Source: Health Products Regulatory Authority (ZA) Revision Year: 2023 Publisher: AstraZeneca Pharmaceuticals (Pty) Ltd, Building 2, Northdowns Office Park, 17 Georgian Crescent West, Bryanston, Johannesburg, 2191, South Africa
Pharmacotherapeutic group: HMG-CoA reductase inhibitors
ATC code: C10AA07
Rosuvastatin is a lipid lowering agent that acts by selective and competitive inhibition of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, leading to reduced hepatic synthesis of cholesterol and VLDL.
This is followed by increased number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL.
Overall, rosuvastatin reduces elevated LDL cholesterol, total cholesterol and triglycerides and increases HDL-cholesterol. It also lowers ApoB, non-HDL-C, VLDL-C, VLDL-TG and increases ApoA-I.
ZUVAMOR also lowers LDL-C/HDL-C, total C/HDL-C, non-HDL-C/HDL and ApoB/ApoA-I ratio’s.
A therapeutic response to ZUVAMOR is evident within 1 week of commencing therapy and 90% of maximum response is usually achieved in 2 weeks. The maximum response is usually achieved by 4 weeks and is maintained after that.
Maximum rosuvastatin plasma concentrations are achieved approximately 5 hours after oral administration.
The absolute bioavailability is approximately 20%.
Rosuvastatin is taken up extensively by the liver which is the primary site of cholesterol synthesis and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, mostly albumin.
Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a poor substrate for cytochrome P450-based metabolism. CYP2C9 was the principal isoenzyme involved, with 2C19, 3A4 and 2D6 involved to a lesser extent. The main metabolites identified are the N-desmethyl and lactone metabolites. The Ndesmethyl metabolite is approximately 50% less active than rosuvastatin whereas the lactone form is considered clinically inactive. Rosuvastatin accounts for greater than 90% of the circulating HMGCoA reductase inhibitor activity.
Approximately 90% of the rosuvastatin dose is excreted unchanged in the faeces (consisting of absorbed and non-absorbed active substance) and the remaining part is excreted in urine.
Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours. The elimination half-life does not increase at higher doses. The geometric mean plasma clearance is approximately 50 litres/hour (coefficient of variation 21,7%). As with other HMG-CoA reductase inhibitors, the hepatic uptake of rosuvastatin involves the membrane transporter OATP-C. This transporter is important in the hepatic elimination of rosuvastatin.
Systemic exposure of rosuvastatin increases in proportion to dose. There are no changes in pharmacokinetic parameters following multiple daily doses.
There was no clinically relevant effect of age or sex on the pharmacokinetics of rosuvastatin in adults.
The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolaemia was similar to or lower than that of adult patients with dyslipidaemia (see “Paediatric population” below).
Pharmacokinetic studies show a 1,26-2,31 fold elevation in geometric mean AUC in Asian subjects compared with Caucasians.
In a study in subjects with varying degrees of renal impairment, mild to moderate renal disease had little influence on plasma concentrations of rosuvastatin. However, subjects with severe impairment (CrCl <30 ml/min) had a 3-fold increase in plasma concentration and a 9-fold increase in the Ndesmethyl metabolite concentration compared to healthy volunteers. Steady-state plasma concentrations of rosuvastatin in subjects undergoing haemodialysis were approximately 50% greater compared to healthy volunteers.
Two pharmacokinetic studies with rosuvastatin (given as tablets) in paediatric patients with heterozygous familial hypercholesterolaemia 10 to 17 or 6 to 17 years of age (total of 214 patients) demonstrated that exposure in paediatric patients appears comparable to or lower than that in adult patients. Rosuvastatin exposure was predictable with respect to dose and time over a 2-year period.
In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study, there was a statistically significant increase in the frequency of diabetes mellitus reported by investigators; 2,8% of patients in the rosuvastatin group and 2,3% of patients in the placebo group (HR: 1,27, 95% CI: 1,05-1,53, p=0.015).
In the JUPITER study, the difference between treatment groups (rosuvastatin versus placebo) in mean HbA1c from baseline was approximately 0,1%.
A post hoc analysis of this study suggests that the risk of development of diabetes on rosuvastatin therapy is limited to patients already at high risk of developing diabetes. The cardiovascular and mortality benefits of rosuvastatin therapy exceeded the diabetes hazard in the trial population as a whole as well as in participants at increased risk of developing diabetes (see section 4.4 and section 4.8).
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