Rosuvastatin - How It Works
Clinical pharmacology details from the US FDA-approved label: how Rosuvastatin works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Rosuvastatin calcium is an inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Rosuvastatin calcium is an inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol.
12.2 Pharmacodynamics Inhibition of HMG-CoA reductase by rosuvastatin accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol.
Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins.
The maximum LDL-C reduction of rosuvastatin calcium is usually achieved by 4 weeks and is maintained after that.
12.3 Pharmacokinetics Absorption In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing.
Both C max and AUC increased in approximate proportion to rosuvastatin calcium dose.
The absolute bioavailability of rosuvastatin is approximately 20%.
The AUC of rosuvastatin does not differ following evening or morning drug administration.
Effect of food Administration of rosuvastatin calcium with food did not affect the AUC of rosuvastatin.
Distribution Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters.
Rosuvastatin is 88% bound to plasma proteins, mostly albumin.
This binding is reversible and independent of plasma concentrations.
Elimination Metabolism Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite.
The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 \ 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of the parent compound.
Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound.
Excretion Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%).
After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.
The elimination half-life of rosuvastatin is approximately 19 hours.
Specific Populations Geriatric Patients There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years).
Pediatric Patients In a population pharmacokinetic analysis of two pediatric trials involving patients with HeFH 10 to 17 years of age and 8 to 17 years of age, respectively, rosuvastatin exposure appeared comparable to or lower than rosuvastatin exposure in adult patients.
Pharmacokinetics
12.3 Pharmacokinetics Absorption In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both C max and AUC increased in approximate proportion to rosuvastatin calcium dose. The absolute bioavailability of rosuvastatin is approximately 20%. The AUC of rosuvastatin does not differ following evening or morning drug administration. Effect of food Administration of rosuvastatin calcium with food did not affect the AUC of rosuvastatin. Distribution Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations. Elimination Metabolism Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 \ 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound. Excretion Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72