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Phase 1 study of DS-3201b to assess the effects of itraconazole and fluconazole on the pharmacokinetics of single oral administration of DS-3201b tablets in healthy Japanese subjects

Phase 1 study of DS-3201b to assess the effects of itraconazole and fluconazole on the pharmacokinetics of single oral administration of DS-3201b tablets in healthy Japanese subjects

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In Group 1, the mean (range) age of the subjects was 28.3 (20 to 38) years, the mean weight was 62.26 kg, and the mean BMI was 21.44 kg/m2. The pharmacokinetic and safety analysis sets of Group 1 were identical. In Group 2, the mean (range) age of the subjects was 30.6 (21 to 38) years, the mean weight was 63.14 kg, and the mean BMI was 21.17 kg/m2. No subject had a medical history. Demographic and other baseline characteristics of the pharmacokinetic analysis set were similar to those of the safety analysis set. * Group 1: Examination of the coadministration of DS-3201b and itraconazole; Group 2: Examination of the coadministration of DS-3201b and fluconazole

In total, 32 (16 per group) subjects were registered for the study. Of the registered subjects, 29 subjects completed the study, and 3 subjects prematurely discontinued the study: 2 subjects owing to a TEAE and deviations from the exclusion criteria for next period; 1 subject withdrew by the subject.

Group 1 Two (12.5%) subjects reported TEAEs. Both the TEAEs were Grade 1 upper respiratory tract infections. One subject experienced the TEAE after the administration of DS-3201b alone and another subject reported the TEAE after the coadministration of DS-3201b and itraconazole. The TEAEs were not considered drug-related and recovered/resolved without any actions taken. Group 2 Eight (50.0%) subjects reported TEAEs. All TEAEs were Grade 1 upper respiratory tract infections except for 1 Grade 2 event. Seven (43.8%) subjects experienced the TEAE after the administration of DS-3201b alone and in 1 (7.7%) subject reported the TEAE after the coadministration of DS-3201b and fluconazole. The TEAEs were not considered drug-related. With the exception of 1 event that required medication, all TEAEs recovered/resolved without treatment. Two of the TEAEs, 1 of which required medication, led to discontinuation of treatment in 2 subjects, after the administration of DS-3201b alone. No deaths, serious TEAEs, or Grade 3 or higher TEAEs were reported in this study.

- PK Group 1 The primary objective of the study was to evaluate the pharmacokinetics of DS-3201a following the administration of DS-3201b alone and the coadministration of DS-3201b and itraconazole in 16 healthy Japanese male adults. The major conclusions were as follows: - DS-3201a at a dose of 25 mg was rapidly absorbed after the administration of DS-3201b alone and after the coadministration of DS-3201b and itraconazole with the median Tmax of 3.50 h after the administration of DS-3201b alone and 3.00 h after the coadministration of DS-3201b and itraconazole. - The mean T1/2 was longer after the coadministration (39.2 h) than after the administration of DS-3201b alone (17.5 h). - The geometric least square mean ratio (90% CIs) of Cmax, AUClast, and AUCinf for DS-3201a estimated by analysis of variance (ANOVA) were 2.924 (2.261 to 3.782), 4.301 (3.531 to 5.238), and 4.191 (3.447 to 5.094) for the coadministration of DS-3201b and itraconazole compared with the administration of DS-3201b alone. Group 2 The primary objective of the study was to evaluate the pharmacokinetics of DS-3201a following the administration of DS-3201b alone and the coadministration of DS-3201b and fluconazole in 13 healthy Japanese male adults. The major conclusions were as follows: - DS-3201a at a dose of 25 mg was rapidly absorbed after the administration of DS-3201b alone and after the coadministration of DS-3201b and fluconazole with the median Tmax of 3.00 h after the administration of DS-3201b alone and 4.00 h after the coadministration of DS-3201b and fluconazole. - The mean T1/2 after the administration of DS-3201b alone (21.7 h) was comparable with that after the coadministration (19.2 h). - The geometric least square mean ratio (90% CIs) of Cmax, AUClast, and AUCinf for DS-3201a estimated by ANOVA were 1.612 (1.121 to 2.318), 1.629 (1.252 to 2.120), and 1.584 (1.233 to 2.035) for the coadministration of DS-3201b and fluconazole compared with the administration of DS-3201b alone.

- Safety Refer to "Adverse events" section.

The coadministration of DS-3201b and itraconazole or fluconazole resulted in increases in Cmax and AUCs of DS-3201a: the coadministration of DS-3201b and itraconazole resulted in approximately 3-fold and 4-fold increases in Cmax and AUCs of DS-3201a, respectively, and the coadministration of DS-3201b and fluconazole resulted in 1.6-fold increases in Cmax and AUCs of DS-3201a. No increases in the incidences of TEAEs or other safety concerns were identified in this study.

Sept. 13, 2023

https://ascpt.onlinelibrary.wiley.com/doi/10.1111/cts.13613

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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

Mar. 23, 2018

Interventional

Open-label, 1 sequence crossover study

1

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)

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, 200 mg

Pharmacokinetics

Safety

Mar. 02, 2018