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Clinical pharmacology study to evaluate the drug-drug interactions of TAS-115 in healthy subjects

Clinical pharmacology study to evaluate the drug-drug interactions of TAS-115 in healthy subjects

60

A total of 60 subjects (12 each in Cohorts 1 and 2, and 18 each in Cohorts 3 and 4) were enrolled. The median age in each cohort ranged from 22.5 to 30.0 years, and the median BMI ranged from 19.95 to 21.55 kg/m2, and all subjects were healthy male Japanese.

[Cohort 1] Enrolled: 12 Treated: 12 Completed: 12 Not Completed: 0 [Cohort 2] Enrolled: 12 Treated: 12 Completed: 12 Not Completed: 0 [Cohort 3] Enrolled: 18 Treated: 18 Completed: 18 Not Completed: 0 [Cohort 4] Enrolled: 18 Treated: 18 Completed: 17 Not Completed: 1* * One subject who discontinued study treatment on Day 3 received administration of metformin alone on Day 1, but did not receive administration of TAS-115 alone scheduled on Day 3 and coadministration of TAS-115 + metformin scheduled on Day 8.

Analysis Population: As-treated population [Cohort 1] AEs occurred in 3/12 subjects (25.0%) in the TAS-115 alone period, 2/12 subjects (16.7%) in the rifampicin alone period and 2/12 subjects (16.7%) in the combined administration period. AEs that occurred in Cohort 1 were rash, headache and hypoaesthesia in 1/12 subjects each in the TAS-115 alone period, headache, malaise, oropharyngeal pain, stomatitis and taste disorder in 1/12 subjects each in the rifampicin alone period, and nasopharyngitis and rash in 1/12 subjects each in the combined administration period. TAS-115-related AEs that occurred in Cohort 1 were 2 events of rash, which were reported in the same subject. Grade 1 rash occurred in the TAS-115 alone period, and Grade 2 rash occurred in the combined administration period. Both events resolved with or without drug treatment. No other >= Grade 2 AEs were reported in Cohort 1. [Cohort 2] AE occurred in 1/12 subjects (8.3%) in the combined administration period. The only AE that occurred was rash (Grade 2), which was considered to be related to TAS-115. The event resolved with drug treatment. [Cohort 3] AE occurred in 1/18 subjects (5.6%) in the combined administration period. The only AE that occurred was meibomian gland dysfunction (Grade 2), which was considered to be not related to TAS-115, digoxin, or rosuvastatin. [Cohort 4] AEs occurred in 2/18 subjects (11.1%) in the metformin alone period and 1/17 subjects (5.9%) in the TAS-115 alone period, and no AEs were reported in the combined administration period. AEs that occurred were increased amylase and back pain in 1/18 subjects each in the metformin alone period, and neuropathy peripheral in 1/17 subjects in the TAS-115 alone period. The neuropathy peripheral was considered to be not related to TAS-115. No subjects experienced adverse events (AEs) leading to death or SAEs in any cohorts. No subjects experienced AEs leading to death or SAEs in any cohorts. One subject in Cohort 4 experienced an AE leading to discontinuation of study medication (Grade 2 amylase increased) in the metformin alone period. The event was considered to be not related to either TAS-115 or metformin. No other subjects experienced AEs leading to discontinuation of study medication in this study.

Primary outcome measures (Analysis Population: PK-Evaluable Population) - Co-administration with rifampicin decreased Cmax, AUClast and AUCinf of TAS-115 by 55%, 77%, and 77%, respectively. - Co-administration with itraconazole increased AUClast and AUCinf of TAS-115 by 62% and 63%, respectively. Cmax for TAS-115 was comparable with and without coadministration of itraconazole. - Co-administration with TAS-115 increased Cmax and AUClast of digoxin by 107% and 12%, respectively. - Co-administration with TAS-115 increased Cmax, AUClast, and AUCinf of rosuvastatin by 77%, 80%, and 78%, respectively. - Co-administration with TAS-115 increased Cmax, AUClast, and AUCinf of metformin by 32%, 28%, and 29%, respectively Secondary outcome measures (Analysis Population: As-treated population) The adverse events are described in the 'Adverse events' section. No clinically significant abnormal variations in laboratory tests, vital signs or 12-lead ECGs were observed.

