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A Single-center, Randomized, Open-label, 2-Cohort, 2-Period Crossover Trial to Investigate the Relative Bioavailability of OPC-131461 Oral Suspension and OPC-131461 Tablet and the Food Effect on the Pharmacokinetics of OPC-131461 in Healthy Adult Male Subjects (Phase 1 Trial)

A Relative Bioavailability and Food Effect Trial of OPC-131461 in Healthy Adult Male Subjects

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-Relative Bioavailability Part All subjects who participated in the Relative Bioavailability Part of the trial were healthy Japanese male subjects and the mean +- standard deviation (SD) of the subjects age was 22.9 +- 2.9 years. No subjects had any medical history or current symptoms. -Food Effect Part All subjects who participated in the Food Effect Part of the trial were healthy Japanese male subjects and the mean +-standard deviation (SD) of the subjects age was 27.5 +- 8.1 years. No subjects had any medical history or current symptoms.

-Relative Bioavailability Part A total of 8 subjects were treated in the Relative Bioavailability Part of the trial, 4 subjects in the suspension first sequence and 4 subjects in the tablet first sequence. All 8 subjects were analyzed for PK and safety, and no subjects discontinued from the trial. -Food Effect Part A total of 8 subjects were treated in the Food Effect Part of the trial, 4 subjects in the fasted state first sequence and 4 subjects in the fed state first sequence. All 8 subjects were analyzed for PK and safety, and no subjects discontinued from the trial.

-Relative Bioavailability Part Six of 8 subjects (75%) receiving the suspension treatment and 5 of 8 subjects (62.5%) receiving the tablet treatment experienced 8 and 9 treatment-emergent adverse events (TEAE)s, respectively, and all were mild in severity and considered related to IMP. Only TEAEs reported were thirst (3 of 8 [37.5%] subjects receiving the suspension treatment and 4 of 8 [50.0%] subjects receiving the tablet treatment) and polyuria (5 of 8 [62.5%] subjects receiving the suspension treatment and 5 of 8 [62.5%] subjects receiving the tablet treatment). There were no deaths, serious TEAEs, or other significant events reported during the trial. There were no clinically meaningful changes from baseline in the laboratory test results, vital signs, and 12-lead ECGs. -Food Effect Part Seven of 8 subjects (87.5%) in the fasted state and 8 of 8 subjects (100%) in the fed state experienced 9 and 13 TEAEs, respectively, and all were mild in severity and considered related to IMP. Only TEAEs reported were thirst (6 of 8 [75.0%] subjects in the fasted state and 7 of 8 [87.5%] subjects in the fed state) and polyuria (3 of 8 [37.5%] subjects in the fasted state and 6 of 8 [75.0%] subjects in the fed state). There were no deaths, serious TEAEs, or other significant events reported during the trial. There were no clinically meaningful changes from baseline in the laboratory test results, vital signs, and 12-lead ECGs

-Relative Bioavailability Part Geometric mean ratios and 90% CIs of the Cmax, AUCinf, and AUCt of OPC-131461 following administration of OPC-131461 tablets to those following administration of OPC-131461 suspension were 0.8856 (0.8270-0.9483), 1.0082 (0.9509-1.0690), and 1.0077 (0.9491 - 1.0698), respectively. The 90% CIs were within the equivalence limit of 0.80-1.25. These results indicated that the bioavailability of OPC-131461 suspension at 20 mg and OPC-131461 tablets at 20 mg (5 mg tablet x 4) were similar. -Food Effect Part Geometric mean ratios and 90% CIs of the Cmax, AUCinf, and AUCt of OPC-131461 tablets in a fed state (after completion of a high-fat meal) to those following administration in a fasted state were 1.2013 (0.9965-1.4482), 1.1354 (1.0431-1.2359), and 1.1376 (1.0460-1.2372), respectively. Although the 90% CIs for AUCinf and AUCt were within the equivalence limit of 0.80-1.25, the upper limit of the 90% CI for the Cmax was higher than 1.25. These results indicated that the Cmax following administration of OPC-131461 tablets at 20 mg (5 mg tablet x 4) in a fed state was slightly higher than that following administration in a fasted state.

