Otagil 10/Otagil 20 Mechanism of Action

MIMS Classification(s): HMG-CoA Reductase Inhibitor.
Pharmacology: Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methyglutaryl coenzyme A to Mevalonate, a precursor for cholesterol. Triglycerides (TG) and cholesterol in the liver are incorporated, with apolipoprotein B (ApoB), into very low density lipoprotein (VLDL) and released into the plasma for delivery to peripheral tissues. VLDL particles are TG-rich. Cholesterol-rich low density lipoprotein (LDL) is formed from VLDL and is cleared primarily through the high affinity LDL receptor in the liver.
Rosuvastatin produces its lipid-modifying effects in two ways: it 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 with total number of VLDL and LDL particles.
High density lipoprotein (HDL), which contains ApoA-I is involved, amongst other things, in transport of cholesterol from tissues back to the liver (reverse cholesterol transport). The involvement of LDL-C in atherogenesis has been well documented. Epidemiological studies have established that high LDL-C, TG, low HDL-C and ApoA-1 have been linked to a higher risk of cardiovascular disease. Intervention studies have shown the benefits on mortality and CV event rates of lowering LDL-C and TG or raising HDL-C. More recent data has linked the beneficial effects of HMG-CoA reductase inhibitors to lowering of non-HDL (i.e. all circulating cholesterol not in HDL) and ApoB or reducing the ApoB/ApoA-I ratio.
Pharmacokinetics: Absorption: In man, peak plasma concentration of Rosuvastatin was reached 3 to 5 hours following oral dosing. Both peak concentration (C_max) and area under the plasma concentration-time curve (AUC) increased in approximate proportion to Rosuvastatin dose. The absolute bioavailability of Rosuvastatin is approximately 20%. Administration of Rosuvastatin with food decreased the rate of drug absorption by 20% as assessed by C_max, but there was no effect on the extent of absorption as assessed by AUC.
Plasma concentrations of Rosuvastatin do not differ following evening or morning drug administration. Significant LDL-C reductions are seen when Rosuvastatin is given with or without food, and regardless of the time of day of drug administration.
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.
Metabolism: Rosuvastatin is not extensively metabolized; approximately 10% of a radio-labelled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 2C9, and in vitro demonstrated that N-desmethyl Rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of Rosuvastatin. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by Rosuvastatin.
Excretion: Following oral administration, Rosuvastatin and its metabolite are primarily excreted in the feces (90%). The elimination half-life (t½) of Rosuvastatin is approximately 19 hours.
After an intravenous dose, approximately 28% of total body clearance was via the renal route and 72% by the hepatic route.
Special populations: Age and sex: There was no clinically relevant effect of age or sex on the pharmacokinetics of Rosuvastatin in adults.
Pediatric use: The safety and effectiveness of Rosuvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia were evaluated. Patients treated with 10 mg and 20 mg daily Rosuvastatin had an adverse experience profile generally similar to that of patients treated with placebo. Although not at all adverse reactions identified in the adult population have been observed in children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents. There was no detectable effect of Rosuvastatin on growth, weight, BMI (body mass index), or sexual maturation in pediatric patients (10 to 17 years of age). Adolescent females should be counseled on appropriate contraceptive methods while on Rosuvastatin therapy.
Pediatric patients (10 to 17 years of age) with heterozygous FH received single and multiple oral doses of Rosuvastatin. Both C_max and AUC of Rosuvastatin were similar to values observed in adult subjects administered the same doses.
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 1.6 fold higher Rosuvastatin exposure (AUC) compared to the SLCO1B1 c.521TT or ABCG c.421CC genotypes. This specific genotyping is not established, but for patients who are known to have these types of polymorphisms, a lower daily dose of Rosuvastatin is recommended.
Race: An approximate 2-fold elevation in median AUC and C_max in Asian subjects compared with Caucasians. A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics between Caucasian, Hispanic and Black or Afro-Caribbean groups.
Patients with renal impairment: Mild to moderate renal impairment (CL_CR ≥30 mL/min/1.73 m²) had no influence on plasma concentrations of Rosuvastatin. However, plasma concentrations of Rosuvastatin increased to a clinically significant extent (about 3-fold) in patients with severe renal impairment (CL_CR 30 mL/min/1.73 m²) not receiving hemodialysis compared with healthy subjects (CL_CR >80 mL/min/1.73 m²).