Systemic exposure of TAS-115 was decreased with rifampicin (strong CYP3A4 inducer) and increased with itraconazole (strong CYP3A4/P-gp inhibitor). Coadministration of TAS-115 increased systemic exposure of digoxin (P-gp substrate), rosuvastatin (BCRP/OATP1B1/OATP1B3 substrate), and metformin (OCT2/MATE1/MATE2-K substrate). No safety concerns were found with coadministration of TAS-115 and rifampicin, itraconazole, digoxin, rosuvastatin, or metformin.

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Data will not be shared according to the Sponsor policy on data sharing. Taiho policy on data sharing may be found at https://www.taiho.co.jp/en/science/policy/clinical_trial_information_disclosure_policy/index.html.

https://jrct.mhlw.go.jp/latest-detail/jRCT2071210113

Jinhong Huang

Taiho Pharmaceutical Co., Ltd.

1-27 Kandanishiki-cho, Chiyoda-ku, Tokyo

ke-watanabe@taiho.co.jp

Keita Watanabe

Taiho Pharmaceutical Co., Ltd.

1-27 Kandanishiki-cho, Chiyoda-ku, Tokyo

+81-3-3293-2113

ke-watanabe@taiho.co.jp

Complete

Mar. 01, 2022

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

(1) Provided written informed consent
(2) Men aged 20 or older and younger than 40 years at the time of consent
(3) Weigh at least 50.0 kg at the time of screening tests with a body mass index (BMI, weight [kg]/[height {m}]2) ranging from 18.5 to < 25.0 kg/m2
(4) Vital signs obtained in screening tests within the following ranges
a) Systolic blood pressure (in supine position), 90 to 139 mmHg
b) Diastolic blood pressure (in supine position), 40 to 89 mmHg
c) Pulse rate ranging from 40 to 99 beats/min
d) Body temperature (axilla) ranging from 35.0 to 37.0
(5) Judged to be healthy by the investigator based on the examination findings (subjective symptoms and objective findings), blood pressure, pulse rate, body temperature, 12-lead ECG, and laboratory tests (hematology test, biochemistry test, and urinalysis) at the time of screening tests

Accompanying diseases considered inappropriate for participation in this study including hepatic diseases, renal diseases, gastrointestinal diseases, cardiovascular diseases, hematologic diseases, respiratory diseases, immunologic or allergic diseases, neurological or psychiatric diseases, metabolic or endocrinological diseases, or malignant tumors, or a history of these diseases

Male

Chronic fibrosing interstitial lung diseases with a progressive phenotype

This study consists of 4 cohorts.
Cohort 1: TAS-115 will be administrated as single dose on Day 1 and Day 12, and Rifampicin will be administrated as repeated dose from Day 6 to Day 13.
Cohort 2: TAS-115 will be administrated as single dose on Day 1 and Day 9, and Itraconazole will be administrated as repeated dose from Day 6 to Day 11.
Cohort 3: Digoxin and rosuvastatin will be administrated as a single dose on Day 1 and Day 12, and TAS-115 will be administrated as a single dose on Day 7 and Day 12.
Cohort 4: Metformin will be administrated as a single dose on Day 1 and Day 8, and TAS-115 will be administrated as a single dose on Day 3 and Day 8.

PK parameters of TAS-115, digoxin, Rosuvastatin, Metformin (Cmax, AUClast, and AUCinf)

- Incidence and severity of adverse events and treatment-related adverse events
- Changes in vital signs and laboratory test values
- Electrocardiogram

+81-92-283-7701

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