title: Pharmacokinetic interaction between everolimus and antifungal triazoles in a liver transplant patient.
abstract: OBJECTIVE
  To describe the management of a pharmacokinetic interaction between azole antifungals (fluconazole and voriconazole) and everolimus in a patient who underwent an orthotopic liver transplant.
  
  
  METHODS
  A 65-year-old male who received an orthotopic liver transplant experienced an iatrogenic retroperitoneal duodenal perforation on postoperative day 55. His condition was subsequently complicated by severe sepsis and acute renal failure. Intravenous fluconazole 400 mg, followed by 100 mg every 24 hours according to impaired renal function, was immediately started; to avoid further nephrotoxicity, immunosuppressant therapy was switched from cyclosporine plus mycophenolate mofetil to oral everolimus 0.75 mg every 12 hours. Satisfactory steady-state minimum concentration (C(min)) of everolimus was achieved (approximately 5 ng/mL). On day 72 posttransplant, because of invasive aspergillosis, antifungal therapy was switched to intravenous voriconazole 400 mg every 12 hours on the first day, followed by 200 mg every 12 hours; to prevent drug toxicity, the everolimus dosage was promptly lowered to 0.25 mg every 24 hours. At that time, the everolimus C(min) averaged approximately 3 ng/mL. The concentration/dose ratio of everolimus (ie, C(min) reached at steady-state for each milligram per kilogram of drug administered) was markedly lower during fluconazole versus voriconazole cotreatment (mean +/- SD, 3.49 +/- 0.29 vs 11.05 +/- 0.81 ng/mL per mg/kg/daily; p < 0.001). Despite intensive care, the patient's condition continued to deteriorate and he died on day 84 posttransplant.
  
  
  CONCLUSIONS
  Both azole antifungals were considered probable causative agents of an interaction with everolimus according to the Drug Interaction Probability Scale. The interaction is due to the inhibition of CYP3A4-mediated everolimus clearance. Of note, prompt reduction of the everolimus dosage since the first azole coadministration, coupled with intensive therapeutic drug monitoring, represented a useful strategy to prevent drug overexposure.
  
  
  CONCLUSIONS
  Our data suggest that during everolimus-azole cotreatment, a dose reduction of everolimus is needed to avoid overexposure. According to the different inhibitory potency of CYP3A4 activity, the reduction should be lower during fluconazole than during voriconazole cotreatment.
authors.affiliation: Institute of Clinical Pharmacology & Toxicology, Department of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine, Udine, Italy. pea.federico@aoud.sanita.fvg.it
authors.forename: Federico
authors.initials: F
authors.lastname: Pea
authors.forename: Umberto
authors.initials: U
authors.lastname: Baccarani
authors.forename: Marcello
authors.initials: M
authors.lastname: Tavio
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Cojutti
authors.forename: Gian Luigi
authors.initials: GL
authors.lastname: Adani
authors.forename: Angela
authors.initials: A
authors.lastname: Londero
authors.forename: Massimo
authors.initials: M
authors.lastname: Baraldo
authors.forename: Loretta
authors.initials: L
authors.lastname: Franceschi
authors.forename: Mario
authors.initials: M
authors.lastname: Furlanut
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Viale
mesh_terms: D000368:Aged; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy; D004347:Drug Interactions; D000068338:Everolimus; D017809:Fatal Outcome; D015725:Fluconazole / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D014230:Triazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D011743:Pyrimidines; D014230:Triazoles; D015725:Fluconazole; D000068338:Everolimus; D065819:Voriconazole; D020123:Sirolimus