Voriconazole and Sirolimus Coadministration after Allogeneic Hematopoietic Stem Cell Transplantation

Article Outline

• Abstract
• Introduction
• Methods
• Results
• Discussion
• Acknowledgments
• References
• Copyright

Abstract 

Sirolimus is increasingly used in transplantation for prevention and treatment of graft-versus-host disease and organ rejection. Voriconazole is contraindicated when used concomitantly with sirolimus because of a substantial increase in sirolimus drug exposure with unadjusted dosing, but voriconazole is also considered the best initial treatment of invasive aspergillosis and other fungal infections. Patients who received voriconazole and sirolimus concomitantly were identified by a review of the medical records of all allogeneic hematopoietic stem cell recipients at our institution from September 1, 2002, to June 1, 2005. Data including baseline characteristics, indications for both drugs, and potential adverse effects were evaluated. Eleven patients received voriconazole and sirolimus concomitantly for a median of 33 days (range, 3-100 days). In 8 patients whose sirolimus dose was initially reduced by 90%, trough sirolimus levels were similar to those obtained before the administration of voriconazole; no obvious significant toxicity from either drug was observed during coadministration. Serious adverse events were observed in 2 patients in whom sirolimus dosing was not adjusted during voriconazole administration. Sirolimus and voriconazole may be safely coadministered if there is an empiric initial 90% sirolimus dose reduction combined with systematic monitoring of trough levels.

Key words:  Voriconazole , Sirolimus , Transplantation , Aspergillosis , Fungal infection

Back to Article Outline

Introduction 

Sirolimus has been increasingly used for the prevention and treatment of graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (HSCT) and of organ rejection in solid organ transplant recipients [1, 2, 3, 4]. Potential advantages of sirolimus administration include synergy and few overlapping toxicities when used in combination with tacrolimus or cyclosporine, a prolonged half-life, and a wide therapeutic window [1]. After transplantation, these patients are at increased risk for invasive aspergillosis (IA) [5, 6] and other invasive fungal infections (IFIs) [7]. Voriconazole is currently considered the best initial treatment of IA [8] and other IFIs, such as those caused by Fusarium species and Scedosporium apiospermum [9, 10].

The use of voriconazole in combination with sirolimus was contraindicated at the time of voriconazole approval because of a substantial increase in sirolimus drug exposure in healthy subjects from voriconazole inhibition of several cytochrome P450 (CYP) isoenzymes [11]. Voriconazole has been shown to cause an 11.1-fold increase in the sirolimus peak plasma concentration and a 6.6-fold increase in the area under the plasma concentration-time curve [11, 12]. Thus, in patients who are receiving sirolimus and develop IA or other IFIs in which voriconazole is considered the best treatment option, clinicians may be faced with the difficult decision of whether to withdraw sirolimus or choose a suboptimal antifungal agent.

Over the past few years, several HSCT patients at our institution who were receiving sirolimus needed antifungal treatment with voriconazole. In some of these cases, because of the need to manage GVHD and the IFI, it was judged to be in the patient’s best interest to coadminister both medications. An empiric dose reduction in sirolimus was made, in most cases, on the basis of the projected increase in sirolimus levels from voriconazole coadministration. We present a series of all patients treated at our institution in whom both drugs were coadministered and report the feasibility and safety of such an approach.

Back to Article Outline

Methods 

The Partners Healthcare System Human Research Committee approved this study. A retrospective medical record review of all HSCT recipients in whom voriconazole and sirolimus were coadministered between September 1, 2002 (when voriconazole became available at our institution), and June 1, 2005, was performed. Patients were identified by using computerized inpatient and outpatient medication-dispensing records. Information regarding patient age at the time of coadministration, sex, underlying hematologic disease, donor relatedness, voriconazole and sirolimus indications for use, drug dose and dosage adjustments, concomitant tacrolimus use, drug levels, use of nephrotoxic medications, need for dialysis, adverse events, vital status, and cause of death was collected from the medical record. Trough tacrolimus and sirolimus levels were routinely obtained for clinical management at the discretion of the treating clinicians.

