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Phase 1 study of DS-3201b to evaluate the pharmacokinetics and safety after single oral administration, the relative bioavailability after administration of tablet and capsule formulations, and the effect of food on the pharmacokinetics in healthy Japanese subjects

Phase 1 study of DS-3201b to evaluate the pharmacokinetics and safety after single oral administration, the relative bioavailability after administration of tablet and capsule formulations, and the effect of food on the pharmacokinetics in healthy Japanese subjects

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In Part 1, the mean age (range) was 28.4 (21 to 40) years and the mean body weight was 62.47 kg. No subject had a medical history. No major differences were found in the baseline subject characteristics among the cohorts in Part 1. In Part 2, the mean age (range) was 24.0 (20 to 38) years in Group 1 and 23.8 (20 to 39) years in Group 2. The mean body weight was 65.41 kg in Group 1 and 63.59 kg in Group 2. No major differences were found in the baseline subject characteristics between subgroups in Group 1 or Group 2. The demographic and other baseline characteristics for the pharmacokinetic analysis set were similar to those for the safety analysis set. * Group 1: Comparison of the bioavailability between DS-3201b capsules and tablets; Group 2: Examination of the effect of food on the pharmacokinetics of DS-3201a following single oral administration of DS-3201b tablets

In Part 1, 6 subjects each were registered to Cohort 1 (50 mg), Cohort 2 (100 mg), and Cohort 3 (200 mg). All of the 18 registered subjects received the study drug. In Part 2, 16 subjects each were registered to Groups 1 and 2. All of the 32 registered subjects received the study drug. Among those, 2 subjects were discontinued from the study treatment: 1 subject by his own decision and 1 subject due to adverse events.

Part 1: No TEAEs were reported. Part 2 (Group 1): No TEAEs were reported. Part 2 (Group 2): TEAEs were reported in 2 of 16 subjects (12.5%). Of those, 1 subject experienced 2 TEAEs after the first administration of DS-3201b under a fasted condition: blood fibrinogen increased and C-reactive protein increased. Both TEAEs were Grade 1 and considered related to the study drug. The subject was withdrawn from the study because of these TEAEs. Another subject experienced a ligament sprain in Period 1 after the first administration of DS-3201b under a fed condition, and then experienced a contusion in Period 2 after the second administration under a fasted condition. Both were Grade 1 and considered unrelated to the study drug. They resolved without any actions being taken. No deaths, serious TEAEs, or Grade 2 or higher TEAEs were reported in the study.

Part 1 - Safety Refer to "Adverse events" section. Part2 '- PK Group 1 The bioavailability of DS-3201b capsules (200 mg) was compared to that of DS-3201b tablets (200 mg) in 15 healthy Japanese male adults, and the following results were obtained. - The geometric least squares mean ratios (90% CIs) of DS-3201b tablets to capsules for the DS-3201a Cmax, AUClast, and AUCinf were 0.956 (0.832 to 1.100), 0.994 (0.884 to 1.119), and 0.988 (0.874 to 1.117), respectively. - No remarkable differences were found between DS-3201b tablets and capsules in the time courses of the mean plasma concentrations or in the pharmacokinetic parameters of DS-3201a. Group 2 The effect of food on the pharmacokinetics of DS-3201a following administration of DS-3201b tablets (200 mg) was examined in 15 healthy Japanese male adults, and the following results were obtained. - The geometric least squares mean ratios of fed to fasted conditions (90% CIs) for the DS-3201a Cmax, AUClast, and AUCinf were 0.487 (0.297 to 0.800), 0.702 (0.493 to 1.000), and 0.703 (0.495 to 1.000), respectively. - Administration of DS-3201b under fed conditions delayed the median DS-3201a Tmax to 6.00 h compared with 3.00 h under fasted conditions.

Part1 '-PK The pharmacokinetics of DS-3201a following single oral administration of DS-3201b tablets at a dose of 50 mg, 100 mg, and 200 mg were assessed in 18 healthy Japanese male adults, and the following results were obtained. - The Tmax of DS-3201a was consistent across all cohorts: the median Tmax was 3.50 h in Cohort 1 (50 mg), 4.00 h in Cohort 2 (100 mg), and 4.50 h in Cohort 3 (200 mg). - The plasma concentration of DS-3201a decreased with a similar T1/2 in all cohorts: the mean T1/2 was 23.1 h in Cohort 1, 20.8 h in Cohort 2, and 20.4 h in Cohort 3. - The mean Cmax, AUClast, and AUCinf of DS-3201a increased as the DS-3201b dose increased. Part2 Group 1 and Group 2 - Safety Refer to "Adverse events" section.

It was well tolerated with no safety concerns in this study. The systemic exposure of DS-3201a increased as the DS-3201b dose increased from 50 mg to 200 mg. The geometric least squares mean ratios of DS-3201b tablets to capsules for the DS-3201a Cmax and AUCs were approximately 1 and the 90% CIs were within 0.8 to 1.25. Food (high-fat) decreased the DS-3201a AUC and Cmax by approximately 30% and 50%, respectively, relative to a fasted condition.

Aug. 11, 2023

https://accp1.onlinelibrary.wiley.com/doi/10.1002/cpdd.1315

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Inoguchi Akihiro

Daiichi Sankyo Co., Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

dsclinicaltrial@daiichisankyo.co.jp

Contact for Clinical Trial Information

Daiichi Sankyo Co., Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

+81-3-6225-1111

Dec. 14, 2017

Interventional

Part 1: Open label, single parallel-group ascending dose study Part 2: randomized, open-label, single-dose, 2-group 2-period crossover study

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Part 1 & 2
1. Japanese males
2. Age: >=20 and =<45 years (at the time of informed consent)
3. Body mass index (BMI) = Body weight (kg) / (Height [m])2: >=18.5 and <25.0 (at screening)

Part 1 & 2
1. Having a history of hypersensitivity to drugs or other substances or being idiosyncratic (eg, having penicillin allergy)
2. Having alcohol or drug dependence

Male

Healthy volunteers

investigational material(s)
Generic name etc : DS-3201b
INN of investigational material :
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : Single oral administration, 50-200 mg

Part 1: Safety, Part 2: Pharmacokinetics

Part 1: Pharmacokinetics, Part 2: Safety

Dec. 01, 2017