Drug Res (Stuttg) 2017; 67(06): 349-357
DOI: 10.1055/s-0043-104779
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Pharmacokinetics and Pharmacodynamics of Tofogliflozin (a Selective SGLT2 Inhibitor) in Healthy Male Subjects

Nahoko Kasahara-Ito
1   Translational Clinical Research Science and Strategy Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
,
Hiroyuki Fukase
2   CPC Clinical Trial Hospital, Medipolis Medical Research Institute, Kagoshima, Japan
,
Yoichiro Ogama
3   Medical Co. LTA, Souseikai Sumida Hospital, Tokyo, Japan
,
Tomohisa Saito
1   Translational Clinical Research Science and Strategy Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
,
Yasuhiro Ohba
1   Translational Clinical Research Science and Strategy Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
,
Sumire Shimada
1   Translational Clinical Research Science and Strategy Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
,
Yasuki Takano
4   Clinical Science and Strategy Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
,
Tomoko Ichihara
5   Development Administration Department, Chugai Clinical Research Center Co., Ltd., Tokyo, Japan
,
Kimio Terao
1   Translational Clinical Research Science and Strategy Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
,
Noboru Nakamichi
6   Medical Co. Shintokai, Yokohama Minoru Clinic, Yokohama, Japan
,
Yuji Kumagai
7   School of Medicine, Kitasato University, Sagamihara, Japan
,
Sachiya Ikeda
4   Clinical Science and Strategy Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
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Weitere Informationen

Publikationsverlauf

received 10. November 2016

accepted 23. Februar 2017

Publikationsdatum:
20. April 2017 (online)

Abstract

Purpose

Tofogliflozin is a selective oral inhibitor of sodium-glucose co-transporter 2 for treatment of type 2 diabetes mellitus. The pharmacokinetics, pharmacodynamics, and safety of tofogliflozin were investigated in healthy male subjects.

Methods

Three studies were conducted: single-ascending dose study (10–640 mg) in 56 Japanese and 24 Caucasian subjects; multiple-ascending dose study (2.5–80 mg once daily for 7 days) in 24 Japanese subjects; and food-effect study (20–40 mg) in 30 Japanese subjects.

Results

Tofogliflozin was absorbed rapidly and eliminated from the systemic circulation with a t1/2 of 5–6 h. Exposure increased dose-proportionally up to 320 mg. Body weight-corrected exposure was similar between Japanese and Caucasian subjects. Urinary excretion of tofogliflozin ranged from 17.1 to 27.4% of dose. Tofogliflozin did not accumulate with once daily administration. Food intake decreased Cmax by approximately 30% but did not change AUC0-inf. Tofogliflozin caused dose-dependent daily urinary glucose excretion (UGE0-24h), but food intake condition at administration did not affect it. The exposure-response relationship between plasma average concentration of tofogliflozin (Cavg) and UGE0-24h fitted Emax model well. There were no serious adverse events leading to discontinuation or episodes of hypoglycemia.

Conclusions

Single and multiple administration of tofogliflozin were generally well tolerated. Exposure to tofogliflozin was dose-proportional up to 320 mg and did not accumulate with multiple once-a-day administration. The model suggests more than 100 ng/mL Cavg corresponding to the dose of between 20 and 40 mg leads to almost maximum effect of tofogliflozin.

Supporting Information