Oral, intranasal, and intravenous abuse potential of serdexmethylphenidate, a novel prodrug of d-methylphenidate

Abstract

Objectives: Serdexmethylphenidate (SDX) chloride (Cl) is a novel prodrug of d-methylphenidate (d-MPH). These studies evaluated the abuse potential of SDX Cl when administered orally, intranasally (IN), and intravenously (IV).

Methods: Three randomized, double-blind, placebo- and active-controlled crossover studies were conducted in recreational drug users to evaluate the abuse-related effects of oral SDX (120 and 240 mg) vs. extended-release (ER) d-MPH (80 mg) and phentermine (60 mg); IN SDX (80 mg) vs. d-MPH (40 mg), and IV SDX (30 mg) vs. d-MPH (15 mg). Abuse-related subjective measures, pharmacokinetics, and safety were assessed.

Results: The primary endpoint of maximum (E_max) Drug Liking (DL) (0-100-point scale) was significantly higher following d-MPH vs. placebo, validating the studies. In the oral study, DL E_max was significantly higher following 80 mg ER d-MPH (E_max = 81.5) than 120 mg SDX (E_max = 62.8, p < .001) and 240 mg SDX (E_max = 63.8, p = .006); and following 60 mg phentermine (E_max = 80.2) than 120 mg SDX (p = .0195), but not 240 mg SDX (p = .0665). DL E_max scores were significantly higher following IN d-MPH vs SDX (E_max = 93.2 vs. 71.0, p < .0001) and following IV d-MPH vs. SDX (E_max = 84.3 vs. 56.6, p = .001). Intravenous SDX was non-inferior to placebo (p = .001) for DL E_max. Secondary endpoints (e.g. Take Drug Again) were generally consistent with the primary endpoint. Maximal and overall d-MPH exposure was lower for SDX than d-MPH for all routes. Adverse events typical of stimulants were more frequent with d-MPH than SDX.

Conclusions: These findings indicate that the novel d-MPH prodrug, SDX, has lower abuse potential than d-MPH and support its classification as a C-IV controlled substance.

Keywords: Attention-deficit/hyperactivity disorder (ADHD); d-methylphenidate; human abuse potential; serdexmethylphenidate (SDX).