Objectives: To characterize the pharmacokinetic and pharmacodynamic data to explore the time course and exposure response relationships in Phase 2 to define dasotraline benefit to risk relationship in adult Attention Deficit Hyperactivity Disorder (ADHD) subjects. Simulations were performed to support Phase 3 study design and dose selection.
Methods: Dasotraline population PK were analyzed using data from 395 subjects after single/multiple doses from 0.2 to 36 mg (3 Phase 1 and Phase 2 studies). PK/ PD models related individual dasotraline exposures to norepinephrine metabolite DHPG concentrations, ADHD RS-IV total scores, and time to study dropout using data from 330 ADHD subjects. Final models were validated using VPCs. Clinical trial simulation scenarios examined a range of doses and durations to predict: minimal effective dose, no effect dose, and optimal duration of treatment for the planned efficacy study and determine the likelihood of a positive trial outcome (statistically significant ADHD RS-IV response comparing dasotraline to placebo with clinically meaningful effect size).
Results: A one-compartment model with dual (linear plus nonlinear) elimination described dasotraline PK. In an ADHD population administered 4 or 8 mg/day, dasotraline was characterized by a mean apparent half-life of 47 hours and steady-state by 10 days of dosing. The exposure response model for DHPG was a power function of predicted concentrations indicating clinically significant NET inhibition. Dasotraline average concentrations (Cav) reduced ADHD RS-IV according to a sigmoid Emax time-course model. A Cox proportional hazard model related time-varying Cav to the log of the survival function for dropout. Clinical trial simulations predicted 4 mg/day minimum effective dose, 2 mg/day no effect dose, and a sufficient likelihood of success for 8 week trials with 200 subjects per group (Figure 1).
Conclusions: Modeling and simulations successfully related dasotraline PK to pharmacological activity via DHPG and ADHD RS-IV scores supporting the concept that maintaining constant, steady-state inhibition of both dopamine and norepinephrine transporters is a novel pharmacological approach to the management of ADHD symptoms.
American Conference on Pharmacometrics (ACoP) Annual Meeting: October 4-7, 2015, Crystal City, VA
By Seth C. Hopkins; Soujanya Sunkaraneni; Estela Skende; Jeremy Hing; Julie Pasarell; Antony Loebel; Kenneth S. Koblan