Dasotraline for the Treatment of Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Trial in Adults

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by symptoms of inattention, hyperactivity, and impulsivity associated with clinically significant impairment in functioning. ADHD has an early onset, but frequently persists, with a prevalence estimate of 4% in adults. Dasotraline is a novel compound that is a potent inhibitor of dopamine and norepinephrine transporters that achieves stable plasma concentrations with once-daily dosing. In this study, adult outpatients meeting DSM-IV-TR criteria for ADHD were randomized to 4 weeks of double-blind, once-daily treatment with dasotraline 4 and 8 mg/day or placebo. The primary efficacy end point was change from baseline at week 4 in the ADHD Rating Scale, Version IV (ADHD RS-IV) total score. Secondary efficacy end points included the Clinical Global Impression, Severity (CGI-S) scale, modified for ADHD symptoms. Least squares (LS) mean improvements at week 4 in ADHD RS-IV total score were significantly greater for dasotraline 8 mg/day vs placebo (−13.9 vs −9.7; P=0.019), and nonsignificantly greater for 4 mg/day (−12.4; P=0.076). The LS mean improvements in modified CGI-S were significantly greater at week 4 for dasotraline 8 mg/day vs placebo (−1.1 vs −0.7; P=0.013), and for 4 mg/day vs placebo (−1.1 vs −0.7; P=0.021). The most frequent adverse events reported were insomnia, decreased appetite, nausea, and dry mouth. Discontinuations due to treatment-emergent adverse events were 10.3% and 27.8% of patients in 4 and 8 mg/day treatment groups, respectively. This study provides preliminary evidence that once-daily dosing with dasotraline, a long-acting, dual monoamine reuptake inhibitor, may be a safe and efficacious treatment for adult ADHD.

Pharmacokinetics and Exposure-Response Relationships of Dasotraline in the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults

“…3 ). The dasotraline concentrations over time observed in adults with ADHD in Study 201 [ 2 ] matched well with the final population pharmacokinetic model predictions over time for dasotraline (Fig. 4 a).…”

“…Study 011 evaluated the pharmacokinetics of single doses of placebo or dasotraline (8, 12, or 16 mg oral solution) in 29 healthy adult volunteers and dasotraline plasma concentrations were measured at 23, 24, and 26 h post dose (total of 19 subjects in dasotraline analysis) in a positron emission tomography (PET) study [ 6 ]. In a phase II clinical trial (Study 201), 341 adult outpatients meeting DSM-IV-TR criteria for ADHD were randomized to 4 weeks of double-blind, once-daily treatment with dasotraline 4, 8 mg/day, or placebo [ 2 ]. The primary efficacy endpoint was change from baseline at week 4 in the ADHD Rating Scale, Version IV, with adult prompts (ADHD RS-IV) total score.…”

“…All virtual subjects that completed each study were assumed to have maintained the target dose level for each simulated dosing regimen scenario. To generate virtual subjects, values of the model predicted significant covariates for the pharmacokinetic and exposure-response models were assigned by randomly resampling these characteristics from subjects in the phase II clinical trial [ 2 ]. The Cox proportional hazard model for dropout was applied to the simulated data for the first 28 days of treatment to obtain a probability of dropout for each subject at each week that was time and concentration dependent as in Study 201.…”

“…The dasotraline pharmacokinetic profile of slow absorption/elimination is unique among current stimulant and nonstimulant medications indicated for ADHD, and can support relatively stable plasma concentrations over a 24-h daily dosing interval. A phase II clinical trial (NCT01692782) with dasotraline demonstrated statistically and clinically meaningful effects in adults with ADHD [ 2 ].…”

Identification of an Esterase Isolated Using Metagenomic Technology which Displays an Unusual Substrate Scope and its Characterisation as an Enantioselective Biocatalyst

“…The tetralin core (α-or β-substituted) is in itself a privileged moiety in drug discovery, being present in a number of drugs and bioactive compounds. [25] When the trans-and cis-acetates 25 and 26 were exposed to esterase 26D, trans-acetate 25 was hydrolysed to a greater degree than cis-acetate 26 ( Table 4, entry 4 and 5). Excellent enantioselectivity was observed in the formation of the cis-tetralol 24 (93% ee).…”