Successful Integration of Nonclinical and Clinical Findings in Interpreting the Clinical Relevance of Rodent Neoplasia with a New Chemical Entity

Toxicologic Pathology

Volumn 43, Issue 1, 2015, Pages 48-56

  Ways, Kirk ^a   Johnson, Mark D ^a   Mamidi, Rao N V S ^a   Proctor, James ^a   de Jonghe, Sandra ^b   Louden, Calvert ^b  

^a JANSSEN RESEARCH AND DEVELOPMENT   (United States)

^b JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

Author keywords

canagliflozin; carbohydrate malabsorption; Leydig cell tumors; pheochromocytomas; rat carcinogenicity; renal tubular tumors; SGLT2 inhibitor

Indexed keywords

ANTIDIABETIC AGENT; CANAGLIFLOZIN; SODIUM GLUCOSE COTRANSPORTER 2; TESTOSTERONE; DAPAGLIFLOZIN; GLUCOSE; LUTEINIZING HORMONE;

ANIMAL; ANTAGONISTS AND INHIBITORS; CARCINOGEN TESTING; CHEMICALLY INDUCED; CLINICAL TRIAL (TOPIC); DIABETES MELLITUS, TYPE 2; EXPERIMENTAL NEOPLASM; HUMAN; MALE; MOUSE; RAT; ADRENAL MEDULLA; ARTICLE; CARBOHYDRATE INTOLERANCE; CARCINOGENESIS; CELL PROLIFERATION; CLINICAL STUDY; DRUG ABSORPTION; DRUG APPROVAL; EXPERIMENTAL ANIMAL; GENOTOXICITY; GLUCOSE BLOOD LEVEL; IC50; KIDNEY TUBULE CELL; KIDNEY TUBULE DAMAGE; LEYDIG CELL TUMOR; NEOPLASM; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PHEOCHROMOCYTOMA; PRIORITY JOURNAL; TOXICITY;

ANIMALS; CANAGLIFLOZIN; CARCINOGENICITY TESTS; CLINICAL TRIALS AS TOPIC; DIABETES MELLITUS, TYPE 2; HUMANS; HYPOGLYCEMIC AGENTS; MALE; MICE; NEOPLASMS, EXPERIMENTAL; RATS; SODIUM-GLUCOSE TRANSPORTER 2; TESTOSTERONE;

RATTUS; RODENTIA;

EID: 84921817866     PISSN: 01926233     EISSN: 15331601     Source Type: Journal    
DOI: 10.1177/0192623314557179     Document Type: Article

References (59)

