Pharmacokinetic analysis of two different doses of simvastatin following oral administration in dogs

Abstract

Simvastatin, used orally to treat hyperlipidemia, exhibits highly variable pharmacokinetics (PKs) in humans. The aim of this study was to investigate simvastatin PKs using noncompartmental analysis and population PK models following a single oral administration of two doses (20 and 80 mg) in dogs. Forty beagle dogs were randomly divided into two groups corresponding to the two doses. Blood samples were collected from each group according to the assigned schedule after oral administration. The plasma concentration of simvastatin was determined using liquid chromatography–tandem mass spectrometry. The area under the curve and maximum concentration of simvastatin increased in a dose‐dependent manner with high variability. A two‐compartment model with first‐order absorption (Ka = 1.83 hr‐1) and first‐order elimination (clearance [CL/F] = 292 L/h; volume of distribution in the central compartment [Vc/F] = 1506 L) well described the PKs of simvastatin in dogs. Large variability in the PKs of simvastatin was quantitated via modeling approaches, allowing the differentiation of between‐subject variability (144.8 CV% for Ka; 94.7 CV% for CL/F; 97.5 CV% for Vc/F) and residual variability (62.7%). These findings will help facilitate the development of an optimal dose regimen of simvastatin in canines with hypercholesterolemia and may be useful in developing novel formulations.