Abstract Details

Title Safety, Pharmacokinetics (PK), and Pharmacodynamics (PD) of TAK-831, a Selective D-amino Acid Oxidase Inhibitor, in Healthy Volunteers

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P2 - Poster Session 2 (5:30 PM-6:30 PM)

Poster/Presentation
Number 9-015

Objective To determine the safety, tolerability, PK, and PD of single and multiple oral doses of TAK-831 when administered in healthy subjects.

Background TAK-831 is a selective and potent inhibitor of D-amino acid oxidase that is being developed for the treatment of Friedreich’s ataxia and as an adjunctive therapy for cognitive impairment and negative symptoms of schizophrenia.

Design/Methods Two phase 1 clinical trials consisted of single-rising dose (SRD) cohorts and multiple-rising dose (MRD) cohorts in a randomized, double-blind (subjects and investigators), placebo-controlled design to evaluate the safety, tolerability, PK, and PD (D-serine) of TAK-831 in healthy subjects. Subjects were randomized in each dose cohort using a 3:1 ratio of active drug to placebo in both studies. Doses for the SRD (10-1200 mg) and MRD (15-1200 mg) cohorts were sequentially escalated to assess TAK-831 exposure and PD levels in both cerebrospinal fluid (CSF) and plasma. Safety was assessed by adverse event (AE) monitoring, clinical laboratory tests, and physical examinations.

Results All doses of TAK-831 were well tolerated. TAK-831 systemic exposures showed dose-dependent increases after single and multiple dosing. The CSF PK profile was in parallel with the plasma PK profile, representing in the range of 0.62% to 1.72% of plasma concentration. A dose-dependent increase from baseline in both plasma and CSF D-serine was observed after SRD and MRD TAK-831. The D-serine elevation appeared to reach a maximum effect in plasma and CSF when the daily doses of TAK-831 were 400 mg and 600 mg, respectively. The elevation in D-serine in both plasma and CSF persisted over the entire 24-hour dosing interval after daily dosing, suggestive of a prolonged PD effect.

Conclusions TAK-831 was safe and well tolerated. The identified PK and PD relationship provides valuable guidance for dose selection in phase 2 trials.

Authors/Disclosures
Lin Xu, PhD (Takeda) PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
Mahnaz Asgharnejad, PharmD (Takeda Pharmaceuticals)	Mahnaz Asgharnejad, PharmD has received personal compensation for serving as an employee of Takeda Pharmaceuticals. Mahnaz Asgharnejad, PharmD has stock in GlaxoSmithKline. Mahnaz Asgharnejad, PharmD has stock in Takeda Pharmaceuticals.
	No disclosure on file
	No disclosure on file
	No disclosure on file

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