Coadministration was defined as the administration of both voriconazole and sirolimus for >1 day. The sirolimus dose and duration of therapy before the initiation of voriconazole were captured and compared with the dose of sirolimus at the time of voriconazole initiation and the steady-state dose of sirolimus during coadministration. Sirolimus trough levels immediately preceding voriconazole initiation, the highest measured sirolimus trough level, and the average sirolimus trough level at steady state during coadministration were determined. These parameters were also captured for tacrolimus if it was used concomitantly with sirolimus and voriconazole.

The indication for sirolimus use was categorized as either treatment of or prophylaxis against GVHD. The indication for voriconazole administration was categorized as treatment of proven or probable IFI on the basis of current diagnostic criteria [13], empiric therapy, or prophylaxis. Potential voriconazole and sirolimus adverse drug events were recorded. Baseline, peak, and coadministration measurements were recorded for creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, cholesterol, triglyceride, and corrected QT intervals (QTc).

Acute renal failure was defined as a serum creatinine level >2 mg/dL or a 50% increase in serum creatinine from baseline. Concomitant use of the following potentially nephrotoxic medications was recorded: amphotericin B products, iodinated intravenous contrast agents, aminoglycosides, cyclosporine, and foscarnet. AST, ALT, or alkaline phosphatase measurements in excess of 3 times the upper limit of normal were considered clinically significant. For patients who died during the study period, conditions present at the time of death were established from autopsy reports or physician notes. Two-tailed Fisher exact tests or Wilcoxon tests were used as appropriate for analysis.

Back to Article Outline

Results 

Twenty-five HSCT patients receiving sirolimus were prescribed voriconazole between September 1, 2002, and June 1, 2005. In 14 patients, sirolimus was discontinued at the time of initiation of voriconazole. These patients are not considered further.

Eleven patients received voriconazole and sirolimus concomitantly during the study period. The baseline characteristics of these patients are presented in Table 1. The median patient age was 40 years (range, 27-58 years). Seven of the 11 patients were male. Underlying hematologic malignancies were acute myelogenous leukemia (3 patients), chronic myelogenous leukemia (3 patients), non-Hodgkins lymphoma (2 patients), and acute lymphoblastic leukemia, aplastic anemia, and chronic lymphocytic leukemia (1 patient each). Nine of the 11 patients received peripheral stem cells, and 2 patients received umbilical cord blood stem cells. The median time from transplantation to voriconazole-sirolimus coadministration was 69 days (range, 7-1170 days). Eight of the 11 patients received sirolimus for treatment of GVHD, and 3 received sirolimus for GVHD prophylaxis. Five patients received voriconazole for proven or probable IA, 4 patients for empiric therapy, 1 patient for probable fusariosis, and 1 patient for antifungal prophylaxis.

Table 1. Demographics

AML indicates acute myelogenous leukemia; CML, chronic myelogenous leukemia; NHL, non-Hodgkin’s lymphoma; ALL, acute lymphocytic leukemia; CLL, chronic lymphocytic leukemia; AA, aplastic anemia; PBSC, peripheral blood stem cells; Cord, umbilical cord stem cells; MMU, mismatched unrelated donor; MU, matched unrelated donor; HSCT, hematopoietic stem cell transplantation; SRL, sirolimus; GVHD, graft-versus-host disease; VCZ, voriconazole; IA, invasive aspergillosis.

All patients received sirolimus before starting voriconazole. Sirolimus and voriconazole were coadministered for a median of 33 days (range, 3-100 days; Table 2), for a total of 427 patient-days of observation. The median duration of sirolimus therapy before voriconazole initiation was 72 days (range, 10-422 days). Patients received a stable daily dose of sirolimus for a median of 12 days (range, 1-50 days) before voriconazole was added. The median voriconazole maintenance dose was 400 mg/d (range, 400-800 mg/d).

Table 2. Sirolimus and Voriconazole Dosing Regimens

SRL indicates sirolimus; VCZ, voriconazole.

