients 6 to 17 years old.

Absorption

The amount of methylphenidate absorbed systemically is a function of both wear time and patch size. In patients with ADHD, peak plasma levels of methylphenidate are reached at about 10 hours after single application and 8 hours after repeat patch applications (12.5cm2 to 37.5cm2) when worn up to 9 hours.

On single dosing with Daytrana to children or adolescents, there was a delay of, on average, 2 hours before d-methylphenidate was detectable in the circulation. On repeat dosing, low concentrations (1.2-3.0 ng/mL in children and 0.5-1.7ng/mL in adolescents, on average across the dose range) were observed earlier in the profile, due to carry-over effect. Following the application of Daytrana once daily with a 9 hour wear time, the mean pharmacokinetic parameters of d-methylphenidate in children and adolescents with ADHD after 4 weeks of therapy are summarized in Table 3.

1 Dose maintained fixed for 28 days;

2 Dose escalated at 7 day intervals from 12.5 cm2 through 18.75 cm2 and 25 cm2 to 37.5 cm2;

3 Dose escalated at 7 day intervals from 18 mg through 27 mg and 36 mg to 54 mg;

4 Median (minimum - maximum); tlag = Last Sampling Time Prior to Time of First Quantifiable Plasma Concentration

Table 3
Mean Plasma d-Methylphenidate Pharmacokinetic Parameters After Repeated 9-Hour Applications of Daytrana or Oral ER-MPH for up to 28 days to Pediatric ADHD Patients (Aged 6 - 17 years)
Children
Parameter Daytrana1
12.5cm2
(N=12)
Daytrana2
37.5cm2
(N=10)
Oral ER-MPH3
18mg
Oral ER-MPH3
54mg
Cssmax
(ng/mL)
15.7 ± 9.39 42.9 ± 22.4 8.37 ± 4.14 26.1 ± 11.2
Cssmin
(ng/mL)
1.04 ± 1.17 1.96 ± 1.73 0.708 ± 1.08 1.19 ± 1.54
AUCss
(ng·hr/mL)
163 ± 101 447 ± 230 97.7 ± 67.0 317 ± 160
tlag
(h)4
0 (0 - 2.0) 0 (0 - 1.0) 0 0
Adolescents
Cssmax
(ng/mL)
8.32 ± 4.60 16.5 ± 6.94 5.23 ± 1.72 18.0 ± 6.97
Cssmin
(ng/mL)
0.544 ± 0.383 1.02 ± 0.629 0.360 ± 0.478 1.50 ± 0.937
AUCss
(ng·hr/mL)
85.7 ± 50.0 167 ± 66.0 59.7 ± 19.1 216 ± 80.8
tlag
(h)4
0 (0 - 2.0) 0 (0 - 2.0) 0 0

Following administration of Daytrana 12.5cm2 to pediatric and adolescent ADHD patients daily for 7 days, there were 13% and 14% increases, respectively, in steady state area under the plasma concentration-time curve (AUCss) relative to that anticipated on the basis of single dose pharmacokinetics (AUC0-∞); after 28 days administration, these increments increased to 64% and 76%, respectively. Cmax increased by nearly 69% and 100% within 4 weeks of daily administration of the starting dose in children and adolescents, respectively.

The observed exposures with Daytrana could not be explained by drug accumulation predicted from observed single dose pharmacokinetics and there was no evidence that clearance or rate of elimination changed between single and repeat dosing. Neither were they explainable by differences in dosing patterns between treatments, age, race, or gender. This suggests that transdermal absorption of methylphenidate may increase with repeat dosing with Daytrana; on average, steady-state is likely to have been achieved by approximately 14 days of dosing.

In the single and multiple dose study described above, exposure to l-methylphenidate was 46% of the exposure to d-methylphenidate in children and 40% in adolescents. l-methylphenidate is less pharmacologically active than d-methylphenidate [ see Pharmacodynamics].

In a phase 2 PK/PD study in children aged 6-12 years, 2/3 of patients had 2-hour d-MPH concentrations < 5 ng/mL on chronic dosing, and at 3 hours 40% of patients had d-MPH concentrations < 5 ng/mL [ see Clinical Studies].

When Daytrana is applied to inflamed skin both the rate and extent of absorption are increased as compared with intact skin. When applied to inflamed skin, lag time is no greater than 1 hour, Tmax is 4 hours, and both Cmax and AUC are approximately 3-fold higher.

When heat is applied to Daytrana after patch application, both the rate and the extent of absorption are significantly increased. Median Tlag occurs 1 hour earlier, Tmax occurs 0.5 hours earlier, and median Cmax and AUC are 2-fold and 2.5-fold higher, respectively.

Application sites other than the hip can have different absorption characteristics and have not been adequately studied in safety or efficacy studies.

Dose Proportionality

Following a single 9-hour application of Daytrana patch doses of 10 mg / 9 hours to 30 mg / 9 hours patches to 34 children with ADHD, Cmax and AUC0-t of d-methylphenidate were proportional to the patch dose. Mean plasma concentration-time plots are shown in Figure 1. Cmax of l-methylphenidate was also proportional to the patch dose. AUC0-t of l-methylphenidate was only slightly greater than proportional to patch dose.

