A phase 1 study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-063, a selective PDE10A inhibitorReportar como inadecuado

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, Volume 233, Issue 21–22, pp 3787–3795

First Online: 30 August 2016Received: 23 March 2016Accepted: 11 August 2016


RationaleSchizophrenia 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.

ObjectiveSafety, tolerability, and pharmacokinetics of TAK-063 were evaluated in a phase 1 study.

MethodsHealthy 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.

ResultsThe 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 Tmax was reached 3 to 4 h postdose. Fed conditions slowed absorption Tmax = 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.

ConclusionsTAK-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.

KeywordsSchizophrenia Pharmacokinetics Safety Phosphodiesterase 10A Single-rising dose Oral Electronic supplementary materialThe online version of this article doi:10.1007-s00213-016-4412-9 contains supplementary material, which is available to authorized users.

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Autor: Max Tsai - Lambros Chrones - Jinhui Xie - Hakop Gevorkyan - Thomas A. Macek

Fuente: https://link.springer.com/article/10.1007/s00213-016-4412-9

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