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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.

Mitchel asserts that the high toxicity of the 160-mg dose was openly revealed by Merck via a press release in 1997. However, in preparing my editorial I searched the medical literature, Merck’s . . . [Full Text of this Article]

Steven E. Nissen, MD
nissens@ccf.org
Department of Cardiology
Cleveland Clinic Foundation
Cleveland, Ohio

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