Eight of 11 patients had their sirolimus reduced to 10% of the stable daily dose at the time voriconazole was initiated. Sirolimus solution (Rapamune 1 mg/mL; Wyeth Pharmaceuticals Inc., Philadelphia, PA) was used for ease of administration of the reduced dosage. Sirolimus was usually ingested with the rest of the patient’s morning medications, which included voriconazole. No patient with an empiric 90% dose reduction had a plasma sirolimus level above the therapeutic target trough range (3-12 ng/mL) [1] during coadministration, except for a single level of 13.9 ng/mL in patient 5 which occurred on day 40 of concomitant use. For these patients, the median average steady-state trough level on the combination was 4.2 ng/mL (range, 1.9-10.4 ng/mL), which was not different from pretreatment levels (P = .72; Table 2). The median highest sirolimus trough level was 6.1 ng/mL (range, 1.9-13.9 ng/mL), which occurred a median of 6 days (range, 0-40 days) after the initiation of voriconazole administration and was not significantly different from previous levels (P = .57). The median number of levels measured was 6.5 (range, 1-53).

Three patients did not have an empiric sirolimus dosage reduction at the time voriconazole was initiated. In patient 4, a local health provider prescribed voriconazole for empiric treatment of sinusitis, but the sirolimus dose was reduced to 10% 6 days later when he was seen in our clinic. All patients without an empiric 90% sirolimus dosage adjustment at the time of voriconazole initiation (patients 4, 10, and 11) had sirolimus levels that exceeded the target therapeutic range. The median average steady-state sirolimus level on the combination was 18.9 ng/mL (range, 10.0-19.2 ng/mL), and the median peak sirolimus level was 23.5 ng/mL (range, 23.4-29.6 ng/mL). The median number of levels measured was 3 (range, 2-4).

Eight patients received tacrolimus [4] in addition to voriconazole and sirolimus (Table 3). In 4 of these patients, there was an empiric 50% tacrolimus dose reduction at the time of voriconazole initiation. Tacrolimus trough concentrations exceeded the therapeutic range in 1 of these patients 3 days after initiation of voriconazole. Of the 4 patients with no tacrolimus dose adjustment at the time of voriconazole initiation, 2 patients had trough concentrations above the target therapeutic range. Patient 11 developed thrombotic microangiopathy (TMA) [14, 15] and severe posterior leukoencephalopathy attributed to tacrolimus toxicity. The patient later died of a subarachnoid hemorrhage.

Table 3. Renal Adverse Effects

VCZ indicates voriconazole; TAC, tacrolimus; L-AmB, liposomal amphotericin B; IV, intravenous; PO, oral.

In 5 of 11 patients, serum creatinine at the end of voriconazole-sirolimus coadministration was similar to baseline levels (Table 3), without evidence of acute renal dysfunction. Five patients developed acute renal failure, which was transient in 1 patient who was receiving liposomal amphotericin B and foscarnet. Two patients required dialysis; patient 8 had hepatorenal syndrome due to veno-occlusive disease of the liver, and patient 6 developed acute tubular necrosis during treatment with liposomal amphotericin B before voriconazole was initiated. When patients were analyzed as a group, we could not demonstrate an association between tacrolimus or liposomal amphotericin B use and acute renal failure (P = 1; Table 3).

Adverse effects associated with voriconazole use were uncommon (Table 4). Four of the 11 patients had peak increases of AST, ALT, or alkaline phosphatase >3 times the upper limit of normal (30, 52, and 118 U/L, respectively, at our institution) during coadministration. Patient 8 had veno-occlusive disease of the liver; in patient 5, peak AST, ALT, and alkaline phosphatase levels occurred before the initiation of voriconazole. Voriconazole was discontinued in patient 6, who developed bradycardia without QTc prolongation during treatment. QTc prolongation compared with baseline was not observed in the 6 patients who had measurements during coadministration. Only patient 3 had trough voriconazole levels measured during the study period. Voriconazole levels ranged between 2.6 and 4.3 ng/mL (n = 4) on an oral dose of 800 mg/d; she experienced no voriconazole-related toxicity.

