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Feb 6, 2015
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A Population-Based PK/PD Analysis Of Dasotraline Efficacy In The Treatment Of ADHD In Adults


Background: Dasotraline (SEP-225289) is a new chemical entity with a slow elimination half-life demonstrating dopamine (DAT) and norepinephrine (NET) transporter inhibition in clinical studies. Here we hypothesized dasotraline plasma concentrations, measured in an efficacy trial of adult ADHD, would be correlated with improvements in ADHD RS-IV across subjects, treatment groups, and visits.

Methods: Plasma concentrations of dasotraline from Phase I and Phase 2 studies were analyzed by population PK methodology. A 1-compartment population PK model with sequential zero-order followed by first-order absorption and dual (nonlinear and linear) elimination described dasotraline PK across a total of 395 subjects after single or multiple dose administrations ranging from 0.2 to 36 mg. Norepinephrine metabolite 3,4-dihydroxyphenylglycol (DHPG) concentrations from 220 subjects were modeled as a power function of the time-matched dasotraline concentrations as derived from the PK model. Population PK/PD model for ADHD RS-IV scores and dasotraline concentrations (Cav) was a sigmoid Emax time-course model.

Results: The population PK/PD model for ADHD RS-IV scores and dasotraline concentrations (Cav) was a sigmoid Emax time-course model. Steady-state plasma concentrations were attained by 2 weeks with a mean apparent half-life of 47 hours. Concentrations of the norepinephrine metabolite DHPG indicated central NET inhibition was achieved within the first days of dosing. An exposure-response relationship was found between increases in Cav, Emax and reductions in ADHD RS-IV.

Discussion: These results demonstrate a dose- and concentration-response relationship of pharmacological activity in ADHD, 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 Professional Society of ADHD and Related Disorders (APSARD) Annual Meeting, Jan. 16 – 18, 2015, Washington DC

By Seth C. Hopkins; Soujanya Sunkaraneni; Estela Skende; Julie Passarell; Jeremy Hing; Antony Loebel; Kenneth S. Koblan

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