Atorvastatin

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Abstract
Atorvastatin is a synthetic HMG-CoA reductase inhibitor which lowers plasma cholesterol levels by inhibiting endogenous cholesterol synthesis. It also reduces triglyceride levels through an as yet unproven mechanism. Dose-dependent reductions in total cholesterol, low density lipoprotein (LDL)-cholesterol and triglyceride levels have been observed with atorvastatin in patients with hypercholesterolaemia and in patients with hypertriglyceridaemia. In large trials involving patients with hypercholesterolaemia, atorvastatin produced greater reductions in total cholesterol, LDL-cholesterol, apolipoprotein B and triglyceride levels than lovastatin, pravastatin and simvastatin. In patients with primary hypercholesterolaemia, the combination of atorvastatin and colestipol tended to produce larger reductions in LDL-cholesterol levels and smaller reductions in triglyceride levels than atorvastatin monotherapy. Although atorvastatin induced smaller reductions in triglyceride levels and more modest increases in high density lipoprotein (HDL)-cholesterol levels than either fenofIbrate or nicotinic acid in patients with combined hyperlipidaemia, it produced larger reductions in total cholesterol and LDL-cholesterol. As with other HMG-CoA reductase inhibitors, the most frequently reported adverse events associated with atorvastatin are gastrointestinal effects. In comparative trials, atorvastatin had a similar adverse event profile to that of other HMG-CoA reductase inhibitors. Clinical data with atorvastatin are limited at present. However, with its ability to markedly reduce LDL-cholesterol levels, atorvastatin is likely to join other members of its class as a first-line agent for the treatment of patients with hypercholesterolaemia, if changes in lipid levels with atorvastatin convert to reductions in CHD mortality and morbidity. Atorvastatin may be particularly suitable for patients with heterozygous or homozygous familial hypercholesterolaemia because of the marked reductions in LDL-cholesterol experienced with the drug. Additionally, because of its triglyceride-lowering properties, atorvastatin appears to have the potential to become an appropriate treatment for patients with combined hyperlipidaemia or hypertriglyceridaemia. Like other members of its class, atorvastatin inhibits HMG-CoA reductase and impedes the formation of mevalonic acid, which is a rate-limiting step in the biosynthesis of cholesterol. The resulting effect is a reduction in intracellular cholesterol leading to an increase in the number of low density lipoprotein (LDL)-receptors and increase in LDL-cholesterol clearance from plasma. HMG-CoA reductase inhibitors may also lower plasma cholesterol levels by decreasing hepatic production of very low density lipoprotein (VLDL)- and LDL-cholesterol. Atorvastatin inhibited cholesterol synthesis by 50% in human liver-derived cell line (Hep-G2) at a concentration of 73 nmol/L. Atorvastatin 80 mg/day reduced fasting plasma mevalonic acid levels by 59% in patients with heterozygous familial hypercholesterolaemia. Patients with hypertriglyceridaemia receiving atorvastatin either 20 or 80 mg/day for 4 weeks experienced significant reductions in plasma levels of total cholesterol, triglycerides and apolipoproteins B, C-II, C-III and E. Two indirect mechanisms have been suggested to explain the reduction in triglycéride levels with atorvastatin. Firstly, marked inhibition of cholesterol synthesis would impair the assembly and secretion of VLDL particles, of which cholesterol is an essential component, therefore causing reductions in triglyceride levels. Secondly, reductions in hepatocyte cholesterol levels caused by substantial inhibition of cholesterol synthesis would lead to increases in LDL-receptor expression and hence increased binding of VLDL particles and LDL, resulting in the reduction of both cholesterol and triglyceride levels. There is some evidence that atorvastatin, like other drugs of its class, may have antiatherogenic effects. The drug inhibits smooth muscle cell proliferation and/or migration. Compared with untreated controls, atorvastatin 2.5 mg/kg significantly reduced rabbit atherosclerotic lesion size by 67%. Furthermore, in patients with hyperlipidaemia, atorvastatin 80 mg/day reduced plasma viscosity by 10%, factor VII activity by 8%, red blood cell sedimentation rate by 33% and arachidonic acid-induced whole blood aggregation by 11%. Multiple daily doses of atorvastatin 2.5 to 80mg produced steady-state maximum plasma concentrations (Cmax) of 1.95 to 252 µg/L within 2 to 4 hours after administration and area under the plasma concentration-time curve (AUC) values of 25.2 to 1293 |Ug/L · h. The drug has an absolute bioavailability of 12%. Atorvastatin is ≥98% protein-bound in plasma and has a mean elimination half-life of about 14 hours, but as a result of active metabolites the half-life of HMG-CoA reductase inhibition is 20 