Sirolimus + Voriconazole Can Be Safe
The two medications can be administered concomitantly if various factors are taken into account.
“When these drugs are combined you can end up with elevated sirolimus concentrations in the blood because voriconazole inhibits CYP 3A4, the enzyme responsible for metabolizing sirolimus,” said lead investigator Dorothy Surowiec, PharmD, clinical pharmacy specialist, infectious diseases,
Elevated sirolimus concentrations may increase patient susceptibility to the dose-dependent adverse effects of sirolimus, including renal dysfunction, leukopenia, thrombocytopenia, and anemia.
Thus, clinicians are in a conundrum when they need to use voriconazole to treat invasive fungal infections while maintaining immunosuppression with sirolimus in transplant patients.
Dr. Surowiec presented data at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy showing that loading doses of sirolimus are not necessary in patients who are already receiving voriconazole. In patients on low doses of sirolimus (0.5-2 mg/day) and whose sirolimus blood concentrations are 12 ng/mL or less, the sirolimus dose may only need to be decreased by 50% with the addition of voriconazole. However, in patients on sirolimus doses of 4 mg/day or more and who have sirolimus blood concentrations greater than 12 ng/mL, a preemptive sirolimus dose decrease of 70%-90% may be required upon initiation of voriconazole.
The investigators retrospectively studied the medical records of inpatients who received at least one dose of voriconazole and sirolimus concomitantly in a 24-hour period. Data were collected for seven days prior to, during, and 14 days following co-administration of the two agents.
The researchers also analyzed data on drug indications, dosing, route of administration, frequency, and administration times of voriconazole and sirolimus. They also examined laboratory values, sirolimus serum concentrations, confounding medications, adverse effects, transplant rejection, and mortality.
Dr. Surowiec's group identified 31 cases involving 23 patients. Approximately 70% of the patients were hematopoietic stem cell transplant recipients. Patients received the two drugs concomitantly for a mean of 4.5 days (range 1-21 days). The mean sirolimus blood concentration was 12.7 ng/mL (range 2.3-60 ng/mL).
Patients receiving 0.5-2 mg of sirolimus a day experienced only minor increases in sirolimus concentrations following the addition of voriconazole. Similarly, one patient who had been receiving concomitant therapy with itraconazole (another CYP 3A4 inhibitor), in combination with sirolimus 1-2 mg a day experienced only a minor increase in sirolimus concentrations after initiation of voriconazole.
In contrast, a 1.5- to 2.6-fold increase in sirolimus concentrations occurred in two patients who received 4-6 mg a day of sirolimus prior to the addition of voriconazole.
Among patients receiving voriconazole and who were started on sirolimus at doses of 0.5-1 mg a day, the researchers found that they had sub-sequent sirolimus concentrations of less than 20 ng/mL. In two patients on voriconazole who received 4 and 12 mg loading doses of sirolimus, subsequent sirolimus concentrations were above 20 mg/nL.
“There have been only a few case reports and one case series on this issue,” Dr. Surowiec told Renal & Urology News. “Our study includes a greater number of cases than has previously been reported. Clinicians need to be aware of these findings because if they have patients on sirolimus who develop invasive fungal infections and need to be treated with voriconazole, they may have to use these two agents together. So they need to know how to adjust the dose of sirolimus. In some cases you may need to decrease the dose of sirolimus by 50%-90%, depending on what dose of sirolimus the patient is on and the sirolimus concentration prior to the addition of voriconazole.”