E21 - Effect of a Single Intravenous Dose of Sirolimus on Insulin Dynamics in Healthy Adult Horses

Abstract: Background: Sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, can suppress insulin production and has therapeutic potential for insulin dysregulated (ID) horses.









Hypothesis/objective: Determine the pharmacokinetics of intravenous sirolimus in healthy adult horses and evaluate its effect on insulin dynamics.









Animals: 8 healthy adult Standardbred geldings.









Methods: A pharmacokinetic study was performed followed by a placebo-controlled, randomized, crossover study. Serial blood sirolimus concentrations were measured by liquid chromatography/mass spectrometry for 72h after an intravenous dose (0.06 mg/kg). PK indices were estimated by fitting a 2-compartment model using non-linear least squares regression. Next, an oral glucose test was conducted before and 4, 24, 72 and 144h after administration of a single dose of sirolimus or placebo (propylene glycol). The effects of time, treatment and animal on blood glucose and insulin concentrations were analyzed using mixed-effects linear regression.









Results: No adverse effects were observed. Median (range) maximum sirolimus concentration was 277.0 (247.5-316.06) ng/mL at 5 (5-10) minutes and half-life was 3552 (3248-4767) minutes. Sirolimus had a significant effect on insulin concentration 24h after dosing only: median (interquartile range) insulin concentration at 60 min (5.0 [3.7-7.0] µIU/mL) was 37% (-5-54%) less than placebo (8.7 [5.8-13.7] µIU/mL, p = 0.03); and at 120 min (10.2 [8.4-12.2] µIU/mL) was 28% (-15-53%) less than placebo (14.9 [8.4-24.8] µIU/mL, p = 0.02). There was no effect on blood glucose.









Conclusion and clinical importance: Sirolimus was well tolerated and decreased the insulinemic response to glucose challenge in healthy horses. Sirolimus warrants investigation for control of hyperinsulinemia in ID horses.