Overall, OPC-131461 as single oral doses of 20 mg were safe and well tolerated in healthy adult Japanese male subjects in the Relative Bioavailability Part and Food Effect Part.

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2071210093

Matsumaru Takehisa

Otsuka Pharmaceutical Co., Ltd.

3-2-27, Otedori, Chuo-ku, Osaka-shi

G_CL_351-102-00002@otsuka.jp

Drug Information Center

Otsuka Pharmaceutical Co., LTD.

2-16-4, Konan, Minato-ku, Tokyo, Japan

+81-3-6361-7314

opc_ctr@otsuka.jp

Complete

Jan. 20, 2022

Interventional

randomized controlled trial

open(masking not used)

active control

crossover assignment

treatment purpose

1) Healthy Japanese men at least 20 years and less than 40 years of age at the time of informed consent.
2) Body mass index (BMI = body weight [kg]/[height {m}]2) of >=18.5 kg/m2 to <25.0 kg/m2 (at screening).
3) Individuals who provide written consent prior to the commencement of any trial-related procedure and who are able to comply with the trial procedures in the opinion of the investigator or subinvestigator.

1) Clinically significant abnormalities are found on screening examinations (eg, a marked deviation from the normal range) or in the subject's medical history that, in the opinion of the investigator, subinvestigator, or sponsor, may pose a risk to the subject or affect the absorption, distribution, metabolism, or elimination of the investigational medicinal product.
Such abnormalities include but are not limited to current or a history of cardiac, hepatic, renal, neurological, gastrointestinal, respiratory, hematological, and immunological conditions.
2) Systolic blood pressure of >140 mmHg or <100 mmHg or diastolic blood pressure of >90 mmHg or <50 mmHg at rest for at least 3 minutes in the supine position at screening.
3) Pulse rate outside the range of 50 to 90 bpm at rest for at least 3 minutes in the supine position at screening.
4) Clinically significant 12-lead ECG findings at screening, such as atrioventricular block, QRS interval of >120 msec, and QTcF interval of >=450 msec.
5) Any of the following hepatitis criteria is met:
-Prior or current hepatitis B, or current hepatitis C. A positive test for hepatitis B surface antigen or hepatitis C virus antibody at screening.
-Prior or current alcoholic hepatitis or non-alcoholic steatohepatitis.
6) Prior or current acquired immunodeficiency syndrome. A positive test for human immunodeficiency virus or syphilis or a positive polymerase chain reaction (PCR) test for SARS CoV 2 at screening.
7) History of serious mental disorders.

Male

Volume overload in heart failure

[Relative bioavailability (BA) arm]
Subjects will receive single oral administration of OPC-131461 at 20 mg (suspension or 5-mg tablet x 4) in a fasting state.

[Food effect arm]
Subjects will receive single oral administration of OPC-131461 at 20 mg (5-mg tablet x 4) in a fasting state or within 10 minutes after completion of a high-fat meal.

Primary Pharmacokinetic Endpoints:
1) Relative BA arm:
Differences in the mean natural-log-transformed values and two-sided 90% confidence intervals (CIs) for the plasma Cmax, AUC(infinity), and AUCt of OPC-131461 between the 2 formulations following administration of OPC-131461 suspension or OPC-131461 tablet in a fasting state
2) Food effect arm:
Differences in the mean natural-log-transformed values and two-sided 90% CIs for the plasma Cmax, AUC(infinity), and AUCt of OPC-131461 between administration of OPC-131461in a fasting state and administration of OPC-131461 tablet in a fed states

Secondary Pharmacokinetic Endpoints:
Plasma OPC-131461 concentration and plasma pharmacokinetic parameters of plasma OPC-131461

Safety:
Clinical laboratory tests (hematology, blood chemistry, and urinalysis), vital signs (blood pressure, pulse rate, and temperature), body weight, 12-lead electrocardiography (ECG), and adverse events (AEs)

+81-92-283-7701

Jan. 17, 2022

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