Table 4. Adverse Effects Potentially Associated with Voriconazole and Sirolimus

QTc indicates corrected QT interval; SRL, sirolimus; VCZ, voriconazole; AST, aspartate aminotransferase; ALT, alanine aminotransferase; AlkPhos, alkaline phosphatase.

Serum cholesterol and triglycerides were infrequently measured during voriconazole-sirolimus coadministration (Table 4). Cholesterol levels were measured in 3 patients during coadministration and were similar to baseline levels. Triglycerides were measured in 4 patients at baseline and during coadministration. In 2 patients, the triglyceride level during coadministration was 2 to 3 times higher than the baseline level. In 1 patient there was a 50% reduction in the triglyceride level during coadministration, and in another patient the triglyceride levels remained unchanged.

At the end of the study period, 6 patients had died (Table 5), 3 of whom were receiving both sirolimus and voriconazole at the time of death. Autopsies were performed in 3 patients (50%). Two patients in whom the sirolimus and tacrolimus doses were not adjusted died. Death was attributed to tacrolimus-associated TMA complicated by posterior leukoencephalopathy and subarachnoid hemorrhage in patient 11. Patient 10 died from complications of catheter-related methicillin-resistant Staphylococcus aureus (MRSA) sepsis and coagulopathy. At autopsy, his lungs exhibited multifocal consolidation on gross examination that was interpreted as consistent with a panlobular bronchopneumonia, but microscopic examination revealed diffuse mild fibrinous exudates, diffuse (but patchy) acute alveolar hemorrhage, and bronchial mucus plugging. Three patients died from bacterial or viral infectious complications, and 1 patient died from veno-occlusive disease of the liver with hepatorenal syndrome (Table 5). No patient died of IFI.

Table 5. Outcomes and Death-Related Data

HSCT indicates hematopoietic stem cell transplantation; DAD/ARDS, diffuse alveolar damage/acute respiratory distress syndrome; CMV, cytomegalovirus; VOD, veno-occlusive disease; MRSA, methicillin-resistant Staphylococcus aureus; TMA, thrombotic microangiopathy; SRL, sirolimus; VCZ, voriconazole; NOS, not otherwise specified.

Back to Article Outline

Discussion 

We report the coadministration of sirolimus and voriconazole in HSCT recipients in whom a strategy of 90% sirolimus dose reduction at the time of initiation of voriconazole was safe and well tolerated. The empiric dose reduction was based on changes in the sirolimus area under the plasma concentration-time curve and peak plasma concentration observed in healthy volunteers with coadministration of voriconazole [12]. Empirically reducing the sirolimus dose to 10% during concomitant voriconazole administration kept sirolimus levels near prevoriconazole levels.

There was no obvious increase in adverse effects with either sirolimus or voriconazole during coadministration for patients with an empiric 90% sirolimus reduction. The regimen was well tolerated for up to 100 days, and most patients received >30 days of both medications.

To date, there is only 1 well-documented report of sirolimus-voriconazole coadministration in 2 renal allograft recipients. Sirolimus dose reductions of 75% to 87.5% were required to achieve target concentrations [16]. However, in both of these cases, the dose reduction was made after coadministration in response to increased sirolimus levels. The overall reduction required was then determined by comparing the prevoriconazole dose with the sirolimus dose that produced levels within the target range. No serious adverse effects were noted during coadministration.

In 1 patient without empiric sirolimus dose reduction in our series, whose death was attributed to MRSA bacteremia with septic embolization to the lungs, an unusual pattern of diffuse alveolar hemorrhage was found at autopsy. There are several reports of sirolimus-associated lung injury in solid organ transplant recipients [17, 18, 19, 20]. Most cases have been associated with a syndrome of interstitial pneumonitis that resolved with the withdrawal of sirolimus. In the few cases in which lung biopsies were performed [17], a spectrum of findings have been described, including diffuse alveolar damage, bronchiolitis obliterans with organizing pneumonia, and pulmonary hemorrhage [21]; no clear association with increased sirolimus levels has been made. Whether increased sirolimus levels contributed to the pulmonary findings in our patient is possible but hard to prove given the synchronous MRSA bacteremia and septic emboli.

In our series, 4 patients did not have any tacrolimus dose adjustment at the time of voriconazole initiation, and 1 of these patients had severe tacrolimus-associated TMA. The interaction between azoles and calcineurin inhibitors is well documented [22, 23]. All systemic azole drugs currently used in transplantation (fluconazole, itraconazole, and voriconazole) inhibit several CYP isoenzymes, especially CYP3A4, which is the main system used for cyclosporine and tacrolimus metabolism, thus reliably increasing their levels. Calcineurin dose adjustments must always be considered when antifungal therapy is initiated and discontinued, to minimize the risk of calcineurin toxicity or the development of GVHD or organ rejection. Initial reductions to at least one third to one half of the preazole administration dose and frequent drug level measurements during the antifungal transition periods (both at initiation and discontinuation) are recommended [24].

In addition, azole antifungal drugs are known to inhibit intestinal P-glycoprotein [25], which may enhance the oral bioavailability of calcineurin inhibitors [25] and sirolimus [26]. The patients in this series received sirolimus and voriconazole together to facilitate patient adherence. The effect of nonsynchronous administration of these drugs on the absorption and levels of sirolimus has not been described but could potentially lead to an empiric dose adjustment of sirolimus different from the 90% reduction reported.

Although this experience is relatively small, it supports that sirolimus and voriconazole can be safely coadministered with an appropriate sirolimus dose reduction and drug level monitoring. An initial empiric 90% sirolimus dose reduction seems adequate, but more frequent sirolimus trough level determinations should be performed at the time of initiation of voriconazole. A prospective evaluation of this strategy should be conducted to confirm that patients may receive both medications safely when clinically required.

Back to Article Outline

Acknowledgments 

We thank Danny A. Milner, MD, for his review of the pertinent pathologic specimens. Supported in part by National Heart, Lung and Blood Institute grant no. HL070149.

