A Randomized Multiple Dose Pharmacokinetic Study of a Novel PDE10A Inhibitor TAK-063 in Subjects with Stable Schizophrenia and Japanese Subjects and Modeling of Exposure Relationships to Adverse Events
Paul Goldsmith, John Affinito, Maggie McCue, Max Tsai, Stefan Roepcke, Jinhui Xie, Lev Gertsik, Thomas A Macek, Paul Goldsmith, John Affinito, Maggie McCue, Max Tsai, Stefan Roepcke, Jinhui Xie, Lev Gertsik, Thomas A Macek
Abstract
Background: Phosphodiesterase 10A (PDE10A) is selectively expressed in medium spiny neurons of the striatum. TAK-063 is a selective inhibitor of PDE10A in clinical development for the treatment of schizophrenia.
Objectives: Safety, tolerability, and pharmacokinetics (PK) of TAK-063 were evaluated following multiple rising oral doses, and PK/adverse event (AE) models were developed to characterize the relationship between TAK-063 exposure and incidence of specific AEs.
Methods: Healthy Japanese subjects (HJS) aged 20-55 years and subjects with stable schizophrenia (SSS) aged 18-55 years were enrolled and randomized to either TAK-063 or placebo. Study medication was administered as a tablet once daily (at night) with food over a 7-day period.
Results: TAK-063 and placebo groups consisted of 62 and 15 subjects, respectively. A majority of subjects (71 of 77) completed the study. AEs were mostly of mild or moderate severity, and no deaths were reported. The most common AE was somnolence. For equivalent doses, the rate of extrapyramidal syndromes (EPS) was higher in SSS than in HJS. PK parameters were comparable between HJS and SSS at equivalent doses. The incidence of somnolence and EPS symptoms increased with exposure, and this was described with the PK/AE model. A maximum tolerated dose was not determined.
Conclusions: Multiple doses of TAK-063 were safe and well tolerated. PK/AE models characterized the incidence of somnolence and EPS with increasing TAK-063 exposure, and simulations suggested that a once-daily dose range of up to 30 mg would be suitable for future studies. CLINICALTRIALS.
Gov identifier: NCT01879722.
Conflict of interest statement
Role of funding sourceThe clinical study was funded by Takeda Development Center Americas, Inc. Medical writing assistance was provided by Stephanie Agbu, Ph.D, and Jake Edelstein, Ph.D, of inVentiv Medical Communications and supported by Takeda Development Center Americas, Inc.
Conflict of interestJohn Affinito and Maggie McCue are employees of Takeda Development Center Americas, Inc., Deerfield, IL. At the time the study was conducted, Max Tsai, Jinhui Xie, and Thomas A. Macek were employees of Takeda Development Center Americas, Inc.; Paul Goldsmith was an employee of Takeda Development Centre Europe Ltd., London, UK; and Stefan Roepcke was an employee of Takeda Pharmaceuticals International GmbH, Zürich, Switzerland. Lev Gertsik is an employee of California Clinical Trials Medical Group/Parexel, Glendale, CA, USA. He is a consultant to Takeda.
Ethical approvalAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consentInformed consent was obtained from all individual participants included in the study.
Study registrationThis study is registered as “Safety, Tolerability and Pharmacokinetic Study of Multiple Rising Doses of TAK-063 in Participants With Stable Schizophrenia and Healthy Participants” (Clinical Trials ID: NCT01879722).
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Source: PubMed