A 58-year-old man on long-term simvastatin 40 mg daily is started on clarithromycin for an exacerbation of bronchiectasis. One week later he presents with severe proximal muscle pain, weakness and a creatine kinase level above 20,000 U/L. The interaction responsible is best explained by:

• A Clarithromycin inhibits CYP3A4, raising plasma concentrations of simvastatin ✓
• B Clarithromycin induces CYP3A4 and accelerates formation of toxic statin metabolites
• C Clarithromycin displaces simvastatin from plasma protein binding sites
• D Clarithromycin competitively inhibits renal tubular secretion of simvastatin

Explanation

Clarithromycin and erythromycin are potent inhibitors of CYP3B4. Simvastatin and atorvastatin are metabolized primarily by CYP3B4, so coadministration markedly raises statin exposure and precipitates rhabdomyolysis. Azithromycin lacks significant CYP3B4 inhibition and is the preferred macrolide in such patients. Simvastatin undergoes minimal renal excretion, so tubular secretion is irrelevant, and enzyme inhibition rather than induction explains the raised levels.

Reference: Katzung Basic and Clinical Pharmacology, 15th ed.

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