Pharmacodynamics

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. 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 12 years old.

Absorption

When Daytrana™ was titrated to effect in the pivotal phase III clinical efficacy study, after at least 6 weeks of therapy with 9 hour wear times when applied to alternating hips, the mean peak d-methylphenidate (d-MPH) plasma concentration was 39 ng/mL with a range of 0 – 114 ng/mL. These mean peak concentrations varied inversely by age ranging from 25 ng/mL, (range 2 – 80 ng/mL) in 12 year olds, to 53 ng/mL (range 18 – 83 ng/mL) in 6 year olds.

Daytrana™ mean peak d-MPH concentrations were approximately 1.9-fold higher than the highest observed concentrations after a once-daily oral methylphenidate formulation over a period of 7.5 to 10.5 hours, when Tmax typically occurs. These higher concentrations were observed for all children 6 – 12 years of age, both overall and when grouped by age. The Daytrana™ peak concentrations on chronic dosing were also higher than Cmaxs seen with Daytrana™ after single dosing, or 4 days of multiple dosing. With single doses of

Daytrana™, peak concentrations were comparable to Cmaxs from single doses of the once daily oral MPH formulation.

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 chronic therapy with the methylphenidate transdermal system.

On multiple dosing of the transdermal system, exposure to l-methylphenidate was 27% to 45% lower, on average, than exposures to d-methylphenidate. For comparison, little if any l– methylphenidate was detectable after administration of a once daily oral MPH formulation. l- methylphenidate is less pharmacologically active than d-methylphenidate.

The average lag time (i.e., the time until any d-MPH is detectable in the circulation) was 3.1 hours, (range 1- 6 hours) with Daytrana™ in the single dose study. In the phase II PK/PD study, 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 - Study 1).

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 T_lag occurs 1 hour earlier and 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 hour to 30 mg / 9 hour patches to 34 children with ADHD, Cmax and AUC_0-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. AUC_0-t of l- methylphenidate was only slightly greater than proportional to patch dose.

FIGURE 1: Mean Concentration-time Profiles for d-Methylphenidate in all Patients (N=34) Following Administration of Single Applications (9-Hour Wear Time) of d,l- Methylphenidate Using Daytrana™ 10 mg (⇔), 20 mg (◊) and 30 mg (Δ) per 9-Hour Patches

Distribution

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