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

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 C was 1.47 and GMR of AUC was 1.70. Moderate hepatic impairment had only a little effect on t and CL 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 C and AUC 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.