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Drug Res (Stuttg) 2020; 70(09): 401-409
DOI: 10.1055/a-1202-0818
Original Article

Effects of Child-Pugh B Cirrhosis on Pharmacokinetics of Tofogliflozin, a New Sodium-Glucose Co-Transporter (SGLT2) Inhibitor

Haruki Yamada
1   Social Insurance Chuo General Hospital, Tokyo, Japan
,
Hiromasa Ohira
2   Fukushima Medical University Hospital, Fukushima, Japan
,
Fumiaki Ikegami
3   Clinical Research Hospital Tokyo, Tokyo, Japan
,
Koichi Nakamura
3   Clinical Research Hospital Tokyo, Tokyo, Japan
,
Atsushi Takahashi
2   Fukushima Medical University Hospital, Fukushima, Japan
,
Kazumichi Abe
2   Fukushima Medical University Hospital, Fukushima, Japan
,
Akihiro Inano
2   Fukushima Medical University Hospital, Fukushima, Japan
,
Sumire Shimada
4   Clinical Pharmacology Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
,
Kumiko Miyata
4   Clinical Pharmacology Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
,
Tomohisa Saito
4   Clinical Pharmacology Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
,
Yasuhiro Ohba
4   Clinical Pharmacology Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
,
Kimio Terao
4   Clinical Pharmacology Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
,
Akihiro Ohnishi
5   The Jikei University School of Medicine, Tokyo, Japan
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Abstract

Background Tofogliflozin is a highly selective sodium-glucose co-transporter 2 (SGLT2) inhibitor. A mass balance study with combinations of microdoses revealed that tofogliflozin has high oral bioavailability (97.5%) and that tofogliflozin in circulation is eliminated primarily by metabolic pathways, with the liver playing a prominent role in elimination.

Objectives This study aimed to evaluate the effect of moderate hepatic impairment on the pharmacokinetics of tofogliflozin and on the pharmacodynamics (urinary glucose excretion [UGE]).

Methods In an open-label, parallel-group study, 17 subjects (9 with moderate hepatic impairment [Child-Pugh Class B, score 7–9] and 8 healthy) received a single oral dose of 40 mg tofogliflozin. Plasma and urine concentrations of tofogliflozin were determined. Accumulated UGE, adverse events, and physiological and laboratory test data were monitored.

Results Geometric mean ratio (GMR; geometric mean value for subjects with moderate hepatic impairment / geometric mean value for healthy subjects) of Cmax was 1.47 and GMR of AUCinf was 1.70. Moderate hepatic impairment had only a little effect on tmax and CLR but it prolonged MRT. The levels of cumulative UGE were similar between the 2 groups. No clinically significant adverse events, laboratory test values, or physiological test values were observed in any subject.

Conclusions Moderate hepatic impairment increased Cmax and AUCinf of tofogliflozin by 47% and 70%, respectively. This increase in tofogliflozin exposure did not increase UGE in hepatically impaired subjects. A single oral dose of 40 mg tofogliflozin was well tolerated, supporting dose adjustment is unnecessary even in moderately hepatically impaired subjects.

Key words

Pharmacokinetics - drug metabolism - human pharmacology


Publication History

Received: 27 November 2019

Accepted: 21 April 2020

Article published online:
24 July 2020

© Georg Thieme Verlag KG
Stuttgart · New York

 

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