A phase 1 study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-063, a selective PDE10A inhibitor.

Autor: Tsai M; Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL, 60015, USA., Chrones L; Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL, 60015, USA., Xie J; Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL, 60015, USA., Gevorkyan H; California Clinical Trials Medical Group, Glendale, CA, USA., Macek TA; Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL, 60015, USA. tom.macek@takeda.com.
Jazyk: angličtina
Zdroj: Psychopharmacology [Psychopharmacology (Berl)] 2016 Oct; Vol. 233 (21-22), pp. 3787-3795. Date of Electronic Publication: 2016 Aug 30.
DOI: 10.1007/s00213-016-4412-9
Abstrakt: Rationale: Schizophrenia is a complex neuropsychiatric disorder characterized, in part, by impaired dopamine signaling. TAK-063 is a selective inhibitor of phosphodiesterase 10A, a key regulator of intracellular signaling pathways that is highly expressed in the striatum.
Objective: Safety, tolerability, and pharmacokinetics of TAK-063 were evaluated in a phase 1 study.
Methods: Healthy Japanese and non-Japanese volunteers were randomized into dose cohorts of 3, 10, 30, 100, 300, and 1000 mg. Each fasting volunteer randomly received a single dose of TAK-063 or placebo. Individuals from the 100-mg cohort also received a post-washout, 100-mg dose under fed conditions. A total of 84 volunteers enrolled (14 per cohort).
Results: The most common drug-related adverse events (AEs) were somnolence (33.3 %), orthostatic tachycardia (19.7 %), and orthostatic hypotension (9.1 %). The three severe AEs recorded occurred at the highest doses: orthostatic hypotension (n = 1; 300 mg) and somnolence (n = 2; 1000 mg). There were no deaths, serious AEs, or discontinuations due to AEs. TAK-063 exposure increased in a dose-dependent manner. Median T max was reached 3 to 4 h postdose. Fed conditions slowed absorption (T max =  6 h) and increased oral bioavailability. Renal elimination was negligible. Safety and pharmacokinetic parameters were similar between Japanese and non-Japanese subjects. Impairments in cognitive function consistent with the effects of other sedative or hypnotic agents were detected using a validated, computerized cognition battery, CNS Vital Signs.
Conclusions: TAK-063 was safe and well tolerated at doses up to 1000 mg and demonstrated a pharmacokinetic profile supporting once-daily dosing. Further evaluation of the clinical safety and efficacy of TAK-063 is warranted.
Competing Interests: Compliance with ethical standards Role of funding source Funding for this study was provided by Takeda Pharmaceutical Company, Limited. Conflicts of interest Max Tsai, Thomas Macek, Lambros Chrones, and Jinhui Xie are employees of Takeda Development Center Americas, Inc., Deerfield, IL. Hakop Gevorkyan is an employee of California Clinical Trials Medical Group, Glendale, CA, and was Principal Investigator of the study.
Databáze: MEDLINE
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