Effect of sirolimus on insulin dynamics in horses

BackgroundSirolimus, a mechanistic target of rapamycin inhibitor, suppresses insulin production in other species and has therapeutic potential for hyperinsulinemia in horses. Hypothesis/ObjectiveDetermine the pharmacokinetics (PKs) of sirolimus and evaluate its effect on insulin dynamics in healthy and insulin dysregulation (ID) horses. AnimalsEight Standardbred geldings. MethodsA PK study was performed followed by a placebo-controlled, randomized, crossover study. Blood sirolimus concentrations were measured by liquid chromatography-mass-spectrometry. PK indices were estimated by fitting a 2-compartment model using nonlinear least squares regression. An oral glucose test (OGT) was conducted before and 4, 24, 72, and 144 hours after administration of sirolimus or placebo. Effects of time, treatment and animal on blood glucose and insulin concentrations were analyzed using mixed-effects linear regression. Sirolimus was then administered to 4 horses with dexamethasone-induced ID and an OGT was performed at baseline, after ID induction and after 7 days of treatment. ResultsMedian (range) maximum sirolimus concentration was 277.0 (247.5-316.06) ng/mL at 5 (5-10) min and half-life was 3552 (3248-4767) min. Mean (range) oral bioavailability was 9.5 (6.8-12.4)%. Sirolimus had a significant effect on insulin concentration 24 hours after a single dose: median (interquartile range) insulin at 60 min (5.0 [3.7-7.0] mu IU/mL) was 37 (-5 to 54)% less than placebo (8.7 [5.8-13.7] mu IU/mL, P = .03); and at 120 min (10.2 [8.4-12.2] mu IU/mL) was 28 (-15 to 53)% less than placebo (14.9 [8.4-24.8] mu IU/mL, P = .02). There was minimal effect on glucose concentration. Insulin responses decreased toward baseline in ID horses after 7 days of treatment. Conclusion and Clinical ImportanceSirolimus decreased the insulinemic response to glucose and warrants further investigation.

Automated summary

This study aimed to determine the pharmacokinetics of sirolimus and evaluate its effect on insulin dynamics in horses. The results showed that sirolimus significantly decreased insulin concentration and the effect lasted for 7 days in insulin dysregulation horses.