CRESTOR (rosuvastatin calcium) is a synthetic, enantiomerically pure lipid-lowering agent. It is a selective, potent and competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in cholesterol biosynthesis.
Studies have shown that CRESTOR lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver by increasing the number of hepatic Low Density Lipoprotein (LDL) receptors on the cell-surface for enhanced uptake and catabolism of LDL. Additionally, CRESTOR inhibits the hepatic synthesis of Very Low Density Lipoprotein (VLDL), thereby reducing the total number of VLDL and LDL particles.
Epidemiologic, clinical and experimental studies have established that high LDL cholesterol (LDL-C), low High Density Lipoprotein Cholesterol (HDL-C) and high plasma triglycerides (TG) promote human atherosclerosis and are risk factors for developing cardiovascular disease. Some studies have also shown that the total cholesterol (TC):HDL-C ratio (TC:HDL-C) is the best predictor of coronary artery disease. In contrast, increased levels of HDL-C are associated with decreased cardiovascular risk. Drug therapies that reduce levels of LDL-C or decrease TG while simultaneously increasing HDL-C have demonstrated reductions in rates of cardiovascular mortality and morbidity.
CRESTOR is administered orally following which rosuvastatin, the active moiety, is rapidly absorbed, reaching peak plasma concentration 3 to 5 hours after dosing.
Both peak concentration (Cmax) and area under the plasma concentration-time curve (AUC) increase in proportion to rosuvastatin dose. The absolute bioavailability of rosuvastatin is approximately 20% and there is no accumulation on repeated dosing. CRESTOR may be given with or without food. Administration in the morning or evening did not affect the rate and extent of absorption nor the ability of rosuvastatin to reduce LDL-C.
Rosuvastatin undergoes first pass extraction in the liver, which is the primary site of cholesterol synthesis and LDL-C clearance. The mean volume of distribution at steady state of rosuvastatin is approximately 134 litres. Rosuvastatin is approximately 90% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.
Rosuvastatin is not extensively metabolized with approximately 90% of a radiolabeled dose recovered as the parent compound. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 2C9, and in in vitro studies has demonstrated to have approximately one-half the HMG-CoA reductase inhibitory activity of rosuvastatin.
Following an oral dose, rosuvastatin and its metabolites are primarily excreted in the feces (90%) with the remainder being excreted in the urine. Fecal recovery represents absorbed drug, metabolites in the bile, and unabsorbed drug. The elimination half-life (t½) of rosuvastatin is approximately 19 hours and does not increase with increasing doses.
A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic and Black or Afro-Caribbean groups. However, pharmacokinetic studies with rosuvastatin, including one conducted in North America, have demonstrated an approximate 2-fold elevation in median exposure (AUC and Cmax) in Asian subjects when compared with a Caucasian control group |
