y with homozygous familial hypercholesterolaemia (see above), the percent reduction in LDL-C (21.0%), Total-C (19.2%) and non-HDL-C (21.0%) from baseline following 6 weeks of treatment with rosuvastatin 20 mg was consistent with that observed in the aforementioned study in children and adolescents with homozygous familial hypercholesterolaemia.
The European Medicines Agency has waived the obligation to submit the results of studies with rosuvastatin in all subsets of the paediatric population in the treatment of homozygous familial hypercholesterolaemia, primary combined (mixed) dyslipidaemia and in the prevention of cardiovascular events (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption: Maximum rosuvastatin plasma concentrations are achieved approximately 5 hours after oral administration. The absolute bioavailability is approximately 20%.
Distribution: 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, mainly to albumin.
Metabolism: 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 N-desmethyl 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 HMG-CoA reductase inhibitor activity.
Excretion: 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.
Linearity: Systemic exposure of rosuvastatin increases in proportion to dose. There are no changes in pharmacokinetic parameters following multiple daily doses.
Special populations:
Age and sex: There was no clinically relevant effect of age or sex on the pharmacokinetics of rosuvastatin in adults. The exposure in children and adolescents with heterozygous familial hypercholesterolemia appears to be similar to or lower than that in adult patients with dyslipidaemia (see “Paediatric population” below).
Race: Pharmacokinetic studies show an approximate 2-fold elevation in median AUC and Cmax in Asian subjects (Japanese, Chinese, Filipino, Vietnamese and Koreans) compared with Caucasians; Asian-Indians show an approximate 1.3-fold elevation in median AUC and Cmax. A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics between Caucasian and Black groups.
Renal insufficiency: In a study in subjects with v |
