"The U.S. Food and Drug Administration today allowed marketing of the first medical device based on brain function to help assess attention-deficit/hyperactivity disorder (ADHD) in children and adolescents 6 to 17 years old. When used as part of "...
Mechanism Of Action
Methylphenidate HCl is a central nervous system (CNS) stimulant.
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 thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.
Following a single, 60 mg oral dose of QUILLIVANT XR in 28 healthy adult subjects in a crossover study under fasting conditions, d-methylphenidate (d-MPH) mean (± SD) peak plasma concentrations of 13.6 (± 5.8) ng/mL occurred at a median time of 5.0 hours after dosing (Figure 2). The relative bioavailability of QUILLIVANT XR compared to Methylphenidate IR oral solution (2x30 mg, q6h) is 95%.
Figure 2: Mean d-Methylphenidate Plasma
The single dose pharmacokinetics of d-MPH under fed conditions are summarized (Table 3) from studies in children and adolescents with ADHD, and healthy adults following an oral dose of 60 mg QUILLIVANT XR.
Table 3: d-MPH PK Parameters
(mean ± SD) after 60 mg oral dosing of QUILLIVANT XR*
|Tmax (hr)‡||4.05 (3.98-6.0)||2.0 (1.98-4.0)||4.0 (1.3-7.3)|
|T½ (hr)||5.2 ± 0.1||5.0 ± 0.2||5.2 ± 1.0|
|Cmax (ng/mL)||34.4 ± 14.0||21.1 ± 5.9||17.0 ± 7.7|
|AUCinf (hr*ng/mL)||378 ± 175||178 ± 54.2||163.2 ± 80.3|
|Cl (L/hr/kg)||4.27 ± 0.70||5.06 ± 1.42||5.66 ± 2.15|
|* Breakfast was given 30 min prior to drug administration
† total MPH measured in children (9-12 years old) and adolescents (13-15 years old), l-MPH < 2% of d-MPH in circulation
‡ data presented as median (range)
Metabolism and Excretion
Following a single 60 mg oral dose of QUILLIVANT XR in 28 healthy adult subjects under fasting conditions, the mean plasma terminal elimination half-life of d-methylphenidate was 5.6 (± 0.8) hours.
In humans, methylphenidate is metabolized primarily via deesterification to alpha-phenyl-piperidine acetic acid (PPAA). The metabolite has little or no pharmacologic activity.
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 a study in adult volunteers to investigate the effects of a high-fat meal on the bioavailability of QUILLIVANT XR at a dose of 60 mg, the presence of food reduced the time to peak concentration by approximately 1 hour (fed: 4 hours vs. fasted: 5 hours). Overall, a high-fat meal increased the average Cmax of QUILLIVANT XR by about 28% and the AUC by about 19%. These changes are not considered clinically significant.
There is insufficient experience with the use of QUILLIVANT XR to detect gender variations in pharmacokinetics. Race There is insufficient experience with the use of QUILLIVANT XR to detect ethnic variations in pharmacokinetics.
The pharmacokinetics of methylphenidate after QUILLIVANT XR administration were studied in pediatric patients with ADHD between 9 and 15 years of age. After a single oral dose of 60 mg QUILLIVANT XR, plasma concentrations of methylphenidate in children (9-12 years old; n=3) were approximately twice the concentrations observed in adults. The plasma concentrations in adolescent patients (13-15 years old; n=4) were similar to those in adults.
There is no experience with the use of QUILLIVANT XR 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 QUILLIVANT XR.
There is no experience with the use of QUILLIVANT XR in patients with hepatic insufficiency.
The efficacy of QUILLIVANT XR was evaluated in a laboratory classroom study conducted in 45 pediatric patients (ages 6 to 12 years) with ADHD. The study began with an open-label dose optimization period (4 to 6 weeks) with an initial QUILLIVANT XR dose of 20 mg once daily in the morning. The dose could be titrated weekly in increments of 10 or 20 mg until an optimal dose or the maximum dose of 60 mg/day was reached. Subjects then entered a 2-week randomized, double-blind, crossover treatment with the individually optimized dose of QUILLIVANT XR or placebo. At the end of each week, school teachers and raters evaluated the attention and behavior of the subjects in a laboratory classroom using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale. The primary efficacy endpoint was the SKAMP-Combined score at 4 hours post-dosing. The key secondary efficacy endpoints were the SKAMP-Combined scores at 0.75, 2, 8, 10, and 12 hours post-dosing.
Results from the first double-blind, placebo-controlled week of the study are summarized in Figure 3. SKAMP-Combined scores were statistically significantly lower (improved) at all time points (0.75, 2, 4, 8, 10, 12 hours) post-dosing with QUILLIVANT XR compared to placebo.
Figure 3: Absolute SKAMP-Combined Score after
treatment with QUILLIVANT XR or Placebo during Period 1.
Last reviewed on RxList: 2/14/2014
This monograph has been modified to include the generic and brand name in many instances.
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