Safety of Anidulafungin in Solid Organ Transplant Recipients

Transcription

1 LIVER TRANSPLANTATION 18: , 2012 ORIGINAL ARTICLE Safety of Anidulafungin in Solid Organ Transplant Recipients J.M. Aguado, 1 E. Varo, 2 P. Usetti, 3 J.C. Pozo, 4 A. Moreno, 5 M. Catalan, 1 O. Len, 6 M. Blanes, 7 A. Sole, 7 P. Mu~noz, 8 M. Montejo, 9 and the TOSCANA Study Group 1 12 de Octubre University Hospital, Madrid, Spain; 2 Central University Hospital, Santiago de Compostela, Spain; 3 Puerta de Hierro University Hospital, Madrid, Spain; 4 Reina Sofía University Hospital, C ordoba, Spain; 5 Hospital Clinic, Barcelona, Spain; 6 Vall d Hebron University Hospital, Barcelona, Spain; 7 La Fe University Hospital, Valencia, Spain; 8 Gregorio Mara~n on University Hospital, Madrid, Spain; and 9 Cruces University Hospital, Bilbao, Spain The aim of this study was the evaluation of the safety of anidulafungin in adult solid organ transplantation (SOT) recipients. During the study period (14 months), we included all consecutive SOT recipients from 14 centers who received anidulafungin for at least 48 hours for the treatment of invasive fungal infections (IFIs) or as prophylaxis. Relevant clinical and analytical information on clinical charts was reviewed. Clinical side effects, liver function tests, and serum creatinine levels were assessed at least weekly. The need for the modification of immunosuppressive drugs was also recorded by the investigators. All patients were followed for at least 1 week after the end of treatment (EOT) or until death. Eighty-six SOT recipients were evaluated (56 transplant recipients, 20 lung transplant recipients, 8 kidney transplant recipients, and 2 heart transplant recipients). Sixty-two patients (72%) received anidulafungin for prophylaxis, and 24 (28%) received anidulafungin for the treatment of IFIs [candidemia/invasive candidiasis (16) or invasive aspergillosis (8)]. At the baseline, only 5% of the patients were neutropenic (<500 neutrophils/ml). There was no need for the modification of immunosuppressive drug doses because of anidulafungin therapy. No patient discontinued anidulafungin because of severe adverse effects. While receiving anidulafungin, 1 patient developed mild liver toxicity, but the liver function normalized without the discontinuation of anidulafungin. At EOT, the median serum creatinine, aspartate aminotransferase, and alanine aminotransferase levels were significantly lower than the baseline levels, even in liver transplant recipients and patients who had higher baseline levels of serum creatinine. In conclusion, these results show that anidulafungin is a well-tolerated drug in SOT recipients. Liver Transpl 18: , VC 2012 AASLD. Received December 10, 2011; accepted January 30, Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; EOT, end of treatment; GGT, gammaglutamyltransferase; IFI, invasive fungal infection; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase; SOT, solid organ transplantation. Jose María Aguado and Evaristo Varo participated in the research design. Jose María Aguado, Evaristo Varo, Juan C. Pozo, Oscar Len, Mercedes Catalan, and Patricia Mu~noz participated in the writing of this article. All the authors participated in the performance of the research. The other investigators were V. Jerez (Infanta Cristina University Hospital, Badajoz, Spain), A. Sole (La Fe Hospital Universitario, Valencia, Spain), C. Aragon (Carlos Haya University Hospital, Malaga, Spain), N. Fernandez-Sabe (Bellvitge University Hospital, Barcelona, Spain), J. L. del Pozo (University Clinic of Navarra, Pamplona, Spain), J. C. Robles (Reina Sofía University Hospital, Cordoba, Spain), J. C. Montejo (12 de Octubre University Hospital, Madrid, Spain), Maricela Valerio and Emilio Bouza (Gregorio Mara~non University Hospital, Madrid, Spain), S. Fernandez (Carlos Haya University Hospital, Malaga, Spain), I. Ba~nos (Puerta de Hierro University Hospital, Madrid, Spain), J. Segovia (Puerta de Hierro University Hospital, Madrid, Spain), and T. Rey (University Hospital Clinic, Santiago de Compostela, Spain). This study was funded by an unrestricted medical grant from Pfizer Laboratories of Spain. Potential Conflicts of Interest: Dr. Blanes is on the speakers bureau for Merck, Astellas, and Pfizer. Address reprint requests to J.M. Aguado, M.D., 12 de Octubre University Hospital, Avenida Andalucía, Km 5400, Madrid, Spain Telephone: þ , extension 1712; FAX: þ ; jaguadog@medynet.com DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2012 American Association for the Study of Liver Diseases.

