Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Unicorn Pharmaceuticals (Pty) Ltd, Corner Searle & Pontac Streets, Cape Town, 8000 enquires@unicornpharma.co.za
Pharmacological Class: A 7.5 Serum-cholesterol reducers
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that is responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Statins exert their major effect by a reduction of low-density lipoprotein (LDL) levels. LDL is formed from VLDL and is catabolised primarily through the receptor with high affinity to LDL (LDL receptor).
Atorvastatin reduces the levels of plasma cholesterol and lipoprotein by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of LDL-C receptors on the cell surface of liver cells, thereby providing for enhanced uptake and catabolism of LDL-C.
Atorvastatin produces an increase in LDL receptor activity together with a change in the quality of circulating LDL particles. The greater number of LDL receptors on the surface of hepatocytes results in increased removal of LDL from the blood, thereby lowering LDL-C levels. Atorvastatin lowers total cholesterol (total-C), LDL-C, apolipoprotein B levels in normal volunteers, and in patients with heterozygous familial hypercholesterolaemia, non-familial hypercholesterolaemia, mixed dyslipidaemia, and in some patients with homozygous familial hypercholesterolaemia. It also reduces serum triglycerides (TG) and produces variable increases in high-density lipoprotein cholesterol (HDL-C) and apolipoprotein-A-1 in non-familial hypercholesterolaemia including mixed dyslipidaemias.
Atorvastatin is well absorbed following oral administration where maximum plasma concentrations (Cmax) occur within 1 to 2 hours. The 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 due to the presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of absorption by approximately 25% and 9% respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening administration compared to morning administration. However, there is no change in LDL-C reduction regardless of the time of administration (See 4.2).
Mean volume of distribution of atorvastatin is approximately 381 litres. Atorvastatin is 98% or more bound to plasma proteins.
Atorvastatin is extensively metabolised by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro, inhibition of HMGCoA 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.
Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism; however, it does not appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin (parent substance) in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is approximately 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is excreted in urine following oral administration.
Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (65 years and older) than in young adults. LDL-C reduction is comparable to that seen in younger patient populations given equal doses of atorvastatin.
Plasma concentrations of atorvastatin in women differ (approximately 20% higher for Cmax and 10% lower for AUC) from those in men; however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.
Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin. Thus dose adjustment in patients with renal dysfunction is not necessary (See 4.2).
While studies have not been conducted in patients with end-stage renal disease, haemodialysis is not expected to markedly increase the clearance of atorvastatin since it is extensively bound to plasma proteins.
Plasma concentrations of atorvastatin are significantly enhanced (approximately 16-fold in Cmax and 11-fold in AUC) in patients with chronic alcoholic liver disease (Child-Pugh B) (See 4.3).
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