Pravastatin

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Abstract
Pravastatin is an HMG-CoA reductase inhibitor which reduces plasma cholesterol levels by inhibiting de novo cholesterol synthesis and increasing the receptor-mediated catabolism of low density lipoprotein (LDL). Several large multicentre placebo-controlled trials have shown that pravastatin reduces total and LDL-cholesterol levels in a dose-proportional manner in patients with familial or nonfamilial hypercholesterolaemia. Reductions in LDL-cholesterol levels reported in the largest study were 18% (10 mg/day), 23% (20 mg/day) and 31% (40 mg/day) after 12 weeks. Once-daily administration appears to be as effective as two daily doses. Pravastatin consistently increases HDL-cholesterol levels and decreases levels of total triglycerides but these changes are not dose dependent. At the study dosages used, the antihypercholesterolaemic effects of pravastatin were superior to those of bezafibrate and clinofibrate, and were similar to those of simvastatin, lovastatin, gemfibrozil and cholestyramine although in some studies a trend towards a superior effect with pravastatin was seen. Pravastatin did not reduce HDL-cholesterol like probucol, or increase triglyceride levels like cholestyramine. Combined treatment with pravastatin and cholestyramine or colestipol enhances the cholesterol-lowering effects of either drug administered alone and offsets the increase in total triglyceride levels seen with cholestyramine or colestipol therapy. Pravastatin is well tolerated during treatment of up to 24 months but longer term tolerability has not yet been established. The effect of pravastatin on cardiovascular events related to elevated plasma cholesterol levels is under investigation in several large scale regression and primary and secondary prevention trials. However, on the basis of available evidence it is reasonable to conclude that pravastatin, like other HMG-CoA reductase inhibitors, offers a novel approach to the management of hypercholesterolaemia. Pravastatin inhibits the rate-limiting step in cholesterol synthesis catalysed by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. The drug markedly reduces hepatic cholesterol synthesis in vitro, and in vivo, and when measured indirectly (as evidenced by a 63% decrease in serum levels of free lathosterol, a precursor of cholesterol) in patients with gallbladder disease. Pravastatin appears to have less effect on cholesterol synthesis in nonhepatocytes than lovastatin or simvastatin. Inhibition of hepatic cholesterol synthesis by pravastatin reduces intracellular cholesterol levels which, in turn, stimulates the synthesis and activity of LDL receptors and thus receptor-mediated clearance of LDL from the systemic circulation. Because of its effects on LDL-receptor-mediated lipoprotein catabolism pravastatin, like other drugs in its class, would be expected to be of less benefit in patients with homozygous familial hypercholesterolaemia who have few, if any, functional LDL receptors. Hypercholesterolaemic patients treated with pravastatin show a decrease in apolipoprotein B (the major protein constituent in LDL) of 12 to 30%. The major proteins in HDL (apo AI and apo All) increase by 12 to 16% with pravastatin therapy, while apo CII, apo CIII and apo E (present mainly in triglyceride-rich VLDL and chylomicrons) decrease by 8, 4 and 8%, respectively. Pravastatin appears to have no effect on adrenocortical function, gallstone formation or cataract development. Other studies have demonstrated that pravastatin suppresses atherosclerotic lesions in WHHL rabbits and reduces tendon xanthomas in patients with familial hypercholesterolaemia. After 4 weeks of twice daily 5, 10 and 20mg doses peak plasma pravastatin concentrations and area under the plasma concentration-time curve values increased dose proportionally in patients with primary hypercholesterolaemia. The major metabolite is about 2.5 to 10% as potent as its parent drug with regard to inhibiting HMG-CoA reductase. Pravastatin has a low (17%) systemic availability after an oral dose and does not appear to accumulate with repeated administration. Tissue distribution studies have demonstrated that pravastatin is selectively distributed to hepatic cells, which is consistent with the drug’s selective inhibition of cholesterol synthesis in the liver. Pravastatin is excreted rapidly, with 71 and 20% of a single oral dose recovered in faeces and urine, respectively, within 96 hours. Biliary excretion appears to be marked since after intravenous administration 34% of the drug is recoverable in faeces. The terminal