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

Clinical Drug Investigation, Nov 2015

Background and Objectives Dasotraline is a novel inhibitor of dopamine and norepinephrine reuptake currently being investigated in clinical studies for the treatment of attention-deficit/hyperactivity disorder (ADHD). Uniquely, relative to current ADHD medications, dasotraline has a slow absorption and long elimination half-life. Here we relate the pharmacokinetics and pharmacodynamics of dasotraline to reduction in ADHD symptoms based on simulated clinical trial outcomes. Methods Dasotraline pharmacokinetics were analyzed by population pharmacokinetic methodologies using data collected from 395 subjects after single or multiple oral dose administrations ranging from 0.2 to 36 mg (three phase I studies and one phase II ADHD study). Population pharmacokinetic and pharmacodynamic models related individual dasotraline exposures to norepinephrine metabolite 3,4-dihydroxyphenylglycol (DHPG) concentrations, ADHD symptoms, and study discontinuation (probability of dropout). Results Dasotraline pharmacokinetics were described by a one-compartment model with dual (linear plus nonlinear) elimination. In an ADHD population treated with dasotraline 4 or 8 mg/day, dasotraline was characterized by a mean apparent half-life of 47 h and plasma concentrations reached steady-state by 10 days of dosing. A population pharmacokinetic and pharmacodynamic model of DHPG indicated clinically significant norepinephrine transporter inhibition was achieved as a function of time-matched dasotraline concentrations. Dasotraline exposure reduced ADHD symptoms in a sigmoid E max time-course model. Clinical trial simulations described the effects of dose, duration, and sample size on clinical outcomes. Conclusion These results related dasotraline pharmacokinetics to pharmacological activity in ADHD, and support the novel concept that maintaining constant, steady-state dopamine and norepinephrine reuptake inhibition throughout a 24-h dosing interval is a novel pharmacological approach to the management of ADHD symptoms. Clinicaltrials.gov identifier: NCT01692782.

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

Clin Drug Investig Pharmacokinetics and Exposure-Response Relationships of Dasotraline in the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults Seth C. Hopkins 0 1 2 3 Soujanya Sunkaraneni 0 1 2 3 Estela Skende 0 1 2 3 Jeremy Hing 0 1 2 3 Julie A. Passarell 0 1 2 3 Antony Loebel 0 1 2 3 Kenneth S. Koblan 0 1 2 3 Key Points 0 1 2 3 0 Sunovion Pharmaceuticals Inc. , Fort Lee, NJ , USA 1 Sunovion Pharmaceuticals Inc. , 84 Waterford Drive, Marlborough, MA 01752 , USA 2 & Seth C. Hopkins 3 Cognigen Corporation , Buffalo, NY , USA Background and Objectives Dasotraline is a novel inhibitor of dopamine and norepinephrine reuptake currently being investigated in clinical studies for the treatment of attentiondeficit/hyperactivity disorder (ADHD). Uniquely, relative to current ADHD medications, dasotraline has a slow absorption and long elimination half-life. Here we relate the pharmacokinetics and pharmacodynamics of dasotraline to reduction in ADHD symptoms based on simulated clinical trial outcomes. Methods Dasotraline pharmacokinetics were analyzed by population pharmacokinetic methodologies using data collected from 395 subjects after single or multiple oral dose administrations ranging from 0.2 to 36 mg (three phase I studies and one phase II ADHD study). Population pharmacokinetic and pharmacodynamic models related individual dasotraline exposures to norepinephrine metabolite 3,4-dihydroxyphenylglycol (DHPG) concentrations, ADHD symptoms, and study discontinuation (probability of dropout). Results Dasotraline pharmacokinetics were described by a one-compartment model with dual (linear plus nonlinear) elimination. In an ADHD population treated with dasotraline 4 or 8 mg/day, dasotraline was characterized by a mean apparent half-life of 47 h and plasma concentrations reached steady-state by 10 days of dosing. A population pharmacokinetic and pharmacodynamic model of DHPG indicated clinically significant norepinephrine transporter inhibition was achieved as a function of time-matched dasotraline concentrations. Dasotraline exposure reduced ADHD symptoms in a sigmoid Emax time-course model. Clinical trial simulations described the effects of dose, duration, and sample size on clinical outcomes. Conclusion These results related dasotraline pharmacokinetics to pharmacological activity in ADHD, and support the novel concept that maintaining constant, steady-state dopamine and norepinephrine reuptake inhibition throughout a 24-h dosing interval is a novel pharmacological approach to the management of ADHD symptoms. Clinicaltrials.gov identifier: NCT01692782. - Population pharmacodynamic models related individual dasotraline exposures to concentrations of the norepinephrine metabolite DHPG, ADHD symptoms, and study discontinuation (probability of dropout), and Monte Carlo simulations described the effects of dose, duration, and sample size on clinical outcomes. 1 Introduction Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by symptoms of inattention, hyperactivity, and impulsivity associated with clinically significant impairment in functioning. Dopamine and norepinephrine are associated with the pathophysiology of ADHD, and drugs that facilitate synaptic concentrations of dopamine and norepinephrine are clinically useful in the pharmacological management of ADHD symptoms [ 1 ]. Dasotraline [(1R,4S)-4(3,4-Dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine] is a novel compound in clinical development for the treatment of ADHD. Dasotraline is a potent inhibitor of human dopamine transporters (DAT; dopamine uptake IC50 3 nM) and norepinephrine transporters (NET; norepinephrine uptake IC50 4 nM), and a weaker inhibitor of human serotonin transporters (SERT; serotonin uptake IC50 15 nM; Sunovion data on file). 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 ]. Pharmacokinetic and pharmacodynamic modeling provides a method for synthesizing data from a variety of sources, including receptor occupancy, clinical pharmacology, efficacy measures, and safety outcomes for new drugs. Pharmacokinetic and pharmacodynamic models can then be used to perform Monte Carlo simulations of clinical trial outcomes under various treatment scenarios. Simulations provide quantitative assessments of drug performance under different clinical trial scenarios, and a basis for deciding whether to proceed with subsequent late-stage clinical development [ 3–5 ]. This paper describes the development of pharmacokinetic and pharmacodynamic models of dasotraline in ADHD and the subsequent clinical trial simulations that were performed to assess dos (...truncated)


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Seth C. Hopkins, Soujanya Sunkaraneni, Estela Skende, Jeremy Hing, Julie A. Passarell, Antony Loebel, Kenneth S. Koblan. Pharmacokinetics and Exposure-Response Relationships of Dasotraline in the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults, Clinical Drug Investigation, 2016, pp. 137-146, Volume 36, Issue 2, DOI: 10.1007/s40261-015-0358-7