1. Abdul-Ghani M. A. Norton L. Defronzo R. A. (2011). Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev 32, 515–31.
2. Baer A. (1988). Sugars and adrenomedullary proliferative lesions: The effects of lactose and various polyalcohols. Int J Toxicol 7, 71–81.
3. Bailey C. J. (2011). Renal glucose reabsorption inhibitors to treat diabetes. Trends Pharmacol Sci 32, 63–71.
4. Bär A. (1992). Significance of Leydig cell neoplasia in rats fed lactitol or lactose. J Am Coll Toxicol 11, 189–207.
5. Barone S. Fussell S. L. Singh A. K. Lucas F. Xu J. Kim C. Wu X. Yu Y. Amlal H. Seidler U. Zuo J. Soleimani M. (2009). Slc2a5 (Glut5) is essential for the absorption of fructose in the intestine and generation of fructose-induced hypertension. J Biol Chem 284, 5056–66.
6. Bode B. Stenlof K. Sullivan D. Fung A. Usiskin K. (2013). Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: A randomized trial. Hosp Pract 41, 72–84.
7. Clayton R. N. Huhtaniemi I. T. (1982). Absence of gonadotropin-releasing hormone receptors in human gonadal tissue. Nature 299, 56–59.
8. Clegg E. D. Cook J. C. Chapin R. E. Foster P. M. Daston G. P. (1997). Leydig cell hyperplasia and adenoma formation: Mechanisms and relevance to humans. Reprod Toxicol 11, 107–21.
9. Cohen S. M. (1998). Urinary bladder carcinogenesis. Toxicol Pathol 26, 121–27.
10. Cohen S. M. Arnold L. L. (2011). Chemical carcinogenesis. Toxicol Sci 120, S76–S92.
11. Cook J. C. Klinefelter G. R. Hardisty J. F. Sharpe R. M. Foster P. M. (1999). Rodent Leydig cell tumorigenesis: A review of the physiology, pathology, mechanisms, and relevance to humans. Crit Rev Toxicol 29, 169–261.
12. Crabbs T. A. Frame S. R. Laast V. A. Patrick D. J. Thomas J. Zimmerman B. Hardisty J. F. (2013). Occurrence of spontaneous amphophilic-vacuolar renal tubule tumors in Sprague-Dawley rats from subchronic toxicity studies. Toxicol Pathol 41, 866–71.
13. Creutzfeldt W. Folsch U. R. Elsenhans B. Ballmann M. Conlon J. M. (1985). Adaptation of the small intestine to induced maldigestion in rats. Experimental pancreatic atrophy and acarbose feeding. Scand J Gastroenterol Suppl 112, 45–53.
14. Defronzo R. A. Davidson J. A. Del Prato S. (2012). The role of the kidneys in glucose homeostasis: A new path towards normalizing glycaemia. Diabetes Obes Metab 14, 5–14.
15. A.P., de Groot, B.B.R., Lina, A.A.M., Hagenaars, V.M., Hollanders, M., Andringa, V.J., Feron, Effects of a dietary load of acid or base on changes induced by lactose in rats, Food Chem Toxicol, (1995), 33, 1-14
16. S., De Jonghe, J., Proctor, P., Vinken, B., Feyen, I., Wynant, D., Marien, H., Geys, R.R.V.S., Mamidi, M.D., Johnson, Carcinogenicity in rats of the SGLT2 inhibitor canagliflozin, Chem Biol Interact, (2014), 224, 1-12
17. Doi A. M. Lou Z. Holmes E. Venugopal C. S. Nyagode B. James M. O. Kleinow K. M. (2006). Intestinal bioavailability and biotransformation of 3,3′,4,4′-tetrachlorobiphenyl (CB 77) in in situ preparations of channel catfish following dietary induction of CYP1A. Aquat Toxicol 77, 33–42.
18. Ehrenkranz J. R. Lewis N. G. Kahn C. R. Roth J. (2005). Phlorizin: A review. Diabetes Metab Res Rev 21, 31–8.
19. Gerich J. E. (2010). Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: Therapeutic implications. Diabet Med 27, 136–42.
20. Gorboulev V. Schurmann A. Vallon V. Kipp H. Jaschke A. Klessen D. Friedrich A. Scherneck S. Rieg T. Cunard R. Veyhl-Wichmann M. Srinivasan A. Balen D. Breljak D. Rexhepaj R. Parker H. E. Gribble F. M. Reimann F. Lang F. Wiese S. Sabolic I. Sendtner M. Koepsell H. (2012). Na(+)-d-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes 61, 187–96.
21. Greim H. Hartwig A. Reuter U. Richter-Reichhelm H. B. Thielmann H. W. (2009). Chemically induced pheochromocytomas in rats: Mechanisms and relevance for human risk assessment. Crit Rev Toxicol 39, 695–718.
22. Hard G. C. Boorman G. A. Wolf D. C. (2000). Re-evaluation of the 2-year chloroform drinking water carcinogenicity bioassay in Osborne-Mendel rats supports chronic renal tubule injury as the mode of action underlying the renal tumor response. Toxicol Sci 53, 237–44.
23. Hard G. C. Khan K. N. (2004). A contemporary overview of chronic progressive nephropathy in the laboratory rat, and its significance for human risk assessment. Toxicol Pathol 32, 171–80.
