Pharmacokinetics of empagliflozin, a sodium glucose cotransporter-2 inhibitor, and simvastatin following co-administration in healthy volunteers

International Journal of Clinical Pharmacology and Therapeutics

Volumn 52, Issue 11, 2014, Pages 973-980

  Macha, Sreeraj ^a   Lang, Benjamin ^b   Pinnetti, Sabine ^b   Broedl, Uli C ^b  

^a BOEHRINGER INGELHEIM PHARMACEUTICALS INC   (United States)

^b BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

Author keywords

Drug drug interaction; Empagliflozin; SGLT2 inhibitor; Simvastatin; Type 2 diabetes

Indexed keywords

DRUG METABOLITE; EMPAGLIFLOZIN; SIMVASTATIN; BENZHYDRYL DERIVATIVE; GLUCOSIDE; SIMVASTATIN ACID; SODIUM GLUCOSE COTRANSPORTER 2;

ADULT; ADVERSE OUTCOME; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; CROSSOVER PROCEDURE; CYST; DRUG BLOOD LEVEL; DRUG DISTRIBUTION; DRUG ELIMINATION; DRUG POTENTIATION; DRUG SAFETY; DRUG TOLERABILITY; FEMALE; HEADACHE; HUMAN; HUMAN EXPERIMENT; MALE; MAXIMUM PLASMA CONCENTRATION; NAUSEA; NORMAL HUMAN; RANDOMIZED CONTROLLED TRIAL; ANALOGS AND DERIVATIVES; ANTAGONISTS AND INHIBITORS; DRUG INTERACTION; MIDDLE AGED;

ADULT; BENZHYDRYL COMPOUNDS; CROSS-OVER STUDIES; DRUG INTERACTIONS; FEMALE; GLUCOSIDES; HEALTHY VOLUNTEERS; HUMANS; MALE; MIDDLE AGED; SIMVASTATIN; SODIUM-GLUCOSE TRANSPORTER 2;

EID: 84911497060     PISSN: 09461965     EISSN: None     Source Type: Journal    
DOI: 10.5414/CP202117     Document Type: Article

References (43)

