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The Effect of Moderate Hepatic Impairment on the Pharmacokinetics of Ipragliflozin, a Novel Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitor

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Abstract

Background

Ipragliflozin (ASP1941), a potent selective sodium glucose co-transporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. Ipragliflozin is primarily eliminated via conjugation by the liver as five pharmacologically inactive metabolites (M1, M2, M3, M4 and M6). This study evaluated the effect of moderate hepatic impairment on the pharmacokinetics of ipragliflozin and its metabolites.

Methods

In an open-label, single-dose, parallel-group study, 16 subjects (eight with moderate hepatic impairment [Child-Pugh score 7–9] and eight healthy, matched controls) received a single oral dose of 100-mg ipragliflozin. Plasma concentrations of ipragliflozin and its metabolites were determined. Adverse events (AEs) and other clinical laboratory parameters were monitored.

Results

All subjects completed the study. Least-squares geometric mean ratios (GMRs) (90 % confidence interval [CI]) for maximum plasma concentration (C max) and area under the plasma concentration–time curve from time zero to infinity (AUC) of ipragliflozin were 127 % (93–173 %) and 125 % (94–166 %), respectively, in moderate hepatic impairment versus controls. No changes in elimination half-life and protein binding of ipragliflozin were observed in moderate hepatic impairment subjects. Least-squares GMRs for C max and AUC of M2, the major metabolite, were respectively 95 % (68–133 %) and 100 % (77–130 %) in moderate hepatic impairment versus controls. No deaths, other serious AEs or AEs leading to discontinuation occurred.

Conclusions

Moderate hepatic impairment had no clinically relevant effects on the single-dose pharmacokinetics of ipragliflozin and its major metabolite, M2. A single oral dose of ipragliflozin, 100 mg, was well tolerated in both healthy subjects and those with moderate hepatic impairment.

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Acknowledgments

WZ was responsible for all analyses and their interpretation, and is the primary author of the manuscript. KCL was the Principal Investigator, who conducted the study. JK, WK, RS and RT provided the design and data interpretation. LP was responsible for all operational aspects of the study conduct, including protocol writing. TK and FU are critical reviewers of the pharmacokinetics aspects in the study report and manuscript.

This study was funded by Astellas Pharma Inc. Ipragliflozin is under development by Astellas Pharma Inc. and Kotobuki Pharmaceutical Co., Ltd. WZ, JK, RT and LP are employees of Astellas Pharma Global Development USA; WK and RS are employees of Astellas Pharma Europe; TK and FU are employees of Astellas Pharma Japan. KCL is a principal investigator at Clinical Pharmacology of Miami, USA.

The authors thank Selina Moy (Astellas Pharma Global Development, Inc.) and Michel van Bruijnsvoort, PhD (Astellas Pharma Europe BV) for their bioanalytical support and Kathy Boon, PhD (Excerpta Medica) for assistance in the preparation of the manuscript.

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Correspondence to Wenhui Zhang.

Additional information

Trial registration: ClinicalTrials.gov identifier: NCT01187186.

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Zhang, W., Krauwinkel, W.J.J., Keirns, J. et al. The Effect of Moderate Hepatic Impairment on the Pharmacokinetics of Ipragliflozin, a Novel Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitor. Clin Drug Investig 33, 489–496 (2013). https://doi.org/10.1007/s40261-013-0089-6

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  • DOI: https://doi.org/10.1007/s40261-013-0089-6

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