Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome
 P450 inhibitors

doi:10.1016/j.amjcard.2004.07.080

The American Journal of Cardiology

Volume 94, Issue 9, 1 November 2004, Pages 1140-1146

https://doi.org/10.1016/j.amjcard.2004.07.080 Get rights and content

Three-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) are first-line treatments for hypercholesterolemia. Although exceedingly well tolerated, treatment with statins incurs a small risk of myopathy or potentially fatal rhabdomyolysis, particularly when coadministered with medications that increase their systemic exposure. Studies compared the multiple-dose pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with 4 inhibitors of cytochrome P450-3A4 isoenzymes in healthy subjects. Compared with pravastatin alone, coadministration of verapamil, mibefradil, or itraconazole with pravastatin was associated with no significant changes in pravastatin pharmacokinetics. However, concomitant verapamil increased the simvastatin area under the concentration:time curve (AUC) approximately fourfold, the maximum serum concentration (C_max) fivefold, and the active metabolite simvastatin acid AUC and C_max approximately four- and threefold, respectively (all comparisons p <0.001). Similar (greater than fourfold) important increases in these parameters and a >60% increase in the serum half-life (p = 0.03) of atorvastatin were observed when coadministered with mibefradil. The half-life of atorvastatin also increased by ≈60% (p = 0.052) when coadministered with itraconazole, which elicited a 2.4-fold increase in the C_max of atorvastatin and a 47% increase in the AUC (p <0.001 for C_max and AUC). Clarithromycin significantly (p <0.001) increased the AUC (and C_max) of all 3 statins, most markedly simvastatin (∼10-fold increase in AUC) and simvastatin acid (12-fold), followed by atorvastatin (greater than fourfold) and then pravastatin (almost twofold). Pravastatin has a neutral drug interaction profile relative to cytochrome P450-3A4 inhibitors, but these substrates markedly increase systemic exposure to simvastatin and atorvastatin.

Section snippets

Overview of study designs

This report summarizes data from 4 small, short-term parallel-group studies that evaluated the effects of CYP3A4 inhibitors on the multiple-dose pharmacokinetics of statins in 4 groups of healthy subjects. These studies, which were conducted from January 6, 1998 through April 4, 1998, evaluated the pharmacokinetics of (1) 40 mg of pravastatin or 40 mg of simvastatin when coadministered with 480 mg of extended-release verapamil; (2) 40 mg of pravastatin or 80 mg of atorvastatin when

Pharmacokinetic effects of verapamil on pravastatin and simvastatin

In this randomized, open-label, parallel-group trial, data were available for 27 of 30 subjects (90%); 3 subjects (20%) in the simvastatin treatment group discontinued because of adverse events, 2 due to mild first-degree atrioventricular block and 1 due to an accelerated junctional rhythm after receiving 40 mg of simvastatin plus 480 mg of verapamil. These events resolved after drug discontinuation. Mean serum concentrations of pravastatin, simvastatin, and simvastatin acid with and without

Discussion

Findings from this series of multiple-dose pharmacokinetics studies of pravastatin, simvastatin, and atorvastatin suggest that the non-CYP substrate pravastatin is the statin least susceptible to pharmacokinetic interactions with CYP3A4 inhibitors. Although rare, rhabdomyolysis with statins remains an important and timely issue. Recently, the manufacturer of rosuvastatin wrote to United Kingdom and European prescribers to remind them that the starting dose of rosuvastatin should be 10 mg.

Acknowledgment

Assistance in manuscript preparation was provided by Rete Biomedical Communications Corp. (Ridgewood, New Jersey). Manuscript review was provided by Joan Staggers, PhD (Bristol-Myers Squibb Co., Princeton, New Jersey).

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: This study was supported by Bristol-Myers Squibb Co., Princeton, New Jersey.

View full text

Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors

Section snippets

Overview of study designs

Pharmacokinetic effects of verapamil on pravastatin and simvastatin

Discussion

Acknowledgment

Toxicol Lett

Lancet

Am J Med

J Urol

Lancet

Clin Ther

Cerivastatin and reports of fatal rhabdomyolysis

N Engl J Med

HMG-CoA reductase inhibitors and myotoxicity

Drug Saf

FDA adverse event reports on statin-associated rhabdomyolysis

Ann Pharmacother

Simvastatin-diltiazem drug interaction resulting in rhabdomyolysis and hepatitis

Tenn Med

Rhabdomyolysis with concurrent atorvastatin and diltiazem

Ann Pharmacother

Rhabdomyolysis associated with concurrent use of simvastatin and diltiazem

Nephron

Rhabdomyolysis associated with concomitant use of atorvastatin and cyclosporine

Ann Pharmacother

Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin

Ann Pharmacother

Lovastatin-induced rhabdomyolysis possibly associated with clarithromycin and azithromycin

Ann Pharmacother

Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole

N Engl J Med

Coadministration of itraconazole with hypolipidemic agents may induce rhabdomyolysis in healthy individuals (letter)

Arch Dermatol

Simvastatin-fluconazole causing rhabdomyolysis

Ann Pharmacother