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January 5, 2005

High-Dose Statins in Acute Coronary Syndromes—Reply

JAMA. 2005;293(1):36-39. doi:10.1001/jama.293.1.39-a

In Reply: Dr Mitchel asserts that the muscle toxicity observed during the failed development of the 160-mg dose of simvastatin is not relevant to the interpretation of the A to Z trial. I strongly disagree. The margin of safety of a drug is always relevant. This is particularly true for drugs such as simvastatin, which is metabolized by cytochrome P450 3A4. Coadministration with 3A4 inhibitors and other agents, including erythromycin, amiodarone, verapamil, or antifungals, can significantly elevate simvastatin blood levels.1 In this way, the blood levels achieved with the 80-mg dose of simvastatin used in the A to Z trial can reach the toxic levels that led to termination of the development of the 160-mg dose of simvastatin.