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
