Cardiovascular (CV) Safety and Pharmacokinetics (PK) of Serdexmethylphenidate (SDX), a Prodrug of d-Methylphenidate (d-MPH) Compared to Ritalin and Ritalin LA in a Single-Dose Crossover Study in Healthy Volunteers

This work was sponsored by Zevra Therapeutics Background: SDX, a prodrug of d-methylphenidate (d-MPH), is in clinical development for the treatment of sleep disorders with excessive daytime sleepiness (idiopathic hypersomnia and narcolepsy) and stimulant use disorder. The objectives were to assess the CV safety and PK in healthy volunteers after single oral doses of SDX compared to Ritalin. Methods: 15 healthy male subjects received single oral doses of 80 and 200 mg SDX, 80 mg Ritalin® (immediate release, IR; 2 × 40 mg, 5 hours apart), and 80 mg Ritalin LA® in a randomized cross-over fashion with a washout period of 7 days between each treatment. Multiple blood PK samples and CV safety parameters (heart rate, blood pressure, ECG) were collected after each administration. Results: d-MPH plasma concentrations after SDX peaked later (6-8 hours) versus Ritalin (2-4 hours – first of 2 peaks). Although the SDX doses were equivalent (80 mg) or 2.5-fold higher (200 mg) on a molar basis, the mean maximum exposure to d-MPH (Cmax) after 80 and 200 mg SDX was approximately 25% and 50% lower compared to Ritalin and Ritalin LA, respectively. The majority of AEs reported was typical for CNS stimulants. Peak heart rate changes after SDX were lower to equal to those after Ritalin. Conclusion: Both SDX doses were generally better tolerated compared to Ritalin. From an overall CV safety perspective, vital signs after a single oral dose of 200 mg SDX (the highest dose tested in this study) were comparable to Ritalin IR 80 mg and Ritalin LA 80 mg.