Pharmacotherapeutic group: HMG-CoA reductase inhibitors.
Pharmacology: Pharmacodynamics: Mechanism of action: Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. The primary site of action of Rosuvastatin is the liver, the target organ for cholesterol lowering. Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.
Pharmacokinetics: This study was designed as a randomized, single blind, two period, single dose, cross-over study with two weeks washout period in 25 healthy subjects under fasting condition. The study was conducted following an oral administration of one tablet 40 mg of the test drug or one tablet 40 mg of the reference drug.
Based on the pharmacokinetic parameters of Rosuvastatin (N = 25), mean ± SD for Test Drug and Reference Drug showed: Cmax values were 87.20 (46.27) and 96.98 (73.21) ng.mL-1, respectively; AUCt values were 699.40 (308.74) and 794.39 (408.08) h.ng.mL-1, respectively; AUCinf values were 723.29 (333.20) and 811.93 (415.65) h.ng.mL-1, respectively; Tmax values were 2.46 (1.13) and 2.42 (1.29) hours, respectively; T½ values were 13.70 (6.02) and 13.86 (5.00) hours, respectively.
Results from bioequivalence study for Test Drug and Reference Drug were as following: 90.00% Confidence Intervals of geometric means ratio of the two bioavailability parameters of Rosuvastatin were 81.45 - 108.95% for Cmax and 80.10 - 101.51% for AUCt. Intra subject CV (%) of Cmax and AUCt for Rosuvastatin were 29.97 and 24.42%, respectively.
Conclusion: These results showed that 40 mg Rosuvastatin film coated tablet was bioequivalent to the reference product.
Special populations: Age and sex: There was no relevant effect of age or sex on the pharmacokinetics of Rosuvastatin in adults.
Race: Pharmacokinetic studies show an approximate 2-fold elevation in median AUC in Asian subjects compared with Caucasians. A population pharmacokinetic analysis revealed no relevant differences in pharmacokinetics among Caucasian, Hispanic and Black or Afro-Caribbean groups.
Renal insufficiency: In subjects with varying degrees of renal impairment, mild to moderate renal disease had no influence on plasma concentrations of Rosuvastatin. However, subjects with severe impairment (CrCl < 30 mL/minute) had a 3-fold increase in plasma concentration compared to healthy volunteers. Steady-state plasma concentrations of Rosuvastatin in subjects undergoing haemodialysis were approximately 50% greater compared to healthy volunteers.
Hepatic impairment: In a study with subjects with varying degrees of hepatic impairment there was no evidence of increased exposure to Rosuvastatin other than in the 2 subjects with the most severe liver disease (Child-Pugh scores of 8 and 9). In these subjects systemic exposure was increased by at least 2-fold compared to subjects with lower Child-Pugh scores. There is no experience in subjects with Child-Pugh scores above 9.
Genetic polymorphisms: Disposition of HMG-CoA reductase inhibitors, including Rosuvastatin, involves OATP1B1 and BCRP transporter proteins. In patients with SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) genetic polymorphisms there is a risk of increased Rosuvastatin exposure. Individual polymorphisms of SLCO1B1 c.521CC and ABCG2 c.421AA are associated with an approximate 1.7-fold higher Rosuvastatin exposure (AUC) or 2.4-fold higher exposure, respectively, compared to the SLCO1B1 c.521TT or ABCG2 c.421CC genotypes. This specific genotyping is not established in clinical practice, but for patients who are known to have these types of polymorphisms, a lower daily dose of Rosuvastatin is recommended.