Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Tofogliflozin (A SELECTIVE SGLT2 Inhibitor) in Patients with Type 2 Diabetes Mellitus

Sachiya Ikeda; Yasuki Takano; Dietmar Schwab; Agnes Portron; Nahoko Kasahara-Ito; Tomohisa Saito; Satofumi Iida

doi:10.1055/a-0662-0209

Drug Research, Table of Contents

Drug Res (Stuttg) 2019; 69(06): 314-322
DOI: 10.1055/a-0662-0209

Original Article

Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Tofogliflozin (A SELECTIVE SGLT2 Inhibitor) in Patients with Type 2 Diabetes Mellitus

Sachiya Ikeda

¹Primary lifecycle Management Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

,

Yasuki Takano

²Clinical Science and Strategy Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

,

Dietmar Schwab

³Pharmaceutical Sciences, Clinical Pharmacology, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland

,

Agnes Portron

³Pharmaceutical Sciences, Clinical Pharmacology, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland

,

Nahoko Kasahara-Ito

⁴Translational Clinical Research, Clinical Pharmacology Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

,

Tomohisa Saito

⁴Translational Clinical Research, Clinical Pharmacology Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

,

Satofumi Iida

⁴Translational Clinical Research, Clinical Pharmacology Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

› Author Affiliations

Abstract

Purpose Tofogliflozin is an orally available selective inhibitor of sodium-glucose co-transporter 2 for treatment of type 2 diabetes mellitus (T2DM). Two studies were conducted to evaluate the effect of renal impairment on pharmacokinetics and pharmacodynamics of tofogliflozin.

Methods The studies were: 1) single dose study in T2DM patients with normal renal function and mild, moderate and severe renal impairment, and 2) multiple dose study for 24 weeks in T2DM patients with normal renal function and moderate renal impairment.

Results Renal function did not have a clinically relevant effect on the PK of tofogliflozin. Urinary glucose excretion up to 24 h after administration of tofogliflozin (UGE24h) decreased with decreasing glomerular filtration rate. Lowering UGE24h resulted in waning glycemic control but not body weight reduction.

Conclusions Single and multiple administrations of tofogliflozin were generally well tolerated in T2DM patients with various renal functions. As far as investigated here, these studies indicate no dose adjustment is required for patients with renal impairment.

Key words

tofogliflozin - renal impairment - urinary glucose excretion - type 2 diabetes mellitus

Full Text

References

References
1 World Health Organization. Global report on diabetes. Geneva: World Health Organization; 2016
2 De Nicola L, Gabbai FB, Liberti ME. et al. Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes. Am J Kidney Dis 2014; 64: 16-24
3 Obata A, Kubota N, Kubota T. et al. Tofogliflozin improves insulin resistance in skeletal muscle and accelerates lipolysis in adipose tissue in male mice. Endocrinology. 2016; 157: 1029-1042
4 Bolinder J, Ljunggren Ö, Johansson L. et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab 2014; 16: 159-169
5 Blonde L, Stenlöf K, Fung A. et al. Effects of canagliflozin on body weight and body composition in patients with type 2 diabetes over 104 weeks. Postgrad Med. 2016; 128: 371-380
6 Ohki T, Isogawa A, Toda N. et al. Effectiveness of ipragliflozin, a sodium-glucose co-transporter 2 inhibitor, as a second-line treatment for non-alcoholic fatty liver disease patients with type 2 diabetes mellitus who do not respond to incretin-based therapies including glucagon-like peptide-1 analogs and dipeptidyl peptidase-4 inhibitors. Clin Drug Investig 2016; 36: 313-319
7 Davies MJ, Trujillo A, Vijapurkar U. et al. Effect of canagliflozin on serum uric acid in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2015; 17: 426-429 Erratum in: Diabetes Obes Metab. 2015;17:708
8 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
9 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
10 Tanizawa Y, Kaku K, Araki E. et al. Tofogliflozin 004 and 005 Study group. 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
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 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
13 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
14 Kasahara-Ito N, Fukase H, Ogama Y. et al. Pharmacokinetics and pharmacodynamics of tofogliflozin (a selective SGLT2 inhibitor) in healthy male subjects. Drug Res (Stuttg) 2017; 67: 349-357
15 Kasahara N, Fukase H, Ohba Y. et al. A pharmacokinetic/pharmacodynamic drug-drug interaction study of tofogliflozin (a new SGLT2 inhibitor) and selected anti-type 2 diabetes mellitus drugs. Drug Res (Stuttg) 2016; 66: 74-81
16 Betônico CC, Titan SM, Correa-Giannella ML. et al. Management of diabetes mellitus in individuals with chronic kidney disease: therapeutic perspectives and glycemic control. Clinics (Sao Paulo) 2016; 71: 47-53
17 World Medical Association. Declaration of Helsinki – Ethical principles for medical research involving human subjects. Available from http://dl.med.or.jp/dl-med/wma/helsinki2013e.pdf Accessed March 11, 2016
18 Stevens LA, Coresh J, Greene T. et al. Assessing kidney function--measured and estimated glomerular filtration rate. N Engl J Med 2006; 354: 2473-2483
19 Guidance for Industry; Pharmacokinetics in Patients with Impaired Renal Function – Study Design, Data Analysis, and Impact on Dosing and Labeling. FDA, May 1998
20 Note for Guidance on the Evaluation of the Pharmacokinetics of Medical Products in Patients with Impaired Renal Function. EMEA, June 2004
21 National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification. Am J Kidney Dis 39: S1-S266 2002; (Suppl. 01)
22 Matsuo S, Imai E, Horio M. et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009; 53: 982-992
23 Yale JF, Bakris G, Cariou B. et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 2013; 15: 463-473
24 Kohan DE, Fioretto P, Tang W. et al. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014; 85: 962-971
25 Barnett AH, Mithal A, Manassie J. et al. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2014; 2: 369-384
26 Kashiwagi A, Takahashi H, Ishikawa H. et al. A randomized, double-blind, placebo-controlled study on long-term efficacy and safety of ipragliflozin treatment in patients with type 2 diabetes mellitus and renal impairment: results of the long-term ASP1941 safety evaluation in patients with type 2 diabetes with renal impairment (LANTERN) study. Diabetes Obes Metab 2015; 17: 152-160
27 Haneda M, Seino Y, Inagaki N. et al. Influence of Renal Function on the 52-Week Efficacy and Safety of the Sodium Glucose Cotransporter 2 Inhibitor Luseogliflozin in Japanese Patients with Type 2 Diabetes Mellitus. Clinical Therapeutics 2016; 38: 66-88
28 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
29 Mahaffey KW, Neal B, Perkovic V. et al. Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation. 2018; 137: 323-334
30 Jerums G, Premaratne E, Panagiotopoulos S. et al. The clinical significance of hyperfiltration in diabetes. Diabetologia. 2010; 53: 2093-2104
31 Ruggenenti P, Porrini EL, Gaspari F. et al. Glomerular hyperfiltration and renal disease progression in type 2 diabetes. Diabetes Care. 2012; 35: 2061-2068

Supplementary Material

Supporting Information