Preventive Cardiologies
Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin

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Abstract

The long-term safety profile of simvastatin, established over 10 years of clinical use, is excellent. The principal adverse effect of all inhibitors of hydroxymethylglutarate co-enzyme A (HMG-CoA) reductase, myopathy, is infrequent. Simvastatin is a substrate for cytochrome P450 3A4 (CYP3A4). CYP3A4 inhibitors can elevate the plasma concentration of HMG-CoA reductase inhibitory activity derived from simvastatin. Clinical experience has shown that concomitant use of potent inhibitors of CYP3A4 increase the risk for myopathy. Evaluation of data from clinical trials and postmarketing surveillance allows assessment of whether concomitant use of weaker CYP3A4 inhibitors, as represented by calcium channel blockers, has any effect on the risk of myopathy. Cases of myopathy in long-term clinical megatrials and in analyses of postmarketing adverse event reports have been surveyed. In megatrials with simvastatin, the overall incidence of myopathy was 0.025%. The proportion of patients developing myopathy who were taking a calcium channel blocker with simvastatin (1 of 3) was similar to the proportion of patients taking a calcium channel blocker overall. Among marketed-use adverse event reports, concomitant medication with a potent CYP3A4 inhibitor was more frequent among reports of myopathy than among reports of nonmusculoskeletal adverse events. No excess use of calcium channel blockers among myopathy reports was observed. We conclude that the overall risk of myopathy during treatment with simvastatin is very low. Potent CYP3A4 inhibitors, especially cyclosporine, significantly increase the risk. There is no evidence that weaker CYP3A4 inhibitors such as calcium channel blockers increase the risk.

Section snippets

Data from megatrials

Two-year safety data from 2 megatrials are available, the Scandinavian Simvastatin Survival Study (4S)5, 6 and the ongoing Heart Protection Study.7 In these analyses, myopathy is defined as unexplained muscle pain or weakness accompanied by an elevation of creatine kinase to ≥10 times the upper limit of normal. This level of creatine kinase elevation will exclude the vast majority of cases due to exercise or minor trauma.

Postmarketing adverse experience data

If it was hypothesized that concomitant therapy with calcium channel

Scandinavian simvastatin survival study

Four thousand four hundred forty-four patients with angina pectoris or previous myocardial infarction and serum cholesterol of 213 to 310 mg/dl (5.5 to 8.0 mmol/L) on a lipid-lowering diet were randomized to double-blind treatment with simvastatin 20 mg (titrated to 40 mg if required) or placebo for a median follow-up period of 5.4 years.5

A single case of myopathy was reported, after 4 years of therapy, in a woman taking simvastatin 20 mg6(Table II). Concomitant medication included diltiazem,

Discussion

The metabolism of simvastatin is quite complex, as shown in Figure 1 , and some factors relevant to drug interactions may not be generally appreciated. Simvastatin is an inactive lactone converted to the corresponding active acid by esterases and by nonenzymatic hydrolysis.10 Both the parent lactone form and the acid are normally present in very small amounts in plasma due to a high hepatic extraction ratio (approximately 95%).10 Because the liver is the pharmacologic target organ, this has the

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