Elevated plasma levels of tacrolimus after concurrent use of tacrolimus and voriconazole in the bone marrow transplant setting

Abstract

Voriconazole is a broad-spectrum triazole antifungal agent used for the prevention and treatment of invasive fungal infections in high-risk transplant recipients. Azole antifungal agents have been associated with numerous drug-drug interactions. Voriconazole is extensively metabolized through the liver via the cytochrome (CYP) P450 enzyme system. The primary isoenzymes involved are CYP2C19, CYP2C9 and CYP3A4. Patients undergoing allogeneic stem cell transplantation at MD Anderson Cancer Center receive tacrolimus for graft versus host disease prophylaxis, dosed to achieve therapeutic plasma levels between 5–12 ng/ml. Reports in the literature have demonstrated the concurrent use of tacrolimus and voriconazole to result in supra-therapeutic tacrolimus levels in liver transplant recipients. Supra-therapeutic tacrolimus levels have been associated with adverse events such as renal failure requiring hemodialysis and seizures. The primary objective of this study was to determine the effect of voriconazole on tacrolimus levels in the bone marrow transplant setting. We performed a retrospective chart review of 30 bone marrow and stem cell transplant recipients who received concurrent therapy with voriconazole and tacrolimus. Data collected included patient demographics, diagnosis, type and date of transplant, concomitant medications, and pertinent laboratory tests (serum creatinine, blood urea nitrogen, liver function tests, and tacrolimus levels). The dose of voriconazole was as follows: 200 mg po BID (n = 18), 200 mg po QD (n = 1), 200 mg IV q12h (n = 4), and 3–4 mg/kg IV q12h (n = 7). Preliminary results reveal that 22 patients (73%) experienced an increase in plasma levels of tacrolimus, which occurred at a median of 5 days (range 2–10 days) of concomitant therapy. Over one-half of these patients had more than a 75% increase in plasma tacrolimus levels thus requiring a significant decrease in tacrolimus dose. Of the 22 patients, 7 (32%) showed mild to moderate elevations in liver function tests which may have contributed to supra-therapeutic tacrolimus levels due to the drug’s extensive hepatic metabolism. While the manufacturer recommends that the tacrolimus dose be reduced to one-third of the original dose when initiating therapy with voriconazole in patients already receiving tacrolimus, our initial results suggest that some patients may require up to a 75% decrease in tacrolimus dose to avoid supra-therapeutic levels of tacrolimus and subsequent sequelae.