Fluconazole-sirolimus drug interaction

Sirolimus, a relatively new immunosuppressant drug, is extensively metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate of the p-glycoprotein (P-gp) drug efflux pump. It is therefore susceptible to interactions with drugs that interfere with CYP3A4 and P-gp function such as the azole antifungals. Literature reports of interactions between azole antifungals and sirolimus are scant, and such interactions have largely been implied from observations between azoles and other CYP3A4 or P-gp substrate drugs such as cyclosporine and tacrolimus. The United States approved Rapamune prescribing information and sirolimus manufacturer have data from an interaction study between oral sirolimus solution (5 mg single dose) and oral ketoconazole (200 mg daily for 10 days) in 24 healthy volunteers (1,2). This showed that multiple dose ketoconazole significantly affected the rate of absorption and extent of sirolimus exposure as reflected by an increase in sirolimus Cmax, tmax, and area under the curve (AUC) by 4.3-fold, 38%, and 10.9-fold, respectively. Because the sirolimus half-life was unchanged, the increases were attributed to an increase in sirolimus bioavailability caused by the inhibitory effect of ketoconazole on gastrointestinal CYP3A4 and P-gp activity. To the best of our knowledge, this is the first report of a clinically significant interaction between fluconazole and sirolimus. CASE REPORT A 49-year-old Australian Aboriginal male with end-stage renal failure secondary to diabetic nephropathy underwent a primary cadaveric renal transplant. Following an uneventful operative procedure, the patient experienced delayed graft function requiring dialysis support. Immediate posttransplant medications included cyclosporine, mycophenolate mofetil, prednisolone, ranitidine, isosorbide di-nitrate, nifedipine, and carvedilol. Cyclosporine was replaced with sirolimus on day 5 to minimize calcineurin inhibitor nephrotoxicity in the nonfunctioning graft. After sirolimus loading doses (15 mg once daily for 3 consecutive days) and dose titration, trough sirolimus blood concentrations (HPLC/UV) were stabilized at approximately 10 μg/L between days 20 and 25. Other medications remained constant except for withdrawal of carvedilol on day 8. On day 18, the patient began complaining of a sore throat and difficulty swallowing. An endoscopy performed on day 23 revealed esophageal candidiasis despite the use of prophylactic amphotericin lozenges. Oral fluconazole (200 mg each evening) was begun on day 25. In anticipation of a possible interaction between fluconazole and sirolimus, the sirolimus dosage was reduced from 4 mg to 3 mg each morning from day 26. The effect on trough sirolimus concentrations and subsequent dosing is shown in Figure 1. On days 26 and 27 (day 1 and 2 following beginning of fluconazole) there was a small, insignificant rise in trough sirolimus concentrations to 12.0 and 12.6 μg/L, respectively. However, trough sirolimus concentrations rose further on days 28 and 29 to 19 and 22.8 μg/L, after which the sirolimus dosage was reduced to 2 mg daily from day 30. Trough concentrations continued to rise, reaching a peak of 35.5 μg/L on day 32. The patient continued to receive fluconazole with mild improvement in his clinical condition. On day 33, when the trough concentration fell to 26.8 μg/L, the patient unexpectedly experienced a cardio-respiratory arrest associated with hyperkalemia. He was transferred to the intensive care unit where his condition rapidly deteriorated, and he died on day 34 secondary to multi-organ failure. Figure 1: Time course of events showing the relationship between sirolimus dosing (shaded columns mg/day), trough sirolimus concentrations (―●―, μg/L), and the effect of concomitant fluconazole (200 mg daily) administration.DISCUSSION The known effect of azole antifungals on CYP3A4 and P-gp function, as well as the strong temporal relationship, suggests a strong likelihood that a drug interaction caused the rise in trough sirolimus concentration in this case. Other possible causes include concurrent sepsis, multiorgan failure, or reduced hepatic function. However, these seem less likely considering that the rise in sirolimus concentrations preceded the sudden deterioration in the patient’s condition. Liver function tests (LFTs) also remained within the normal range (except for a consistently mild elevation in γ-glutamyl transpeptidase [GGT] 80 to 180 U/L) until day 33 posttransplant. All LFT parameters then rose sharply on days 33 to 35 posttransplant as the patient’s condition deteriorated (aspartate aminotransferase [AST] 1692 U/L; alanine aminotransferase [ALT] 627 U/L; alkaline phosphatase [ALP] 213 U/L; GGT 299 U/L; and lactate dehydrogenase [LDH] 3201 U/L). Of the systemic azole antifungals, fluconazole is the weakest in vitro inhibitor of CYP3A4, and, even accounting for its lower degree of plasma protein binding, its in vivo CYP3A4 inhibitor potency is low relative to ketoconazole and itraconazole (3). Despite this, this case highlights the unpredictable nature and magnitude of such interactions and the need for timely therapeutic drug monitoring to guide dosing. The management of such interactions involving sirolimus may be complicated by its long half-life. Matthew J. Cervelli