Clinical Pathology: Clinical Chemistry

254) An orthotopic liver transplant (OLTx) recipient, who was previously taking cyclosporine and mycophenolate mofetil, was readmitted on post-transplantation day 55 with severe sepsis and acute renal failure. Empirical wide-spectrum antimicrobial therapy with piperacillin-tazobactam, teicoplanin, and fluconazole was started, and immunosuppressant therapy was temporarily withdrawn. After partial recovery, everolimus was started. Concomitant treatments included ranitidine, heparin, methylprednisolone, octreotide, insulin, and furosemide. In the absence of any published data on appropriate dosing of everolimus during cotreatment with fluconazole, a moderately reduced starting dosage of everolimus (0.75 mg every 12 hours orally) was used, which is a 25% to 50% reduction from the usual dose of 1 to 1.5 mg every 12 hours. Therapeutic drug monitoring of everolimus, measured by fluorescence-polarization immunoassay (FPIA) was planned to maintain the whole blood minimum concentration (C_min)within the desired range of 3 to 8 ng/mL. On day 70, the patient was transferred to another hospital. On day 72, antifungal therapy was switched to voriconazole (intravenous loading dose of 400 mg every 12 hours for two doses, followed by maintenance doses of 200 mg every 12 hours) to treat invasive pulmonary aspergillosis. The everolimus dose was reduced to 0.25 mg every 24 hours. The everolimus C_min, now measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS), was within the range of 3 to 8 ng/mL (shown in the figure). Which one of the following reasons best explains the relatively higher C_min of everolimus during voriconazole treatment?