Voriconazole Inhibition of Tacrolimus Metabolism

Sir—Voriconazole (Pfizer) is a new triazole antifungal agent used in the management of invasive infections caused by molds such as Aspergillus species, Fusarium species and Scedosporium apiospermum. This agent is known to inhibit the cytochrome P450 (CYP) isoenzymes 3A4, 2C9, and 2C19, and is consequently associated with a number of drug interactions [1]. Preliminary observations have demonstrated that voriconazole significantly increases the trough concentrations of tacrolimus [2]. The manufacturer recommends reducing the daily tacrolimus dose by one-third when it is concurrently administered with voriconazole [3]. We describe a patient who required a 90% reduction in the manufacturer's recommended maintenance dose of tacrolimus. A 44-year-old, 62-kg woman with a history of hepatitis C, alcoholic liver disease, and liver transplantation (6 years earlier) presented to the emergency department of the University Hospital (Albuquerque, NM) with multiple complaints. The patient had a 10-day history of severe headaches, nausea, and anorexia with a 6-kg weight loss over that period. She also reported a loss of balance, light-headedness, and generalized weakness. Her vital signs were within normal limits, and the only abnormality detected by a physical examination was the patient's inability to walk across the room unassisted. With the exception of a low serum sodium level (126 mg/dL), all laboratory values, including those for CSF, were within normal limits. No abnormalities were noted on a head CT scan (without contrast), but an MRI of the head revealed multiple white matter changes consistent with a diagnosis of leukoencephalopathy. A chest radiograph revealed a right lower lobe mass. The patient was admitted for an additional diagnostic workup. The patient's medications prior to admission included mycophenolate mofetil, lansoprazole, tacrolimus, promethazine, spironololactone, prednisone, allopurinol, citalopram, and furosemide. The tacrolimus concentration was assessed and was found to be elevated (29.9 ng/mL). Tacrolimus therapy was withheld, producing a dramatic resolution in the patient's symptoms within 48 h. A second MRI of the patient's head no longer demonstrated the previously observed white matter changes. These findings were consistent with the diagnosis of tacrolimus-induced multifocal leukoecephalopathy [4]. A history of coccidioidomycosis (valley fever) 4 years earlier was elicited from the patient and was confirmed through medical records. Treatment with liposomal amphotericin B (AmBisome; Fujisawa Healthcare; 3.5 mg/kg) was initiated on day 10 of her hospitalization, on the assumption that the patient had had a relapse of coccidiodomycosis (indicated by fevers and abnormal chest radiograph findings), but was discontinued because of nephrotoxicity. A needle-guided biopsy of the lesion was performed on day 30 of hospitalization, and treatment with voriconazole (400 mg po b.i.d.) and trimethoprim/sulfamethoxazole (5 mg/kg iv b.i.d.) was initiated empirically. Tacrolimus therapy was started again, but the daily dose (1.5 mg po q.d.) was reduced by one-third, as recommended by the manufacturer of voriconazole. Tacrolimus trough concentrations in blood were monitored daily (figure 1) and, ultimately, the patients regimen was required to be reduced to 0.15 mg po q.d. to maintain the tacrolimus blood concentrations within the therapeutic range (5–15 ng/mL). This change in the tacrolimus doseage was performed 10 days after the initiation of voriconazole therapy. The patient's condition worsened and was thought to be a combination of adult respiratory distress syndrome, pulmonary edema, and hepatorenal syndrome. The patient's family decided to withdraw care, and the patient died on day 46 of hospitalization. Daily trough tacrolimus blood concentrations in a patient also receiving voriconazole Voriconazole has recently been reported to elevate trough tacrolimus blood concentrations by 10-fold [2]. Such elevated levels have the potential to induce serious adverse events in patients who are not carefully monitored. The present case documents the consequence of elevated tacrolimus concentrations in a patient who developed multifocal leucoencephalopathy. Daily monitoring of tacrolimus trough blood concentrations was performed to adjust the tacrolimus doseage and prevent a potential repetition of this adverse event. The current recommendation to reduce the daily tacrolimus dose by one-third may not maintain tacrolimus concentrations within the therapeutic range. In addition, the duration of inhibition of tacrolimus metabolism after voriconazole therapy is discontinued is not known. Careful monitoring of tacrolimus concentrations is crucial when voriconazole is coadministered with tacrolimus, especially for outpatients.