1. World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO consultation. whqlibdoc.who.int/hq/1999/who-ncd-ncs-99.2.pdf. 1999.
2. Barnett KN, Ogston SA, McMurdo ME, Morris AD, Evans JM. A 12-year follow-up study of allcause and cardiovascular mortality among 10,532 people newly diagnosed with Type 2 diabetes in Tayside, Scotland. Diabet Med. 2010; 27: 1124-1129. CrossRef PubMed
3. Fowler MJ. Microvascular and macrovascular complications of diabetes. Clinical Diabetes. 2008; 26: 77-82. CrossRef
4. Rydén L, Standl E, Bartnik M, Van den Berghe G, Betteridge J, de Boer MJ, Cosentino F, Jönsson B, Laakso M, Malmberg K, Priori S, Ostergren J, Tuomilehto J, Thrainsdottir I, Vanhorebeek I, Stramba-Badiale M, Lindgren P, Qiao Q, Priori SG, Blanc JJ, et al Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD). Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. Eur Heart J. 2007; 28: 88-136. PubMed
5. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000; 321: 405-412. CrossRef PubMed
6. Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, Ingelsson E, Lawlor DA, Selvin E, Stampfer M, Stehouwer CD, Lewington S, Pennells L, Thompson A, Sattar N, White IR, Ray KK, Danesh J; Emerging Risk Factors Collaboration. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010; 375: 2215-2222. CrossRef PubMed
7. Wannamethee SG, Shaper AG, Whincup PH, Lennon L, Sattar N. Impact of diabetes on cardiovascular disease risk and all-cause mortality in older men: influence of age at onset, diabetes duration, and established and novel risk factors. Arch Intern Med. 2011; 171: 404-410. CrossRef PubMed
8. Centers for Disease Control and Prevention. National Diabetes Fact Sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs-2011.pdf. 2011.
9. Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia. 2001; 44 (Suppl 2): S14-S21. CrossRef PubMed
10. American Diabetes Association. Standards of medical care in diabetes - 2011. Diabetes Care. 2011; 34 (Suppl 1): S11-S61. CrossRef PubMed
11. Handelsman Y, Mechanick JI, Blonde L, Grunberger G, Bloomgarden ZT, Bray GA, Dagogo-Jack S, Davidson JA, Einhorn D, Ganda O, Garber AJ, Hirsch IB, Horton ES, Ismail-Beigi F, Jellinger PS, Jones KL, Jovanovič L, Lebovitz H, Levy P, Moghissi ES, et al; AACE Task Force for Developing a Diabetes Comprehensive Care Plan. American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan: executive summary. Endocr Pract. 2011; 17: 287-302. CrossRef PubMed
12. Kalyani RR, Saudek CD, Brancati FL, Selvin E. Association of diabetes, comorbidities, and A1C with functional disability in older adults: results from the National Health and Nutrition Examination Survey (NHANES), 1999-2006. Diabetes Care. 2010; 33: 1055-1060. CrossRef PubMed
13. Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab. 2009; 5: 150-159. CrossRef PubMed
14. Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA. 2004; 291: 335-342. CrossRef PubMed
15. National Heart Lung and Blood Institute. National Cholesterol Education Program (NCEP): detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdf. 2002.
16. Standl E. Statins and beyond: concurrent strategies for prevention of cardiovascular disease in patients with type 2 diabetes. Diab Vasc Dis Res. 2013; 10: 99-114. CrossRef PubMed
17. DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab. 2012; 14: 5-14. CrossRef PubMed
18. Abdul-Ghani MA, Norton L, DeFronzo RA. Efficacy and safety of SGLT2 inhibitors in the treatment of type 2 diabetes mellitus. Curr Diab Rep. 2012; 12: 230-238. CrossRef PubMed
19. Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, Bakker RA, Mark M, Klein T, Eickelmann P. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012; 14: 83-90. CrossRef PubMed
20. Heise T, Seman L, Macha S, Jones P, Marquart A, Pinnetti S, Woerle HJ, Dugi K. Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of empagliflozin in patients with T2DM. Diabetes Ther. 2013; 4: 331-345. CrossRef PubMed
21. Macha S, Rose P, Mattheus M, Pinnetti S, Woerle HJ. Lack of drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and warfarin in healthy volunteers. Diabetes Obes Metab. 2013; 15: 316-323. CrossRef PubMed
22. Macha S, Sennewald R, Rose P, Schoene K, Pinnetti S, Woerle HJ, Broedl UC. Lack of clinically relevant drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and verapamil, ramipril, or digoxin in healthy volunteers. Clin Ther. 2013; 35: 226-235. CrossRef PubMed
23. Macha S, Mattheus M, Pinnetti S, Woerle HJ, Broedl UC. Effect of empagliflozin on the steady-state pharmacokinetics of ethinylestradiol and levonorgestrel in healthy female volunteers. Clin Drug Investig. 2013; 33: 351-357. CrossRef PubMed
24. Brand T, Macha S, Mattheus M, Pinnetti S, Woerle HJ. Pharmacokinetics of empagliflozin, a sodium glucose cotransporter-2 (SGLT-2) inhibitor, coadministered with sitagliptin in healthy volunteers. Adv Ther. 2012; 29: 889-899. CrossRef PubMed
25. Macha S, Mattheus M, Pinnetti S, Seman L, Woerle HJ. Pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, and glimepiride following co-administration in healthy volunteers: A randomised, open-label, crossover study. Journal of Diabetes Research and Clinical Metabolism. 2012; 1: 14. CrossRef
26. Friedrich C, Metzmann K, Rose P, Mattheus M, Pinnetti S, Woerle HJ. A randomized, open-label, crossover study to evaluate the pharmacokinetics of empagliflozin and linagliptin after coadministration in healthy male volunteers. Clin Ther. 2013; 35: A33-A42. CrossRef PubMed
27. Macha S, Rose P, Mattheus M, Cinca R, Pinnetti S, Broedl UC, Woerle HJ. Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment. Diabetes Obes Metab. 2014; 16: 118-123. PubMed
28. Macha S, Mattheus M, Halabi A, Pinnetti S, Woerle HJ, Broedl UC. Pharmacokinetics, pharmacodynamics and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with renal impairment. Diabetes Obes Metab. 2014; 16: 215-222. CrossRef PubMed
29. Riggs MM, Staab A, Seman L, MacGregor TR, Bergsma TT, Gastonguay MR, Macha S. Population pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with type 2 diabetes. J Clin Pharmacol. 2013; 53: 1028-1038. CrossRef PubMed
30. Ring A, Brand T, Macha S, Breithaupt-Groegler K, Simons G, Walter B, Woerle HJ, Broedl UC. The sodium glucose cotransporter 2 inhibitor empagliflozin does not prolong QT interval in a thorough QT (TQT) study. Cardiovasc Diabetol. 2013; 12: 70. CrossRef PubMed
31. Heise T, Seewaldt-Becker E, Macha S, Hantel S, Pinnetti S, Seman L, Woerle HJ. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks' treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes Metab. 2013; 15: 613-621. CrossRef PubMed
32. Seman L, Macha S, Nehmiz G, Simons G, Ren B, Pinnetti S, Woerle HJ, Dugi K. Empagliflozin (BI 10773), a potent and selective SGLT-2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clinical Pharm in Drug Dev. 2013; 2: 152-161. CrossRef
33. Ferrannini E, Seman L, Seewaldt-Becker E, Hantel S, Pinnetti S, Woerle HJ. A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes Obes Metab. 2013; 15: 721-728. Cross-Ref PubMed
34. Rosenstock J, Seman LJ, Jelaska A, Hantel S, Pinnetti S, Hach T, Woerle HJ. Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia. Diabetes Obes Metab. 2013; 15: 1154-1160. CrossRef PubMed
35. Slater EE, MacDonald JS. Mechanism of action and biological profile of HMG CoA reductase inhibitors. A new therapeutic alternative. Drugs. 1988; 36 (Suppl 3): 72-82. CrossRef PubMed
36. Merck & Co Inc. ZOCOR (simvastatin) tablets: prescribing information. http://www.merck.com/product/usa/pi-circulars/z/zocor/zocor-pi.pdf.2012.
37. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006; 80: 565-581. CrossRef PubMed
38. Mauro VF. Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet. 1993; 24: 195-202. CrossRef PubMed
39. Armitage J, Bowman L, Wallendszus K, Bulbulia R, Rahimi K, Haynes R, Parish S, Peto R, Collins R; Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010; 376: 1658-1669. CrossRef PubMed
40. Reinoso RF, Sánchez NA, García MJ, Prous JR. Pharmacokinetic interactions of statins. Methods Find Exp Clin Pharmacol. 2001; 23: 541-566. CrossRef PubMed
41. Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011; 63: 157-181. CrossRef PubMed
42. Arnadottir M, Eriksson LO, Thysell H, Karkas JD. Plasma concentration profiles of simvastatin 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitory activity in kidney transplant recipients with and without ciclosporin. Nephron. 1993; 65: 410-413. CrossRef PubMed
43. Ichimaru N, Takahara S, Kokado Y, Wang JD, Hatori M, Kameoka H, Inoue T, Okuyama A. Changes in lipid metabolism and effect of simvastatin in renal transplant recipients induced by cyclosporine or tacrolimus. Atherosclerosis. 2001; 158: 417-423. CrossRef PubMed