Rodent Carcinogenicity Profile of the Antidiabetic Dual PPAR α and γ Agonist Muraglitazar

Abstract

The carcinogenic potential of muraglitazar, a dual human peroxisome proliferator-activated receptor alpha/gamma agonist, was evaluated in 2-year studies in mice (1, 5, 20, and 40 mg/kg) and rats (1, 5, 30, and 50 mg/kg). Benign gallbladder adenomas occurred at low incidences in male mice at 20 and 40 mg/kg (area under the curve [AUC] exposures > or = 62 times human exposure at 5 mg/day) and were considered drug related due to an increased incidence of gallbladder mucosal hyperplasia at these doses. There was a dose-related increased incidence of transitional cell papilloma and carcinoma of the urinary bladder in male rats at 5, 30, and 50 mg/kg (AUC exposures > or = 8 times human exposure at 5 mg/day). At 30 and 50 mg/kg, the urinary bladder tumors were accompanied by evidence of increased urine solids. Subsequent investigative studies established that the urinary bladder carcinogenic effect was mediated by urolithiasis rather than a direct pharmacologic effect on urothelium. Incidences of subcutaneous liposarcoma in male rats and subcutaneous lipoma in female rats were increased at 50 mg/kg (AUC exposures > or = 48 times human exposure at 5 mg/day) and attributed, in part, to persistent pharmacologic stimulation of preadipocytes. Toxicologically relevant nonneoplastic changes in target tissues included thinning of cortical bone in mice and hyperplastic and metaplastic adipocyte changes in mice and rats. Considering that muraglitazar is nongenotoxic, the observed tumorigenic effects in mice and rats have no established clinical relevance since they occurred at either clinically nonrelevant exposures (gallbladder and adipose tumors) or by a species-specific mechanism (urinary bladder tumors).

A Nonthiazolidinedione Peroxisome Proliferator-Activated Receptor α/γ Dual Agonist CG301360 Alleviates Insulin Resistance and Lipid Dysregulation in db/db Mice

“…However, side effects of PPAR␣/␥ dual agonists still make them unsuitable for treatment of obesity and insulin resistance (Hellmold et al, 2007;Mittra et al, 2007;Tannehill-Gregg et al, 2007). In this regard, the failure of former PPAR␣/␥ dual agonists prompted us to develop novel PPAR␣/␥ dual agonists without (or with less) deleterious effects by screening different backbone structures of PPAR ligands.…”

“…However, recently identified PPAR␣/␥ dual agonists were ineffective because of undesirable side effects during preclinical or clinical trials. For example, muraglitazar, a synthetic PPAR␣/␥ dual agonist, was aborted during clinical trials because of increased mortality, fluid retention, edema, and cancer (Mittra et al, 2007;Tannehill-Gregg et al, 2007), and tesaglitazar was reported to cause fibrosarcoma in subcutaneous tissues (Hellmold et al, 2007). Furthermore, it has recently been reported that several types of TZDs induce tissue toxicity (Lloyd et al, 2002;Nissen and Wolski, 2007).…”

Current Status of Carcinogenicity Assessment of Peroxisome Proliferator-Activated Receptor Agonists by the US FDA and a Mode-of-Action Approach to the Carcinogenic Potential

“…Sustained urothelial proliferation may cause fixation of spontaneous mutation of mucosal cells, and finally develop tumors in urinary bladder and/or renal pelvis. Recently, a 2-year carcinogenicity study and a mechanistic study of Muragliazar, a PPAR dual agonist, provided some evidence for the proposed MOA 19,20 . Similar working hypotheses on M O A s a r e b e i n g p r o p os e d b y t he H e m a n g i o m a / Hemangiosarcoma and Fibrosarcoma/Liposarcoma Working Groups of the project, and further work toward elucidation of MOAs and evaluation of human risks is expected.…”

PAR-1622 is a selective peroxisome proliferator-activated receptor γ partial activator with preserved antidiabetic efficacy and broader safety profile for fluid retention

“…These safety concerns include potential carcinogenicity, weight gain, fluid retention, and increased risk of cardiac failure (Mittra et al, 2007;Nissen et al, 2005;Tannehill-Gregg et al, 2007).…”