2 LIVER TRANSPLANTATION, Vol. 18, No. 6, 2012 AGUADO ET AL. 681 Invasive fungal infections (IFIs) are associated with a high mortality rate for recipients of solid organ transplantation (SOT). 1,2 Although most IFIs are due to Candida species, the risk and severity of invasive aspergillosis in SOT recipients are well known, 3 with mortality rates greater than 90%. 1 Antifungal prophylaxis is generally required for high-risk SOT recipients, but drug-related toxicity is an important limitation of some antifungals (amphotericin B and azoles). In a recently published study, the Spanish Transplantation Infection Study Group reported that caspofungin was useful as prophylaxis against IFIs in high-risk liver transplant recipients. 4 However, the concomitant use of cyclosporine A and caspofungin was associated with transient elevations of serum aminotransferases, and caspofungin had to be discontinued in 6 of 71 patients (8.45%) because of toxicity. Anidulafungin has potent in vitro activity against Candida and Aspergillus species, 5,6 and a good safety profile has been demonstrated. 7,8 A unique attribute of anidulafungin is that it is eliminated almost exclusively through biotransformation by slow chemical degradation without hepatic metabolism or renal elimination. 9 Thus, anidulafungin does not require dosage adjustments in patients with renal or hepatic dysfunction. 9 Because anidulafungin does not interact significantly with the cytochrome P450 isoenzymes, no specific drug interactions have been detected with cyclosporine A or tacrolimus. 10,11 Anidulafungin, therefore, may have unique beneficial effects with respect to other antifungals in SOT recipients. The aim of this study was to evaluate the safety of anidulafungin in SOT recipients who received this drug for the treatment of IFIs or as prophylaxis. PATIENTS AND METHODS Study Objectives The primary objective of this study was to evaluate the frequency of adverse events related to anidulafungin and the proportion of patients requiring the discontinuation of this drug because of adverse effects. The secondary objectives included evaluations of (1) the number of rejection or graft loss episodes related to the simultaneous use of anidulafungin and antirejection drugs and (2) the need for changing doses of calcineurin inhibitor agents while patients were receiving anidulafungin. Study Design This was an observational, retrospective, multicenter, noncomparative, open-label study. The study was performed at 14 tertiary hospitals in Spain. The protocol was approved by the institutional review board of the 12 de Octubre University Hospital (Madrid, Spain). All consecutive SOT recipients who received anidulafungin for at least 48 hours for the treatment of IFIs or as prophylaxis between April 2008 and June 2009 were included in the study. Relevant clinical and analytical information on clinical charts was revised and collected through an electronic case report form. All authors had free access to the Web and study data. An independent data safety monitoring board oversaw the study. Patients were followed for at least 1 week after the end of treatment (EOT) with anidulafungin or until death. Overall clinical assessments, including demographic data, comorbid conditions, transplant types, vital signs, X-ray studies, other simultaneously administered medications, IFI characteristics, laboratory blood tests (complete blood counts, liver function tests, and serum creatinine levels), rejection episodes, allograft losses, and patient outcomes, were made at study entry, on anidulafungin therapy days 2, 4, 7, 10, and 14, and weekly if the treatment was prolonged for more than 14 days until EOT. An additional clinical and laboratory safety evaluation was performed 7 days after the end of anidulafungin administration (posttherapy follow-up). A medication history specific to organ transplantation was taken at the baseline and was updated throughout the study s drug administration period. This included (1) the primary immunosuppressive agent (eg, tacrolimus or cyclosporine A), (2) the use of antimetabolites (eg, azathioprine or mycophenolate mofetil), (3) the use of corticosteroids (including the dosage), and (4) modifications of immunosuppressive therapy. Patients with IFIs (candidiasis, aspergillosis, or infections by other fungi) were classified as probable or proven according to the revised consensus criteria of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group. 