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

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 source

The 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 interest

John 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 approval

All 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 consent

Informed consent was obtained from all individual participants included in the study.

Study registration

This 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).

Figures

Fig. 1

Subject disposition. HJS healthy Japanese subjects, SSS subjects with stable schizophrenia. aReason for discontinuation: pretreatment event/adverse event. bReasons for discontinuations: voluntary withdrawal or other

Fig. 2

Mean concentration of TAK-063 at day 1 and day 7 following once-daily administration in healthy Japanese subjects and subjects with stable schizophrenia: a healthy Japanese subjects (day 1); b healthy Japanese subjects (day 7); c subjects with stable schizophrenia (day 1); d subjects with stable schizophrenia (day 7)

Fig. 3

TAK-063 exposure on day 7 following once-daily oral doses: a AUC(0–24) for healthy Japanese subjects; b AUC(0–24) for subjects with stable schizophrenia; cCmax for healthy Japanese subjects; dCmax for subjects with stable schizophrenia. Box plots extend from the 25th to 75th percentiles, and whiskers extend from minimum to maximum values. Plus (+) sign denotes the mean. AUC(0–24) area under the plasma concentration–time curve from time 0 to 24 h postdose, Cmax maximum observed plasma concentration

Fig. 4

Probability of adverse event occurrence with multiple rising doses of TAK-063 in healthy Japanese subjects and SSS: aCmax vs somnolencea; b AUC vs somnolenceb; cCmax vs extrapyramidal syndromesc; d AUC vs extrapyramidal syndromesd; Observed (points) and predicted (blue line) incidence of EPS (SSS only) and somnolence vs TAK-063 Cmax or AUC. Vertical lines indicate the mean TAK-063 Cmax or AUC by dose; shaded regions indicate the 95% confidence interval. AUC area under the plasma concentration–time curve, Cmax maximum observed plasma concentration, EPS extrapyramidal syndromes, MRD multiple rising dose, SE standard error, SSS subjects with stable schizophrenia. aβ (SE) = − 1.22 (0.40); slope (SE) = 0.012 (0.0038). bβ (SE) = − 1.18 (0.39); slope (SE) = 0.001 (0.0003). cβ (SE) = − 1.95 (0.62); slope (SE) = 0.011 (0.0043). dβ (SE) = − 1.70 (0.56); slope (SE) = 0.001 (0.0003)