Abstract & Commentary
Source: Jacobson TA. Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors. Am J Cardiol 2004;94:1140-1146.
Statins have become the mainstay of preventive cardiology. However, concern continues regarding the potential for rhabdomyolysis, especially at higher doses of these agents. Thus, Jacobson studied four groups of healthy subjects to assess the pharmacokinetics of: 1) 40 mg pravastatin or 40 mg simvastatin coadministered with 480 mg verapamil; 2) 40 mg pravastatin or 80 mg atorvastatin plus 100 mg mibefradil; 3) 40 mg pravastatin or 80 mg atorvastatin plus 200 mg itraconazole; and 4) 40 mg pravastatin, 40 mg simvastatin, or 80 atorvastatin plus 500 mg clarithromycin.
When compared with pravastatin alone, coadministration of verapamil, mibefradil, or itraconazole with pravastatin did not alter pravastatin pharmacokinetics. Clarithromycin did increase the area under the curve (AUC) of plasma pravastatin (100% P < .001), but increased the AUC of simvastatin 219% and atorvastatin 343%. Verapamil increased simvastatin AUC four-fold. Mibefradil increased atorvastatin AUC more than four-fold, and itraconazole increased atorvastatin AUC 47%. Clarithromycin increased the AUC of all three statins; simvastatin ten-fold, atorvastatin more than four-fold, and pravastatin almost two-fold. Jacobson concluded that pravastatin is the statin with the fewest interactions with cytochrome P450-(CYP) 3A4 inhibitors.
Commentary by Michael H. Crawford, MD
The withdrawal of cervastatin from the market, and the recent physician notification that the starting dose of rosuvastatin is 10 mg, underscores the concern about anything that may increase the incidence of the rare, but serious, adverse reaction of rhabdomyolysis, which is dose related. Coadministration of other agents that share the CYP receptor may lead to increased serum levels of certain statins for prolonged periods. These agents include gemfibrozil, calcium-channel blockers, immunosuppressives, macrolide antibiotics, certain antifungal agents, protease inhibitors of HIV, amiodarone, and grapefruit juice.
Some have estimated that more than half the rhabdomyolysis cases reported to the FDA involved coadministration of other CYP inhibitors. In fact, the package insert for simvastatin recommends a daily dose no higher than 20 mg with the coadministration of verapamil or amiodarone. Simvastatin and atorvastatin are lipophilic statins that demonstrate profound increases in drug levels over time when given with CYP inhibitors. Pravastatin is hydrophilic and is not a CYP substrate. Mibefradil is a T-channel calcium blocker, which is a strong CYP inhibitor and was withdrawn from the U.S. market because of numerous serious drug interactions. However, in this study, it did not interact with pravastatin. Other studies have shown an overall extremely low incidence of rhabdomyolysis with pravastatin, 0.04 per million prescriptions vs 0.12 for simvastatin, 0.10 for lovastatin and 3.2 for cerivastatin.
The down side of pravastatin is that it is not a particularly potent statin and may require concomitant lipid-lowering agents to achieve the desired effect. This may be the reason that Merck developed Vytorin, which combines lower doses of simvastatin with ezetimibe. Thus, when using more potent statins, one must weigh the tiny risk of rhabdomyolysis against the major benefits of effective lipid-lowering in patients with vascular disease. However, care must be taken when the coadministration of CYP inhibitors is necessary. In these situations, pravastatin may be an alternative if lipid targets can be met.
Dr. Crawford, Professor of Medicine, Associate Chief of cardiology for Clinical programs, University of California San Francisco, is Editor of Clinical Cardiology Alert.