plasma elimination half-life of pravastatin in healthy volunteers and hypercholesterolaemic patients has ranged from 1.3 to 2.6 hours. The efficacy of pravastatin has been well established in large placebo-controlled multicentre studies in which patients were treated for up to 3 months. The largest study reported decreases in LDL-cholesterol levels of 18, 23 and 31% after 12 weeks of twice-daily 5, 10 and 20mg doses, respectively. Dose-proportional reductions in LDL-cholesterol levels have also been observed but the increases in HDL-cholesterol levels and decreases in total triglyceride levels were not related to pravastatin dosage. A once-daily pravastatin 40mg dose appears to be as effective as a 20mg dose given twice daily. Pravastatin reduces LDL-cholesterol levels after 1 week, and this becomes maximal after 4 weeks. Numerous studies have compared the effects of pravastatin with those of other hypolipidaemic drugs. When administered as a 20mg twice-daily dose over 1.75 to 6 months, pravastatin reduces total and LDL-cholesterol levels to a similar degree as lovastatin 20mg twice daily or the bile acid sequestrant cholestyramine 8 to 24 g/day. At a lower dosage (10 mg/day) pravastatin has comparable cholesterol-lowering effects as simvastatin 10 mg/day. Pravastatin 40 mg/day has a greater effect on total and LDL-cholesterol levels than gemfibrozil 1200 mg/day in patients with familial hypercholesterolaemia. Gemfibrozil is, however, more effective with regard to increasing HDL-cholesterol levels and reducing total triglyceride levels. Statistically significant differences in favour of pravastatin were seen over bezafibrate 400 mg/day with regard to total and LDL-cholesterol levels, but bezafibrate produces a greater reduction in serum triglyceride levels. Clinical trials in Japanese patients have used a lower (10 mg/day) pravastatin dosage. In these investigations, pravastatin was superior to clinofibrate 600 mg/day with regard to lowering total and LDL-cholesterol levels, appeared to have a similar effect to simvastatin 5 mg/day, and had a superior effect on LDL-cholesterol levels compared with probucol 500 mg/day. Combined treatment with pravastatin and a bile acid sequestrant (cholestyramine or colestipol) reduces plasma levels of total cholesterol and LDL-cholesterol below those achieved when either drug was administered as monotherapy. When pravastatin and probucol are administered concomitantly the effect on total- and LDL-cholesterol levels is not consistent; this combination appears to reduce HDL-cholesterol levels more than pravastatin monotherapy. In patients with hypercholesterolaemia secondary to diabetes, pravastatin 10 or 20 mg/day reduced total and LDL-cholesterol by 19 and 17%, respectively; HDL-cholesterol increased by 8% and total triglycerides decreased by 27%. This effect was maintained during 12 months of treatment. Pravastatin is well tolerated in short and longer (24 months) term clinical trials, with no differences in overall rates of adverse effects between pravastatin and placebo recipients in an analysis of 1142 patients. Skin rash has been reported more frequently during pravastatin therapy than placebo administration but was only attributed to drug treatment in 1.3% of patients. During an average of 18 months of therapy in 1142 patients, gastrointestinal symptoms were the most common cause of treatment withdrawal (1.4%). Mild and transient abnormal laboratory results have been observed during pravastatin treatment of 6 to 16 weeks duration. These increases were mild and transient. Lens opacities have not been associated with pravastatin treatment. Myopathy (myalgia and markedly elevated creatine phosphokinase levels) has been associated with HMG-CoA reductase inhibitors, particularly when administered with immunosuppressant therapy or fibric acid derivatives. No data regarding combined therapy with pravastatin and these agents are available. The longer term (>2 years) adverse effect profile of pravastatin remains to be established. The initial recommended adult oral dosage is 10 or 20mg once daily at bedtime. Depending on patient response, the daily dosage may be increased to 40mg. Indeed, if total plasma cholesterol is >7.8 mmol/L (300 mg/dl) the dosage may be started at 40 mg/day. In Japanese studies a dose of 5mg twice daily, increased to 10mg twice daily if necessary, has been effective. No dosage adjustment appears necessary in elderly hypercholesterolaemic patients. The drug is contraindicated in patients with active hepatic disease or unexplained increases in transaminase levels.
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