12,13 Rejection was defined as either biopsy-proven rejection or a clinical event compatible with rejection for which the patient received augmented immunosuppression. Inclusion and Exclusion Criteria All SOT (kidney, liver, heart, and lung) recipients more than 18 years old who had received at least 48 hours of treatment with anidulafungin (at least a loading dose of 200 mg given intravenously followed by at least 1 dose of 100 mg) were considered for inclusion in the study. Anidulafungin doses were the same for treatment and prophylaxis. Patients with a life expectancy of less than 72 hours were excluded from the study. Safety Evaluation The main safety analysis considered the proportion of SOT recipients who developed a serious adverse effect related to anidulafungin during therapy. Serious adverse effects were defined with the US Food and Drug Administration MedWatch form. 14 A serious adverse effect was any adverse event (without respect to causality) that was life-threatening or resulted in any of the following outcomes: death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, or a

3 682 AGUADO ET AL. LIVER TRANSPLANTATION, June 2012 TABLE 1. Baseline Demographics and Clinical Characteristics of the Patients (n 5 86) Characteristic Value Male sex [n (%)] 53 (61.6) Age (years)* 52 (21-73) Weight (kg)* 70 (45-115) Type of SOT [n (%)] Liver 56 (65.1) Lung 20 (23.2) Kidney 8 (9.3) Heart 2 (2.3) Immunosuppression therapy [n (%)] Cyclosporine A 18 (21.0) Tacrolimus 58 (67.4) Corticosteroids 75 (87.2) Mycophenolate 41 (47.7) Azathioprine 7 (8.1) Sirolimus 5 (5.8) Everolimus 5 (5.8) Monoclonal anti interleukin-2 23 (26.7) receptor antagonists Admission to intensive care unit [n (%)] 57 (66.3) Mechanical ventilation [n (%)] 31 (36.0) Renal insufficiency [n (%)] Serum creatinine > 1.5 mg/dl 28 (32.6) Serum creatinine > 0.7 mg/dl 66 (76.7) Renal replacement technique [n (%)] 20 (23.3) Hemodialysis 5 (5.8) Peritoneal dialysis 1 (1.2) Other (including hemofiltration) 14 (16.3) Hepatic insufficiency [n (%)] SGOT SGPT > 200 U/L 23 (26.7) Bilirubin > 2 mg/dl 44 (51.2) Leukocyte count < (4.6) neutrophils/ml [n (%)] *The data are presented as means and ranges. Regimen when anidulafungin was initiated. Some patients fulfilled more than 1 condition. congenital anomaly or birth defect. Any other medical event that, in the medical judgment of the investigator, might jeopardize the subject or require medical or surgical intervention for preventing one of the listed outcomes was also considered a serious adverse effect. Statistical Analysis We performed a descriptive analysis of all variables and analyzed the qualitative variables by absolute and relative frequencies, whereas quantitative variables were studied with means, standard deviations, and confidence intervals if they followed a normal distribution or with medians, minima, maxima, and ranges if they did not follow a Gaussian distribution. In order to determine whether statistically significant differences could be found between quantitative variables with paired observations, we used Student t test for paired data if parametric assumptions were fulfilled or the sign test otherwise. Estimates were made with a confidence level of 95%; the statistical package SPSS 17.0 (or a later version) was used. RESULTS During the study period (14 months), 90 patients were enrolled. Four patients were later excluded because they were treated with anidulafungin for less than 48 hours (2 patients) or were less than 18 years old (2 patients). The final population consisted of 86 patients. Table 1 shows the baseline clinical characteristics of these patients. Most patients were male. The mean age of the patients enrolled in the study was 52 years (range ¼ years). The transplanted organs were livers [56 (65.1%)], lungs [20 (23.2%)], kidneys [8 (9.3%)], and hearts [2 (2.3%)]. Most patients received tacrolimus and corticosteroids as immunosuppressive therapy; mycophenolate was also administered to 47.7% of the patients. Comorbidity factors such as diabetes mellitus and ischemic heart disease were frequently noted in the study population. Most patients (66.3%) were admitted to the intensive care unit, and 36.0% required mechanical ventilatory assistance. Only 4.6% of the patients were neutropenic (<500 neutrophils/ml) at the time of their inclusion in the study; 23.3% of the patients required renal replacement while they were receiving anidulafungin. TABLE 2. Evolution of Selected Baseline Laboratory Parameters Before Anidulafungin Therapy and During the Posttherapy Follow-Up (Final) Period Parameter Median* Baseline Final P Value (Baseline Versus Final) Bilirubin (mg/dl) 2.14 ( ) 1.40 ( ) 0.14 ALT (U/L) ( ) ( ) <0.05 AST (U/L) ( ) ( ) <0.05 GGT (U/L) ( ) ( ) 0.30 Alkaline phosphatase (U/L) ( ) ( ) 0.08 Creatinine (mg/dl) 1.30 ( ) 0.90 ( ) <0.05 *The 25th and 75th percentiles are shown in parentheses. The median follow-up was 23.6 days (range ¼ 9-68 days).