to 30 hours. Less than 2% of the parent drug and metabolites are excreted renally. Atorvastatin Cmax and AUC values may be prolonged in patients with hepatic impairment. Renal impairment had no effect on atorvastatin pharmacokinetic parameters. Although some accumulation was evident in the elderly, this did not produce clinically significant changes in lipid reduction. Currently, results of studies investigating the potential benefits of atorvastatin on mortality and morbidity in patients with or without coronary heart disease are not available. Therefore, clinical evaluation of atorvastatin at this time is based on lipid-lowering effects, a surrogate marker of clinical efficacy. In placebo-controlled dose-response studies in patients with primary hyper-cholesterolaemia, atorvastatin 10 to 80 mg/day produced 35 to 61% reductions in LDL-cholesterol levels. 90% of the maximum observed reduction in LDL-cholesterol levels was attained after 2 weeks of treatment. In patients with hypertriglyceridaemia, atorvastatin 5,20 or 80 mg/day reduced triglyceride levels by 26 to 46%, LDL-cholesterol levels by 17 to 41% and total cholesterol levels by 20 to 43%. In large double-blind trials of 1 year’s duration involving patients with hypercholesterolaemia, reductions in total cholesterol, LDL-cholesterol, apolipoprotein B and triglyceride levels were significantly greater with atorvastatin 10 to 20 mg/day than with lovastatin 20 to 40 mg/day, pravastatin 20 to 40 mg/day or simvastatin 10 to 20 mg/day. Atorvastatin, lovastatin, pravastatin and simvastatin all raised HDL-cholesterol levels by 7 to 10%. A greater number of patients tended to reach US National Cholesterol Education Program (NCEP) LDL-cholesterol goals with atorvastatin than with lovastatin, pravastatin or simvastatin. As a result, fewer patients receiving atorvastatin than these other agents tended to require upward dosage titration after 16 weeks of treatment. In one study, the combination of atorvastatin 10 mg/day and colestipol 20 g/day tended to produce larger reductions in LDL-cholesterol levels and smaller reductions in triglyceride levels than atorvastatin 10 mg/day monotherapy, in patients with primary hypercholesterolaemia. In patients with combined hyperlipidaemia (elevated LDL-cholesterol and triglyceride levels), atorvastatin 10 mg/day produced larger reductions in total cholesterol and LDL-cholesterol than fenofibrate 100mg 3 times daily or nicotinic acid (niacin) 100 to 1000mg 3 times daily. However, smaller reductions in triglyceride levels and more modest increases in high density lipoprotein (HDL)-cholesterol levels were achieved with atorvastatin than with both fenofibrate and nicotinic acid. Atorvastatin 10 to 20 mg/day caused a greater reduction in triglyceride levels than simvastatin 10 to 20 mg/day in patients with raised cholesterol and triglyceride levels secondary to non-insulin-dependent diabetes mellitus (NIDDM). Atorvastatin has been generally well tolerated in clinical studies of up to 52 weeks’ duration. Like other HMG-CoA reductase inhibitors, gastrointestinal effects (including flatulence, dyspepsia, constipation and abdominal pain) are the most frequently reported adverse events associated with atorvastatin. In total, 10 times the normal limit) are the most serious tolerability concerns associated with HMG-CoA reductase inhibitors. To date, myopathy has not yet been reported with atorvastatin, although the drug has not been used as extensively as other HMG-CoA reductase inhibitors. 3% of the atorvastatin group (n=132) in one study reported myalgia, but no patients had persistent increases in creatine phosphokinase levels >10 times the normal limit. Elevated serum transaminase levels were reported in 0.2, 0.6,0.6 and 2.3% of patients receiving atorvastatin 10, 20,40 and 80 mg/day, respectively. In patients receiving atorvastatin in clinical trials, the total incidence of persistent elevations in serum transaminases was 0.7%. After 52 weeks of treatment in a large study, the incidence of abnormal transaminase levels was similar with atorvastatin and lovastatin. Pancreatitis was reported in 1 of 1135 patients receiving atorvastatin in 3 trials. Atorvastatin 10 to 80 mg/day may be used to reduce the raised lipid levels in patients with primary hypercholesterolaemia (heterozygous familial, homozygous familial or nonfamilial) or combined dyslipidaemia The dosage of atorvastatin should be adjusted according to response. Atorvastatin may be taken at any time of day with or without food. In patients with hepatic insufficiency dosage reductions may be required. The drug is contraindicated in patients with active hepatic disease or unexplained persistent elevations in serum transaminases. Concomitant use of atorvastatin with cyclosporin, nicotinic acid, fibric acid derivatives, erythromycin or azole antifungals is likely to increase the risk of adverse events (e.g. myopathy or rhabdomyolysis), and these combinations should be avoided where possible.