New Prodrug for ADHD in School-aged Children

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Drug Topics Journal, Drug Topics August 2021, Volume 165, Issue 8

Ser/dex is a dexmethylphenidate-based prodrug for ADHD in patients 6 years and older.

Attention-deficit/hyperactivity disorder (ADHD) affects 11% of school-aged children, and more than 75% of these cases will continue into adulthood.1 Without proper diagnosis and treatment, ADHD can lead to serious consequences, including school failure, social difficulties, depression, substance abuse, or job failure. Extensive clinical research has led to well-developed diagnostic criteria and multiple treatment options for ADHD. Serdexmethylphenidate and dexmethylphenidate (Azstarys; Corium), also called ser/dex, is a dexmethylphenidate-based prodrug for ADHD in patients 6 years and older.

Serdexmethylphenidate

Although the mechanism of action for serdexmethylphenidate is not well understood, investigators believe it is mostly converted to dexmethylphenidate in the lower gastrointestinal tract. The combination of immediate-release dexmethylphenidate and slow-absorbed serdexmethylphenidate allows a quick onset and all-day effect.

Efficacy

A 4-week randomized, double-blind, placebo-controlled, parallel-group, classroom study (NCT03292952) evaluated the efficacy of ser/dex versus placebo for the treatment of ADHD in patients 6 to 12 years old. Study results showed a statistically significant lowering of the primary efficacy end point, which was the mean change from baseline of the Swanson, Kotkin, Agler, M-Flynn, and Pelham-Combined (SKAMP-C) ­­scores averaged across the test day.

The study analyzed 150 patients who met Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria and received a diagnosis of ADHD. Patients underwent a 5-day washout period, then a 3-week open-label dose-optimization period followed by a 1-week randomized, double-blind treatment phase. At the end of the 1-week treatment period, raters evaluated the attention and behavior of subjects in a laboratory classroom using the SKAMP-C scale. Assessments were conducted at 0.5, 1, 2, 4, 8, 10, 12, and 13 hours post dose. The overall mean change in SKAMP-C score from baseline (17.9 for both arms of the study) in the ser/dex arm was –4.87 and 0.54 for the placebo arm, which was statistically significant. The proportion of composite responders was similar regardless of age, gender, ethnicity, or race. The trial demonstrated superiority over placebo for the primary end point.2

Safety

The most commonly reported adverse effects (AEs) were headache (5.41%), upper abdominal pain (4.05%), pharyngitis (2.7%), and insomnia (2.7%). There were no serious AEs, nor all-cause mortality reported. Ser/dex is a controlled substance, central nervous system (CNS) stimulant, methylphenidate-containing product, and amphetamine, so there is a boxed warning for a high potential for abuse and dependence. As with many CNS stimulants, there is potential for serious cardiovascular reactions, increased blood pressure and heart rate, psychiatric AEs, peripheral vasculopathy, and long-term growth suppression.

Ser/dex has not been studied in pregnant women; animal embryo-fetal development studies conducted in rats and rabbits showed no malformations. No data are available on the presence of serdexmethylphenidate in human breast milk, effects on the breastfed infant, or effects on milk production. There is limited published literature on dexmethylphenidate present in human breast milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of AEs on the breastfed infant and no effects on milk production. Ser/dex has not been studied in individuals 65 years and older.3

Dosing

The recommended dose for patients 6 to 12 years old is a starting dosage of 39.2 mg/7.8 mg orally once daily in the morning. The dosage may be increased to the maximum dose of 52.3 mg/10.4 mg daily or decreased to 26.1 mg/5.2 mg daily after 1 week. For adults and patients 13 to 17 years old, the recommended starting dosage is 39.2 mg/7.8 mg orally once daily in the morning. The dosage can be increased after 1 week to 52.3 mg/10.4 mg once daily. Ser/dex can be administered without regard to food, and patients can swallow capsules whole or open and sprinkle onto applesauce or add to water. To avoid substitution errors and overdosage, do not substitute for other methylphenidate products on a milligram-per-milligram basis.3

References

  1. About ADHD. CHADD. Updated 2018. Accessed June 30, 2021. https://chadd.org/wp-content/uploads/2018/03/aboutADHD.pdf
  2. KP415 classroom study in children (6-12 years of age) with ADHD. ClinicalTrials.gov. Updated June 30, 2021. Accessed June 30, 2021. https://clinicaltrials.gov/ct2/show/results/NCT03292952?term=03292952&draw=2&rank=1&view=results
  3. Azstarys. Prescribing Information. Corium, Inc; 2021. Accessed June 30, 2021. https://www.corium.com/products/AZSTARYS/AZSTARYS_PI_ENGLISH_US.pdf

Andre S. Wang, PharmD, is a PGY-1 pharmacy resident at UConn John Dempsey Hospital in Farmington, Connecticut.

Kevin W. Chamberlin, PharmD, FASCP, is the university director of pharmacy residency programs at UConn Health in Farmington, Connecticut.