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Clozapine-Erythromycin Interaction — MRCPsych Paper B MCQ

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HardSchizophrenia & PsychosisClozapine-Erythromycin InteractionMRCPsych Paper B

A 30-year-old man has been stable on clozapine 500 mg daily. He develops febrile community-acquired pneumonia and is prescribed erythromycin. Five days later, he has marked sedation and postural hypotension, and his plasma clozapine concentration is substantially above his previous stable level. His smoking and caffeine consumption have not changed. Which mechanism is most likely to explain the rise in clozapine concentration?

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Correct answer: B — Inflammation-related suppression of CYP1A2-mediated clozapine clearance

The best answer is B. Acute systemic inflammation, especially from pneumonia, can reduce clozapine clearance through functional suppression of CYP1A2, its principal metabolic pathway. This can markedly increase clozapine exposure and cause concentration-related sedation and hypotension. The unchanged smoking and caffeine intake exclude two important alternative causes of altered CYP1A2 activity. Erythromycin inhibits CYP3A4, making E superficially plausible, but CYP3A4 has a relatively minor role in clozapine clearance; the UK SmPC states that clinically important pharmacokinetic interactions with erythromycin are unlikely, although occasional reports exist. Erythromycin does not reduce clozapine absorption or induce CYP1A2, excluding A and C. Clozapine does not induce erythromycin metabolism, excluding D.

Reference: de Leon J, et al. Letter to the FDA Proposing Major Changes in the US Clozapine Package Insert Supported by Clozapine Experts Worldwide. Part I: A Review of the Pharmacokinetic Literature and Proposed Changes. Journal of Clinical Psychopharmacology. 2025;45(3):179–196. https://pubmed.ncbi.nlm.nih.gov/40198781/