Major
Ketoconazole × tacrolimus
Systemic antimycotics. Imidazole derivatives×Calcineurin inhibitor (immunosuppressant)
Mechanism
Ketoconazole is the most potent CYP3A4 inhibitor available – the main tacrolimus metabolic route. Tacrolimus plasma levels rise 3- to 5-fold. The narrow therapeutic window makes any rise clinically dangerous.
Symptoms
Acute nephrotoxicity: rising creatinine and falling glomerular filtration rate. Tremor, headache, hypertension, hyperglycaemia, hyperkalaemia. In transplant patients: accelerated graft function decline.
Management
Avoid the combination. Alternative antifungals: terbinafine for dermatophytosis or echinocandins for systemic mycoses. If unavoidable, reduce tacrolimus 2- to 3-fold and check trough (C0) levels daily.