CLINICAL PHARMACOKINETICS AND PRACTICAL APPLICATIONS OF SIMVASTATIN

Abstract

The objective of this article is to review the clinical pharmacokinetics of simvastatin and outline practical applications in patient management. Information was obtained from a systematic search of published literature using PubMed and the Cochrane Library. Additional references were obtained from review articles and textbooks. Simvastatin acid is the active form of the prodrug simvastatin and is a specific, competitive inhibitor of 3-hydroxy-3-methylglutaryl co-enzyme A reductase. Its primary site of action is the liver. Simvastatin is a substrate for the cytochrome P450 enzyme CYP3A4, and inhibitors or inducers of this enzyme system can cause respectively increased or decreased plasma concentrations of simvastatin. Plasma concentrations of simvastatin acid correlate poorly with LDL cholesterol reductions, although higher doses of simvastatin do lead to greater reductions in LDL cholesterol. Patients with homozygous familial hypercholesterolaemia exhibit much greater reductions in LDL cholesterol compared with other patient groups. Simvastatin has a low volume of distribution and is highly bound to plasma proteins. Information on simvastatin in elderly patients and those with renal or hepatic impairment is lacking, but dose reductions are recommended for patients with severe renal impairment. Studies have shown a significant drug interaction between simvastatin and ciclosporin, and caution is recommended when considering concurrent use. Simvastatin is teratogenic and contraindicated during pregnancy. High-intensity cholesterol-lowering therapy using statins such as simvastatin is now recommended in the primary and secondary prevention of atherosclerotic vascular disease. Adherence to the traditional LDL cholesterol target is no longer advised, and rather patients are now to be assessed using a cardiovascular risk calculator. Under the guidance of the risk calculator, patients may benefit from higher doses of simvastatin or other high-intensity statin therapy. Adverse effects from simvastatin do occur, some of which are caused by drug interactions, and monitoring of these patients is important. An application of simulated annealing has also been discussed in this article, outlining a method for optimizing doses of simvastatin in individual patients. This is followed by a mathematical model based on recent clinical trial evidence, suggesting the possibility of a fixed-dose combination therapy of ezetimibe and simvastatin. Overall, this article provides an understanding of the pharmacokinetics and role of simvastatin in current clinical practice, as well as potential future implications.(Foll et al., 2014)