Fluvastatin Fibrates

The catabolism of lovastatin, simvastatin, and atorvastatin proceeds chiefly through CYP3A4, whereas that of fluvastatin and rosuvastatin is mediated by CYP2C9. Pravastatin is catabolized through other pathways, including sulfation. The 3A4-dependent reductase inhibitors tend to accumulate in plasma in the presence of drugs that inhibit or compete for the 3A4 cytochrome. These include the macrolide antibiotics, cyclosporine, ketoconazole and its congeners, HIVprotease inhibitors, tacrolimus, nefazodone, fibrates, and others (see Chapter 4). Concomitant use of reductase inhibitors with amiodarone or verapamil also causes an increased risk of myopathy. 

Certain drug combinations present challenges. Because resins interfere with the absorption of certain reductase inhibitors (pravastatin, cerivastatin, atorvastatin, and fluvastatin), these must be given at least 1 hour before or 4 hours after the resins. The combination of reductase inhibitors with either fibrates or niacin may increase the risk of myopathy. 

The plasma levels of lovastatin, simvastatin, atorvastatin and pravastatin are increased by gemfibrozil, the levels of fluvastatin are increased by bezaflbrate, and the levels of pravastatin are increased by fenoflbrate. No pharmacokinetic interactions occur with the combinations of fluvastatin with gemfibrozil, lovastatin with bezaflbrate, and pravastatin, rosuvastatin or simvastatin with fenoflbrate. Both statins and fibrates are known to cause rhabdomyolysis, and their concurrent use increases the risk of this reaction. 

In a review of the FDA spontaneous reports of statin-associated rhabdomyolysis covering the period November 1997 to March 2000, fibrates (unspeeified) were potentially implieated in 10 of 73 cases of rhabdomyolysis seen with atorvastatin, 4 of 10 with fluvastatin, 5 of 40 with lovastatin, 6 of 71 with pravastatin, and 33 of 215 with simvastatin. 

All other statins, which entered the market, are produced by total synthesis (Fig. 5.153). Fluvastatin is marketed as the racemate. After the Lipobay scandal, cerivastatin was withdrawn from the market worldwide in 2001, due to reports of fatal rhabdomyolysis associated with renal failure. The reasons behind these toxicities were a too narrow therapeutic window (effective dose compared to toxic dose) and the drug interaction with fibrates, especially with gemfibrozil. 

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