Back to Article Outline

References 

1. Cutler C , Antin JH . Sirolimus for GVHD prophylaxis in allogeneic stem cell transplantation . Bone Marrow Transplant . 2004;34:471–476
   • View In Article
   • MEDLINE
   • CrossRef
2. MacDonald AS . Rapamycin in combination with cyclosporine or tacrolimus in liver, pancreas, and kidney transplantation . Transplant Proc . 2003;35(3 suppl):201S–208S
   • View In Article
   • MEDLINE
3. Antin JH , Kim HT , Cutler C , et al.   Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation . Blood . 2003;102:1601–1605
   • View In Article
   • MEDLINE
   • CrossRef
4. Cutler C , Kim HT , Hochberg E , et al.   Sirolimus and tacrolimus without methotrexate as graft-versus-host disease prophylaxis after matched related donor peripheral blood stem cell transplantation . Biol Blood Marrow Transplant . 2004;10:328–336
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (211 KB)
   • CrossRef
5. Marty FM , Lee SJ , Fahey MM , et al.   Infliximab use in patients with severe graft-versus-host disease and other emerging risk factors of non-Candida invasive fungal infections in allogeneic hematopoietic stem cell transplant recipients (a cohort study) . Blood . 2003;102:2768–2776
   • View In Article
   • MEDLINE
   • CrossRef
6. Singh N , Paterson DL . Aspergillus infections in transplant recipients . Clin Microbiol Rev . 2005;18:44–69
   • View In Article
   • MEDLINE
   • CrossRef
7. Marr KA , Carter RA , Crippa F , Wald A , Corey L . Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients . Clin Infect Dis . 2002;34:909–917
   • View In Article
   • CrossRef
8. Herbrecht R , Denning DW , Patterson TF , et al.   Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis . N Engl J Med . 2002;347:408–415
   • View In Article
   • CrossRef
9. Center for Drug Evaluation and Research, Food and Drug Administration . NDA 21-266 and 21-267, Vfend™⃝ (voriconazole) . 2002; May 24. Available at: http://www.fda.gov/cder/foi/appletter/2002/21266ltr.pdf. Accessed August 21, 2005
   • View In Article
10. Perfect JR , Marr KA , Walsh TJ , et al.   Voriconazole treatment for less-common, emerging, or refractory fungal infections . Clin Infect Dis . 2003;36:1122–1131
    • View In Article
    • CrossRef
11. Product Information (Vfend(R), Voriconazole) . New York: Pfizer Inc; 2005;
    • View In Article
12. Abel S , Allan R , Fielding A . Effect of voriconazole on the pharmacokinetics of sirolimus (poster) . 12th European Congress of Clinical Microbiology and Infectious Diseases . 2002; April 24-27, Milan, Italy
    • View In Article
13. Ascioglu S , Rex JH , de Pauw B , et al.   Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants (an international consensus) . Clin Infect Dis . 2002;34:7–14
    • View In Article
    • CrossRef
14. Ho VT , Cutler C , Carter S , et al.   Blood and marrow transplant clinical trials network toxicity committee consensus summary (thrombotic microangiopathy after hematopoietic stem cell transplantation) . Biol Blood Marrow Transplant . 2005;11:571–575
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (99 KB)
    • CrossRef
15. Cutler C , Henry NL , Magee C , et al.   Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation . Biol Blood Marrow Transplant . 2005;11:551–557
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (125 KB)
    • CrossRef
16. Mathis AS , Shah NK , Friedman GS . Combined use of sirolimus and voriconazole in renal transplantation (a report of two cases) . Transplant Proc . 2004;36:2708–2709
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (68 KB)
    • CrossRef
17. Garrean S , Massad MG , Tshibaka M , Hanhan Z , Caines AE , Benedetti E . Sirolimus-associated interstitial pneumonitis in solid organ transplant recipients . Clin Transplant . 2005;19:698–703
    • View In Article
    • MEDLINE
    • CrossRef
18. Morelon E , Stern M , Israel-Biet D , et al.   Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients . Transplantation . 2001;72:787–790
    • View In Article
    • MEDLINE
    • CrossRef
19. Morelon E , Stern M , Kreis H . Interstitial pneumonitis associated with sirolimus therapy in renal-transplant recipients . N Engl J Med . 2000;343:225–226
    • View In Article
    • MEDLINE
    • CrossRef
20. Singer SJ , Tiernan R , Sullivan EJ . Interstitial pneumonitis associated with sirolimus therapy in renal-transplant recipients . N Engl J Med . 2000;343:1815–1816
    • View In Article
    • MEDLINE
    • CrossRef
21. Vlahakis NE , Rickman OB , Morgenthaler T . Sirolimus-associated diffuse alveolar hemorrhage . Mayo Clin Proc . 2004;79:541–545
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (89 KB)
    • CrossRef
22. Tintillier M , Kirch L , Goffin E , Cuvelier C , Pochet JM . Interaction between voriconazole and tacrolimus in a kidney-transplanted patient . Nephrol Dial Transplant . 2005;20:664–665
    • View In Article
    • MEDLINE
    • CrossRef
23. Venkataramanan R , Zang S , Gayowski T , Singh N . Voriconazole inhibition of the metabolism of tacrolimus in a liver transplant recipient and in human liver microsomes . Antimicrob Agents Chemother . 2002;46:3091–3093
    • View In Article
    • MEDLINE
    • CrossRef
24. Piscitelli SC , Rodvold K . Drug Interactions in Infectious Diseases . 2nd ed.. Totowa, NJ: Humana Press; 2005;
    • View In Article
25. Yasuda K , Lan LB , Sanglard D , Furuya K , Schuetz JD , Schuetz EG . Interaction of cytochrome P450 3A inhibitors with P-glycoprotein . J Pharmacol Exp Ther . 2002;303:323–332
    • View In Article
    • MEDLINE
    • CrossRef
26. Paine MF , Leung LY , Lim HK , et al.   Identification of a novel route of extraction of sirolimus in human small intestine (roles of metabolism and secretion) . J Pharmacol Exp Ther . 2002;301:174–186
    • View In Article
    • MEDLINE
    • CrossRef