Fasting glucose and triglycerides as biomarkers of mTOR inhibition, evidence of a categorical response.

3091 Background: Hyperglycemia and hypertriglyceridemia are mechanism-based toxicities of mammalian target of rapamycin (mTOR) inhibitors, but have not been intensively studied as potential pharmacodynamic biomarkers. Methods: Changes in fasting serum glucose and triglyceride concentrations were determined in 127 patients (pts) before, and 4 weeks after treatment with the mTOR inhibitor sirolimus/rapamycin (S). Pts were enrolled in three different trials of S administered to achieve AUC of 1,000-6,000 ng-hr/ml. Results: Of these pts (67 male; 60 female; median age 62 y [range of 27-82], 72 had fasting measures for both glucose and triglycerides. Twelve pts had Type II diabetes. Mean/median change: in glucose = 17/8 mg/dL (SD=32, 95% CI 10-25, p< 0.0001), in triglycerides = 51/31 mg/dL (SD= 76, 95% CI 33-69, p< 0.0001) (p values for paired T-test). Changes were not associated with sex, S dose, baseline triglycerides, or use of lipid lowering agents. Change in glucose was significantly associated with a his...