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.
Nissen SE. High-Dose Statins in Acute Coronary Syndromes—Reply. JAMA. 2005;293(1):36–39. doi:10.1001/jama.293.1.39-a
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