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Pharmacology: Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to Mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low-density lipoproteins (VLDL) and released into the plasma for delivery to peripheral tissues. Low-density lipoprotein (LDL) is formed from VLDL and is catabolized primarily through the receptor with high affinity to LDL (LDL receptor).
Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL.
Atorvastatin has been shown to reduce concentrations of total-C (30%-46%), LDL-C (41%-61%), apolipoprotein B (34%-50%), and triglycerides (14%-33%) while producing variable increases in HDL-C and apolipoprotein A1 in a dose response study. These results are consistent in patients with heterozygous familial hypercholesterolemia, nonfamilial forms of hypercholesterolemia, and mixed hyperlipidemia, including patients with noninsulin-dependent diabetes mellitus. Reductions in total-C, LDL-C, and apolipoprotein B have been proven to reduce risk for cardiovascular events and cardiovascular mortality.
Pharmacokinetics: Absorption: Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations (Cmax) occur within 1 to 2 hours. Extent of absorption increases in proportion to Atorvastatin dose. After oral administration, Atorvastatin film coated tablets are 95% to 99% bioavailable compared to the oral solution. The absolute bioavailability of Atorvastatin is approximately 12% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism.
Distribution: Mean volume of distribution of Atorvastatin is approximately 381 L. Atorvastatin is ≥98% bound to plasma proteins.
Biotransformation: Atorvastatin is metabolized by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation products. Apart from other pathways these products are further metabolized via glucuronidation. In vitro, inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of Atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.
Elimination: Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism. However, Atorvastatin does not appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-life of Atorvastatin in humans is approximately 14 hours. The half-life of inhibitory activity for HMG-CoA reductase is approximately 20 to 30 hours due to the contribution of active metabolites. Atorvastatin is a substrate of the hepatic transporters, organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) transporter. Metabolites of Atorvastatin are substrate of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporters multi-drug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit the intestinal absorption and biliary clearance of Atorvastatin.
Special populations: Elderly: Plasma concentrations of Atorvastatin and its active metabolites are higher in healthy elderly subjects than in young adults while the lipid effects were comparable to those seen in younger patient populations.
Pediatric population: In an open-label, 8-week study, Tanner Stage 1 (N=15) and Tanner Stage ≥2 (N=24) pediatric patients (ages 6-17 years) with heterozygous familial hypercholesterolemia and baseline LDL-C ≥4 mmol/L were treated with 5 or 10 mg of chewable or 10 or 20 mg of film-coated Atorvastatin Tablets once daily, respectively. Body weight was the only significant covariate in Atorvastatin population PK model. Apparent oral clearance of Atorvastatin in pediatric subjects appeared similar to adults when scaled allometrically by body weight. Consistent decreases in LDL-C and TC were observed over the range of Atorvastatin and o-hydroxyatorvastatin exposures.
Gender: Concentrations of Atorvastatin and its active metabolites in women differ from those in men (Women: approx. 20% higher for Cmax and approx. 10% lower for AUC). These differences were of no clinical significance, resulting in no clinically significant differences in lipid effects among men and women.
Renal impairment: Renal disease has no influence on the plasma concentrations or lipid effects of Atorvastatin and its active metabolites.
Hepatic impairment: Plasma concentrations of Atorvastatin and its active metabolites are markedly increased (approx. 16-fold in Cmax and approx. 11-fold in AUC) in patients with chronic alcoholic liver disease (Child-Pugh B).
SLOC1B1 polymorphism: Hepatic uptake of all HMG-CoA reductase inhibitors including Atorvastatin, involves the OATP1B1 transporter. In patients with SLCO1B1 polymorphism there is a risk of increased exposure of Atorvastatin, which may lead to an increased risk of rhabdomyolysis. Polymorphism in the gene encoding OATP1B1 (SLCO1B1 c.521CC) is associated with a 2.4-fold higher Atorvastatin exposure (AUC) than in individuals without this genotype variant (c.521TT). A genetically impaired hepatic uptake of Atorvastatin is also possible in these patients. Possible consequences for the efficacy are unknown.
