Dasotraline in Children with Attention-Deficit/Hyperactivity Disorder: A Six-Week, Placebo-Controlled, Fixed-Dose Trial

Abstract

Objective: Dasotraline is a potent inhibitor of presynaptic dopamine and norepinephrine reuptake with a pharmacokinetic profile characterized by slow absorption and a long elimination half-life. The aim of this study was to evaluate the efficacy and safety of dasotraline in children with attention-deficit/hyperactivity disorder (ADHD). Methods: Children aged 6-12 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of ADHD were randomized to 6 weeks of double-blind once-daily treatment with dasotraline (2 or 4 mg) or placebo. The primary efficacy endpoint was change from baseline in the ADHD Rating Scale Version IV-Home Version (ADHD RS-IV HV) total score at week 6. Results: A total of 342 patients were randomized to dasotraline or placebo (mean age 9.1 years, 66.7% male). Treatment with dasotraline was associated with significant improvement at study endpoint in the ADHD RS-IV HV total score for the 4 mg/day dose versus placebo (-17.5 vs.-11.4; p < 0.001; effect size [ES], 0.48), but not for the 2 mg/day dose (-11.8 vs.-11.4; ns; ES, 0.03). A regression analysis confirmed a significant linear dose-response relationship for dasotraline. Significant improvement for dasotraline 4 mg/day dose versus placebo was also observed across the majority of secondary efficacy endpoints, including the Clinical Global Impression (CGI)-Severity score, the Conners Parent Rating Scale-Revised scale (CPRS-R) ADHD index score, and subscale measures of hyperactivity and inattentiveness. Discontinuation rates due to adverse events (AEs) were higher in the dasotraline 4 mg/day group (12.2%) compared with the 2 mg/day group (6.3%) and placebo (1.7%). The most frequent AEs associated with dasotraline were insomnia, decreased appetite, decreased weight, and irritability. Psychosis-related symptoms were reported as AEs by 7/219 patients treated with dasotraline in this study. There were no serious AEs or clinically meaningful changes in blood pressure or heart rate on dasotraline. Conclusion: In this placebo-controlled study, treatment with dasotraline 4 mg/day significantly improved ADHD symptoms and behaviors, including attention and hyperactivity, in children aged 6-12 years. The most frequently reported AEs observed on dasotraline included insomnia, decreased appetite, decreased weight, and irritability.

Efficacy and Safety of Dasotraline in Children With ADHD: A Laboratory Classroom Study

“…Body weight in these patients ranged from 21.1 to 33.0 kg, resulting in a weight-adjusted dasotraline dose in the range of 0.182 to 0.284 mg/kg. An increased risk of perceptual disturbance has previously been reported in a 6-week clinical trial (Goldman et al, 2019), notably transient hallucinations in children weighing less than 30 kg treated with dasotraline 4 mg/day, yielding a weight-adjusted dose of ≤0.15 mg/kg. Therefore, the current results indicate that the weight-adjusted dose of dasotraline should generally not exceed 0.15 mg/kg.…”

Dasotraline as a selective cytochrome 2B6 inhibitor for reaction phenotyping

“…If both CYP2B6 and CYP2D6 contribute to the clearance of a compound, it will be difficult to discern the f m between the two enzymes due to the inhibitor cross‐talk. Dasotraline is a serotonin‐norepinephrine‐dopamine reuptake inhibitor under development for ADHD (attention‐deficit/hyperactivity disorder) and possibly other indications (Findling et al, ). Recently, dasotraline has been reported as a time‐dependent inhibitor of CYP2B6 with a K I of 0.12 μM and k inact of 0.15 min −1 in human liver microsomes (Lin, ).…”

“…Dasotraline is a serotonin-norepinephrine-dopamine reuptake inhibitor under development for ADHD (attention-deficit/hyperactivity disorder) and possibly other indications (Findling et al, 2019).…”

Emerging drugs for the treatment of attention-deficit hyperactivity disorder (ADHD)

“…Another placebo controlled randomized double-blind trial [47] was conducted in children. Dasotraline was used at 2 or 4 mg/d for 6 weeks.…”