Which drug pair is associated with a clinically significant interaction when the second drug is added to the first?

• A. Simvastatin and Clarithromycin
• B. Simvastatin and Metformin
• C. Atorvastatin and Clarithromycin
• D. Simvastatin and Amoxicillin

Answer: (A)

When a strong inhibitor of the enzyme that metabolizes a drug is added, the levels of that drug can rise and cause toxicity. Simvastatin is heavily dependent on CYP3A4 for its breakdown, so adding clarithromycin, a potent CYP3A4 inhibitor, markedly increases simvastatin exposure. This raises the risk of muscle toxicity, including myopathy and rhabdomyolysis, making this pairing the most clinically significant interaction.

Metformin does not meaningfully affect simvastatin levels, and amoxicillin doesn’t inhibit the same metabolic pathway, so those pairings don’t carry the same risk. While clarithromycin can interact with atorvastatin as well, the interaction is typically less pronounced than with simvastatin, so it’s not as clinically significant in this context.