4 LIVER TRANSPLANTATION, Vol. 18, No. 6, 2012 AGUADO ET AL. 683 Figure 1. Evolution of tran saminase levels during anidu lafungin administration and follow-up in the general SOT population and liver transplant recipients: (A) ALT/SGOT in the general SOT population, (B) ALT/SGOT in liver transplant recipients, (C) AST/SGPT in the general SOT population, and (D) AST/SGPT in liver transplant recipients. Anidulafungin was started at a mean of 359 days (range ¼ days) after transplantation. The mean duration of treatment was 16.6 days (range ¼ 2-61 days). Thirty-nine patients (45.3%) received anidulafungin for more than 14 days, 28 (32.6%) received anidulafungin for 7 to 14 days, and 19 patients (22.1%) received less than 7 days of treatment. The indications for anidulafungin therapy were prophylaxis against IFIs in 62 high-risk patients (72%) and the treatment of IFIs (probable or proven) in 24 patients (28%). Anidulafungin prophylaxis was administered for at least 7 days. The duration of treatment with anidulafungin varied and depended on the patient s condition. Liver Side Effects At the baseline, 26.7% and 51.2% of patients presented with any grade of elevation of hepatic enzymes [aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT)] and bilirubin levels, respectively. Table 2 illustrates the evolution of select laboratory parameters

5 684 AGUADO ET AL. LIVER TRANSPLANTATION, June 2012 Figure 2. Evolution of serum creatinine levels during treatment with anidulafungin: (A) the general SOT population and (B) patients with baseline serum creatinine levels > 1.5 mg/dl. TABLE 3. Evolution of Tacrolimus Blood Levels During Anidulafungin Therapy Mean 6 standard deviation Median (interquartile interval) Baseline (n ¼ 19) Day 2 (n ¼ 17) Day 4 (n ¼ 17) Day 7 (n ¼ 15) Tacrolimus Blood Level (ng/ml) Day 10 (n ¼ 15) Day 14 (n ¼ 15) ( ) 7.30 ( ) 6.10 ( ) 9.60 ( ) 8.60 ( ) 9.30 ( ) during anidulafungin therapy from the initial (baseline) evaluation to the posttherapy (final) evaluation. The AST/SGOT and ALT/SGPT levels decreased during the treatment course. No significant changes were observed during the anidulafungin treatment period in alkaline phosphatase, gamma-glutamyltransferase (GGT), or bilirubin levels. ALT/SGOT and AST/SGPT levels remained stabilized during the administration of anidulafungin in the general population (Fig. 1A,C) and in liver transplant recipients (Fig. 1B,D). While receiving anidulafungin, only 1 patient developed mild liver toxicity (less than twice the baseline values of ALT/AST), but the liver function normalized without the discontinuation of anidulafungin. Renal Side Effects Twenty-eight patients (32.6%) had a serum creatinine level higher than 1.5 mg/dl when the treatment with anidulafungin was initiated. No significant changes in serum creatinine levels were observed during the administration of anidulafungin (Table 2). In fact, we observed a continuous reduction of serum creatinine levels during this time in the general population (Fig. 2A). A decrease in the serum creatinine levels was also observed in patients with higher baseline levels of creatinine (>1.5 mg/ml; Fig. 2B). Other Adverse Effects Anidulafungin did not have to be prematurely discontinued in any patient because of serious clinical or laboratory adverse events or because of interference with immunosuppressive drugs. No modifications of tacrolimus, cyclosporine, or mycophenolate mofetil levels were required during anidulafungin administration. Adequate blood levels of immunosuppressive drugs were achieved during treatment with anidulafungin, as shown in Table 3 for tacrolimus. There was no episode of rejection or graft loss related to the simultaneous use of anidulafungin and antirejection drugs. Overall, 6 patients (7%) died during the study period. Two patients died because of IFIs during anidulafungin administration (disseminated aspergillosis in one case and disseminated zygomycosis in the other case). These deaths were not related to anidulafungin toxicity.

