Abstract

HMG-CoA reductase inhibitors were potent hits against a mouse ependymoma cell line, but their effectiveness against CNS tumors will depend on their ability to cross the blood-brain barrier and attain a sufficient exposure at the tumor. Among HMG-CoA inhibitors that had activity in vitro, we prioritized simvastatin as the lead compound for preclinical pharmacokinetic studies based on its potential for CNS penetration as determined from in-silico models. Further we performed systemic plasma disposition and cerebral microdialysis studies of simvastatin (100 mg/kg, PO) in a murine model of ependymoma to characterize plasma and tumor extracellular fluid (tECF) pharmacokinetic properties. The murine dosage of simvastatin (100 mg/kg, oral) was equivalent to the MTD in patients (7.5 mg/kg, PO) based on equivalent plasma exposure of simvastatin acid (SVA) between the two species. Simvastatin (SV) is rapidly metabolized in murine plasma with 15 times lower exposure compared to human plasma. SVA exposure in tECF was 26.7 ± 11.0 μg/L*hr, whereas tumor to plasma partition coefficient of SVA (Kp,u) was 0.068 ± 0.020. Compared to in vitro washout IC50s, we did not achieve sufficient exposure of SVA in tECF to suggest tumor growth inhibition, therefore simvastatin was not carried forward in subsequent preclinical efficacy studies.