24. Hard G. C. Seely J. C. Kissling G. E. Betz L. J. (2008). Spontaneous occurrence of a distinctive renal tubule tumor phenotype in rat carcinogenicity studies conducted by the national toxicology program. Toxicol Pathol 36, 388–96.
25. Hollander P. (1992). Safety profile of acarbose, an alpha-glucosidase inhibitor. Drugs 44, 47–53.
26. Huhtaniemi I. T. (1983). Gonadotrophin receptors: Correlates with normal and pathological functions of the human ovary and testis. Clin Endocrinol Metab 12, 117–32.
27. Janssen Research & Development, LLC. (2012). Integrated summary of safety. Canagliflozin as an adjunctive treatment to diet and exercise alone or co-administered with other antihyperglycemic agents to improve glycemic control in adults with type 2 diabetes mellitus.
28. Janssen Research & Development, LLC. Endocrinologic and metabolic drugs advisory committee. 2013. Canagliflozin as an adjunctive treatment to diet and exercise alone or co-administered with other antihyperglycemic agents to improve glycemic control in adults with type 2 diabetes mellitus. JNJ-28431754 (Canagliflozin). NDA 204042. Accessed June 30, 2014. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM334551.pdf.
29. Kissner T. Doyle N. Samadfam R. Krupp E. Heinrichs M. Haile S. Smith S. (2010). Bone as a target tissue in the toxicological assessment of anti-diabetes drug class of SGLT1 inhibitors. Poster presented at: 49th Annual Meeting of the Society of Toxicology, March 7-11, 2010, Salt Lake City, Utah.
30. Lembcke B. Loser C. Folsch U. R. Wohler J. Creutzfeldt W. (1987). Adaptive responses to pharmacological inhibition of small intestinal alpha-glucosidases in the rat. Gut 28, 181–87.
31. Liang Y. Arakawa K. Ueta K. Matsushita Y. Kuriyama C. Martin T. Du F. Liu Y. Xu J. Conway B. Conway J. Polidori D. Ways K. Demarest K. (2012). Effect of canagliflozin on renal threshold for glucose, glycemia, and body weight in normal and diabetic animal models. PLoS One 7, e30555.
32. Lock E. A. Hard G. C. (2004). Chemically induced renal tubule tumors in the laboratory rat and mouse: Review of the NCI/NTP database and categorization of renal carcinogens based on mechanistic information. Crit Rev Toxicol 34, 211–99.
33. Lynch B. S. Tischler A. S. Capen C. Munro I. C. McGirr L. M. McClain R. M. (1996). Low digestible carbohydrates (polyols and lactose): Significance of adrenal medullary proliferative lesions in the rat. Regul Toxicol Pharmacol 23, 256–97.
34. R.R.V.S., Mamidi, J., Proctor, S., De Jonghe, B., Feyen, E., Moesen, P., Vinken, J.Y., Ma, S., Bryant, S., Snook, C., Louden, G., Lammens, K., Ways, M.F., Kelley, M.D., Johnson, Carbohydrate malabsorption mechanism for tumor formation in rats treated with the SGLT2 inhibitor canagliflozin, Chem Biol Interact, (2014), 221, 109-118
35. Mann D. R. Adams S. R. Gould K. G. Orr T. E. Collins D. C. (1989). Evaluation of the possible direct effects of gonadotrophin-releasing hormone analogues on the monkey (Macaca mulatta) testis. J Reprod Fertil 85, 89–95.
36. Moriya R. Shirakura T. Ito J. Seo T. (2009). Activation of sodium-glucose cotransporter 1 ameliorates hyperglycemia by mediating incretin secretion in mice. Am J Physiol Endocrinol Metab 297, E1358–65.
37. Niswender G. D. Midgley A. R. Jr Monroe S. E. Reichert L. E. Jr (1968). Radioimmunoassay for rat luteinizing hormone with antiovine LH serum and ovine LH-131-I. Proc Soc Exp Biol Med 128, 807–11.
38. Nomura S. Sakamaki S. Hongu M. Kawanishi E. Koga Y. Sakamoto T. Yamamoto Y. Ueta K. Kimata H. Nakayama K. Tsuda-Tsukimoto M. (2010). Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem 53, 6355–60.
39. Nyirjesy P. Zhao Y. Ways K. Usiskin K. (2012). Evaluation of vulvovaginal symptoms and candida colonization in women with type 2 diabetes mellitus treated with canagliflozin, a sodium glucose co-transporter 2 inhibitor. Curr Med Res Opin 28, 1173–78.
40. Prentice D. E. Meikle A. W. (1995). A review of drug-induced Leydig cell hyperplasia and neoplasia in the rat and some comparisons with man. Hum Exp Toxicol 14, 562–72.
41. F.F.J., Roe, Relevance for man of the effects of lactose, polyols and other carbohydrates on calcium metabolism seen in rats: A review, Hum Toxicol, (1989), 8, 87-98
42. Roe F. J. Bar A. (1985). Enzootic and epizootic adrenal medullary proliferative disease of rats: Influence of dietary factors which affect calcium absorption. Hum Toxicol 4, 27–52.
43. Rosenstock J. Aggarwal N. Polidori D. Zhao Y. Arbit D. Usiskin K. Capuano G. Canovatchel W., and for the Canagliflozin DIA 2001 Study Group. (2012). Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care 35, 1232–38.
44. Rossetti L. Smith D. Shulman G. I. Papachristou D. Defronzo R. A. (1987). Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest 79, 1510–15.
45. Rothenberg P. L. Devineni D. Ghosh A. Polidori D. Hompesch M. Arnolds S. Morrow L. Spitzer H. Blake J. Wexler D. Tan Y. Smulders K. Demarest K. Sha S. (2010). Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, improved glucose control in subjects with type 2 diabetes: Results of a phase 1b study. Diabetologia 53, S350–51. Abstract 876.
46. Santer R. Calado J. (2010). Familial renal glucosuria and SGLT2: From a mendelian trait to a therapeutic target. Clin J Am Soc Nephrol 5, 133–41.
47. Schulter G. (1988). Toxicology of acarbose with special reference to long-term carcinogenicity studies. In Acarbose for the Treatment of Diabetes Mellitus, 2nd International Symposium on Acarbose (Creutzfeldt W., ed.), 5–14. Springer-Verlag, New York.
48. Schwartz S. Morrow L. Hompesch M. Devineni D. Skee D. Vandebosch A. Murphy J. Pfeifer M. (2010). Canagliflozin improves glycemic control in subjects with type 2 diabetes (T2D) not optimally controlled on stable doses of insulin. Presented at the 70th Scientific Sessions of the American Diabetes Association (ADA), June 25-29, 2010, Orlando, FL. Abstract 564-P.
49. E.J., Sinkeldam, R.A., Woutersen, V.V.H., Hollanders, H.P., Til, A., Van Garderen-Hoetmer, A., Bär, Subchronic and chronic toxicology/carcinogenicity feeding studies with lactitol in rats, J Am Coll Toxicol, (1992), 11, 165-188
50. Tirmenstein M. Dorr T. E. Janovitz E. B. Hagan D. Abell L. M. Onorato J. M. Whaley J. M. Graziano M. J. Reilly T. P. (2013). Nonclinical toxicology assessments support the chronic safety of dapagliflozin, a first-in-class sodium-glucose cotransporter 2 inhibitor. Int J Toxicol 32, 336–50.
51. Tischler A. S. Delellis R. A. (1988). The rat adrenal medulla. I. the noramal adrenal. Int J Toxicol 7, 1–21.
52. Tischler A. S. Powers J. F. Downing J. C. Riseberg J. C. Shahsavari M. Ziar J. McClain R. M. (1996). Vitamin D3, lactose, and xylitol stimulate chromaffin cell proliferation in the rat adrenal medulla. Toxicol Appl Pharmacol 140, 115–23.
53. Ursin G. Bjelke E. Heuch I. Vollset S. E. (1990). Milk consumption and cancer incidence: A Norwegian prospective study. Br J Cancer 61, 454–59.
54. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. (2014). Pharmacology/Toxicology review(s) of canagliflozin NDA 204042 for the treatment of type 2 diabetes. Accessed July 2, 2014. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000PharmR.pdf.
55. Vallon V. Platt K. A. Cunard R. Schroth J. Whaley J. Thomson S. C. Koepsell H. Rieg T. (2011). SGLT2 mediates glucose reabsorption in the early proximal tubule. J Am Soc Nephrol 22, 104–12.
56. Wang N. G. Sundaram K. Pavlou S. Rivier J. Vale W. Bardin C. W. (1983). Mice are insensitive to the antitesticular effects of luteinizing hormone-releasing hormone agonists. Endocrinology 112, 331–35.
57. Woutersen R. A. (1986). Chronic toxicity and carcinogenicity of lactitol in rats: Comparison with lactose. In Low-digestibility Carbohydrates. Proceedings of a Workshop Held at the TNO-CINO Institutes (Leegater D. C. Feron V. J. Hermus R. J. J., eds.), 51–60. TNO-CINO Institutes, Zeitst, the Netherlands.
58. Yale J. F. Bakris G. Cariou B. Nieto J. David-Neto E. Yue D. Wajs E. Figueroa K. Jiang J. Law G. Usiskin K. Meinginger G. (2014). Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes Metab 16, 1016–27.
59. Yao C. H. Song J. S. Chen C. T. Yeh T. K. Hung M. S. Chang C. C. Liu Y. W. Yuan M. C. Hsieh C. J. Huang C. Y. Wang M. H. Chiu C. H. Hsieh T. C. Wu S. H. Hsiao W. C. Chu K. F. Tsai C. H. Chao Y. S. Lee J. C. (2011). Discovery of novel N-beta-d-Xylosylindole derivatives as sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the management of hyperglycemia in diabetes. J Med Chem 54, 166–78.