6 LIVER TRANSPLANTATION, Vol. 18, No. 6, 2012 AGUADO ET AL. 685 DISCUSSION The precise safety profile of anidulafungin in SOT recipients is not well known. We hypothesized that because interactions between anidulafungin and immunosuppressive drugs have not been reported 15 and the metabolism of anidulafungin is not affected by changes in liver or renal function, 10,11 anidulafungin would be better tolerated and would be at least as useful as other systemic antifungal drugs in SOT recipients. To our knowledge, this is the first study to date designed primarily to evaluate the safety of anidulafungin in SOT recipients. The present study shows that anidulafungin is generally safe and well tolerated in SOT recipients. There was no need to discontinue the use of anidulafungin in any patient because of severe adverse effects. In particular, there were no cases of severe hepatotoxicity directly attributable to the use of anidulafungin. Transaminases (AST/SGOT and ALT/SGPT) remained stable or decreased during the administration of anidulafungin, and there were no differences in the grade of alteration of hepatic enzymes in liver transplant patients versus other SOT recipients (Fig. 1). The use of anidulafungin was associated with an increase in liver enzyme levels (less than twice the baseline values) in 1 patient, but his liver enzymes returned to normal levels even though he continued to receive anidulafungin for 14 days. Alkaline phosphatase and GGT levels slightly increased during the administration of anidulafungin (Table 2). This occurred especially in patients receiving parenteral nutrition or in the context of early posttransplant hemodynamic changes, which typically lead to significant alterations of laboratory parameters in the absence of other causes of toxicity. Treatment was not discontinued for this reason in any patient. There was no episode of renal failure directly attributable to anidulafungin use. In general, serum creatinine levels decreased significantly during treatment even in patients with poorer renal function at the onset of treatment (Fig. 2). Among patients on hemofiltration, anidulafungin was well tolerated, and there was no need to change doses in any patient. Importantly, there was no need to change the doses of immunosuppressive drugs while patients were receiving anidulafungin, and there were no episodes of acute rejection or graft loss due to the pharmacological interference of anidulafungin with these drugs. In particular, the concomitant use of cyclosporine A and anidulafungin (unlike caspofungin 4 ) was not associated with transient elevations of serum aminotransferases. Anidulafungin was generally safe and well tolerated during concomitant tacrolimus administration, and anidulafungin did not appear to have any significant impact on tacrolimus blood levels. In conclusion, the results of this study show that anidulafungin is well tolerated in SOT recipients who receive the drug as antifungal prophylaxis or for the treatment of IFIs. REFERENCES 1. Pappas PG, Alexander BD, Andes DR, Hadley S, Kauffman CA, Freifeld A, et al. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANS- NET). Clin Infect Dis 2010;50: Singh N, Paterson DL. Aspergillus infections in transplant recipients. Clin Microbiol Rev 2005;18: Paterson DL, Singh N. Invasive aspergillosis in transplant recipients. Medicine (Baltimore) 1999;78: Fortun J, Martín-Davila P, Montejo M, Mu~noz P, Cisneros JM, Ramos A, et al.; for GESITRA Study Group. Prophylaxis with caspofungin for invasive fungal infections in high-risk liver transplant recipients. Transplantation 2009;87: Serrano Mdel C, Valverde-Conde A, Chavez MM, Bernal S, Claro RM, Peman J, et al. In vitro activity of voriconazole, itraconazole, caspofungin, anidulafungin (VER002, LY303366) and amphotericin B against Aspergillus spp. Diagn Microbiol Infect Dis 2003;45: Marco F, Pfaller MA, Messer SA, Jones RN. Activity of MK-0991 (L-743,872), a new echinocandin, compared with those of LY and four other antifungal agents tested against blood stream isolates of Candida spp. Diagn Microbiol Infect Dis 1998;32: Vazquez JA, Sobel JD. Anidulafungin: a novel echinocandin. Clin Infect Dis 2006;43: Menichetti F. Anidulafungin, a new echinocandin: effectiveness and tolerability. Drugs 2009;69(suppl 1): Cleary JD. Echinocandins: pharmacokinetic and therapeutic issues. Curr Med Res Opin 2009;25: Dowell JA, Stogniew M, Krause D, Henkel T, Weston IE. Assessment of the safety and pharmacokinetics of anidulafungin when administered with cyclosporine. J Clin Pharmacol 2005;45: DowellJA,StogniewM,KrauseD,HenkelT,DamleB. Lack of pharmacokinetic interaction between anidulafungin and tacrolimus. J Clin Pharmacol 2007;47: De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al.; for European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008;46: Segal BH, Herbrecht R, Stevens DA, Ostrosky-Zeichner L, Sobel J, Viscoli C, et al. Defining responses to therapy and study outcomes in clinical trials of invasive fungal diseases: Mycoses Study Group and European Organization for Research and Treatment of Cancer consensus criteria. Clin Infect Dis 2008;47: U.S. Food and Drug Administration. MedWatch: the FDA safety information and adverse event reporting program. htm. Accessed January Steinbach WJ, Singh N, Miller JL, Benjamin DK Jr, Schell WA, Heitman J, Perfect JR. In vitro interactions between antifungals and immunosuppressants against Aspergillus fumigatus isolates from transplant and nontransplant patients. Antimicrob Agents Chemother 2004; 48: