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 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.
Eingereicht: 27. November 2019
Angenommen: 21. April 2020
Artikel online veröffentlicht:
24. Juli 2020
© Georg Thieme Verlag KG
Stuttgart · New York
- 1 Garber AJ, Abrahamson MJ, Barzilay JI. et al. Consensus Statement by the American Association of Clinical Endcrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm—2018 Executive Summary. Endocr Pract 2018; 24: 91-120
- 2 Scheen AJ. SGLT2 Inhibitors: Benefits/Risk Balance. Curr Diab Rep 2016; 16: 92
- 3 Zinman B, Wanner C, Lachin JM. et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373: 2117-2128
- 4 Neal B, Perkovic V, Mahaffey KW. et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377: 644-657
- 5 Wanner C, Inzucchi SE, Lachin JM. et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med 2016; 375: 323-334
- 6 Kosiborod M, Cavender MA, Fu AZ. et al. Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation 2017; 136: 249-259
- 7 Suzuki M, Honda K, Fukazawa M. et al. Tofogliflozin, a Potent and Highly Specific Sodium/Glucose Cotransporter 2 Inhibitor, Improves Glycemic Control in Diabetic Rats and Mice. J Pharmacol Exp Ther 2012; 341: 692-701
- 8 Kasahara-Ito N, Fukase H, Ogama Y. et al. Pharmacokinetics and Pharmacodynamics of Tofogliflozin (a Selective SGLT2 Inhibitor) in Healthy Male Subjects. Drug Res. 2017; 67: 349-357
- 9 Schwab D, Portron A, Backholer Z. et al. A Novel Double-Tracer Technique to Characterize Absorption, Distribution, Metabolism and Excretion (ADME) of [14C]Tofogliflozin After Oral Administration and Concomitant Intravenous Microdose Administration of [13C]Tofogliflozin in Humans. Clin Pharmacokinet 2013; 52: 463-473
- 10 Kaku K, Watada H, Iwamoto Y. et al. Efficacy and safety of monotherapy with the novel sodium/glucose cotransporter-2 inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus: a combined Phase 2 and 3 randomized, placebo-controlled, double-blind, parallel-group comparative study. Cardiovasc Diabetol. 2014; 13: 65
- 11 Yamane M, Kawashima K, Yamaguchi K. et al. In vitro profiling of the metabolism and drug–drug interaction of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, using human liver microsomes, human hepatocytes, and recombinant human CYP. Xenobiotica 2015; 45: 230-238
- 12 Zell M, Husser C, Kuhlmann O. et al. Metabolism and mass balance of SGLT2 inhibitor tofogliflozin following oral administration to humans. Xenobiotica 2014; 44: 369-378
- 13 Holstein A, Hinze S, Thiessen A. et al. Clinical implications of hepatogenous diabetes in liver cirrhosis. J. Gastroenterol Hepatol 2002; 17: 677-681
- 14 Wlazlo N, Beijers HJ, Schoon EJ. et al. High prevalence of diabetes mellitus in patients with liver cirrhosis. Diabet Med 2010; 27: 1308-1311
- 15 Garcia-Compeán D, Jáquez-Quintana JO, Lavalle-González FJ. et al. The prevalence and clinical characteristics of glucose metabolism disorders in patients with liver cirrhosis. A prospective study. Ann Hepatol. 2012; 11: 240-248
- 16 Lunati ME, Grancini V, Agnelli F. et al. Metabolic syndrome after liver transplantation: Short-term prevalence and pre- and post-operative risk factors. Dig Liver Dis 2013; 45: 833-839
- 17 Grancini V, Trombetta M, Lunati ME. et al. Contribution of β-cell dysfunction and insulin resistance to cirrhosis-associated diabetes: Role of severity of liver disease. J Hepatol 2015; 63: 1484-1490
- 18 Seko Y, Sumida Y, Tanaka S. et al. Effect of sodium glucose cotransporter 2 inhibitor on liver function tests in Japanese patients with non-alcoholic fatty liver disease and type 2 diabetes mellitus. Hepatol Res 2017; 47: 1072-1078
- 19 Shibuya T, Fushimi N, Kawai M. et al. Luseogliflozin improves liver fat deposition compared to metformin in type 2 diabetes patients with non-alcoholic fatty liver disease: A prospective randomized controlled pilot study. Diabetes Obes Metab 2018; 20: 438-442
- 20 Sumida Y, Yoneda M. Current and future pharmacological therapies for NAFLD/NASH. J Gastroenterol 2018; 53: 362-376
- 21 U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Guidance for Industry Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling. May 2003 Clinical Pharmacology.
- 22 Child CG, Turcotte JG. Surgery and portal hypertension. Major Probl Clin Surg 1964; 1: 1-85
- 23 Pugh RN, Murray-Lyon IM, Dawson JL. et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60: 646-649
- 24 Zhang W, Krauwinkel WJJ, 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 2013; 33: 489-496
- 25 Kasichayanula S, Liu X, Zhang W. et al. Influence of Hepatic Impairment on the Pharmacokinetics and Safety Profile of Dapagliflozin: An Open-Label, Parallel-Group, Single-Dose Study. Clin Ther. 2011; 33: 1798-1808
- 26 Macha S, Rose P, Mattheus M. et al. Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment. Diabetes Obes Metab 2014; 16: 118-123
- 27 Samukawa Y, Sata M, Furihata K. et al. Luseogliflozin, an SGLT2 Inhibitor, in Japanese Patients With Mild/Moderate Hepatic Impairment: A Pharmacokinetic Study. Clin Pharmacol Drug Dev 2017; 6: 439-447
- 28 Michitaka K, Nishiguchi S, Aoyagi Y. et al. Etiology of liver cirrhosis in Japan: a nationwide survey. J Gastroenterol. 2010; 45: 86-94
- 29 Tanizawa Y, Kaku K, Araki E. et al. Long-term safety and efficacy of tofogliflozin, a selective inhibitor of sodium-glucose cotransporter 2, as monotherapy or in combination with other oral antidiabetic agents in Japanese patients with type 2 diabetes mellitus: multicenter, open-label, randomized controlled trials. Expert Opin Pharmacother 2014; 15: 749-766
- 30 Ramos-Lopez O, Martinez-Lopez E, Roman S. et al. Genetic, metabolic and environmental factors involved in the development of liver cirrhosis in Mexico. World J Gastroenterol 2015; 21: 11552-11566