Distribution

Upon removal of Daytrana, methylphenidate plasma concentrations in children with ADHD decline in a biexponential manner. This may be due to continued distribution of MPH from the skin after patch removal.

Metabolism and Excretion

Methylphenidate is metabolized primarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity.

Transdermal administration of methylphenidate exhibits much less first pass effect than oral administration. Consequently, a much lower dose of Daytrana on a mg/kg basis compared to oral dosages may still produce higher exposures of d-MPH with transdermal administration compared to oral administration. In addition, very little, if any, l-methylphenidate is systemically available after oral administration due to first pass metabolism, whereas after transdermal administration of racemic methylphenidate exposure to l-methylphenidate is nearly as high as to d-methylphenidate.

The mean elimination t1/2 from plasma of d-methylphenidate after removal of Daytrana in children aged 6 to 12 years and adolescents aged 13-17 years was approximately 4 to 5 hours. The t1/2 of l-methylphenidate was shorter than for d-methylphenidate and ranged from 1.4 to 2.9 hours, on average.

The Cmax and AUC of d-methylphenidate were approximately 50% lower in adolescents, compared to children, following either a 1-day or 7 day administration of Daytrana (10mg/9hr). Multiple-dose administration of Daytrana did not result in significant accumulation of methylphenidate; following 7 days of Daytrana administration (10mg/9hr) in children and adolescents, the accumulation index of methylphenidate was 1.1, based on the mean steady state area under the plasma concentration-time curve (AUCss) relative to that anticipated on the basis of single dose pharmacokinetics (AUC0-∞).

Food Effects

The pharmacokinetics or the pharmacodynamic food effect performance after application of Daytrana has not been studied, but because of the transdermal route of administration, no food effect is expected.

Special Populations

Gender

The pharmacokinetics of methylphenidate after single and repeated doses of Daytrana were similar between boys and girls with ADHD, after allowance for differences in body weight.

Race

The influence of race on the pharmacokinetics of methylphenidate after administration of Daytrana has not been defined.

Age

The pharmacokinetics of methylphenidate after administration of Daytrana have not been studied in children less than 6 years of age.

Renal Impairment

There is no experience with the use of Daytrana in patients with renal insufficiency.

Hepatic Impairment

There is no experience with the use of Daytrana in patients with hepatic insufficiency.

NONCLINICAL TOXICOLOGY

Carcinogenesis/Mutagenesis and Impairment of Fertility

Carcinogenesis

Carcinogenicity studies of transdermal methylphenidate have not been performed. In a lifetime carcinogenicity study of oral methylphenidate 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. 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.

Orally administered 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.

In a 24-week oral carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. In this study, 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.

Mutagenesis

Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay, and was negative in vivo in the mouse bone marrow micronucleus 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.

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.

CLINICAL STUDIES

Daytrana was demonstrated to be effective in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in two (2) randomized double-blind, placebo-controlled studies in children aged 6 to 12 years and one (1) randomized, double-blind, placebo-controlled study in adolescents aged 13 to 17 years who met Diagnostic and Statistical Manual (DSM-IV-TR®) criteria for ADHD. The patch wear time was 9 hours in all three (3) studies.

In Study 1, conducted in a classroom setting, symptoms of ADHD were evaluated by school teachers and observers using the Deportment Subscale from the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale which assesses behavior symptoms in the classroom setting. Daytrana was applied for 9 hours before removal. There was a 5-week open-label Daytrana dose optimization phase using dosages of 10, 15, 20, and 30 mg / 9 hours, followed by a 2-week randomized, double-blind, placebo-controlled crossover treatment phase using the optimal patch dose for each patient or placebo. The mean differences between Daytrana and placebo in change from baseline in SKAMP Deportment Scores were statistically significant in favor of Daytrana beginning at 2 hours and remained statistically significant at all subsequent measured time points through 12 hours after application of the Daytrana patch.

In Study 2, conducted in the outpatient setting, Daytrana or placebo was blindly administered in a flexible-dose design using doses of 10, 15, 20, and 30 mg / 9 hours to achieve an optimal regimen over 5 weeks, followed by a 2-week maintenance period using the optimal patch dose for each patient. Symptoms of ADHD were evaluated by the ADHD-Rating Scale (RS)-IV. Daytrana was statistically significantly superior to placebo as measured by the mean change from baseline for the ADHD-RS-IV total score. Although this study was not designed specifically to evaluate dose response, in general there did not appear to be any additional effectiveness accomplished by increasing the patch dose from 20 mg / 9 hours to 30 mg / 9 hours.

In Study 3, conducted in the outpatient setting, Daytrana or placebo was blindly administered in a flexible-dose design using doses of 10, 15, 20, and 30 mg / 9 hours during a 5-week dose-optimization phase, followed by a 2-week maintenance period using the optimal patch dose for each patient. Symptoms of ADHD were evaluated using the ADHD-Rating Scale (RS)-IV. Daytrana was statistically significantly superior to placebo as measured by the mean change from baseline in the ADHD-RS-IV total score.

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