Title: Effects of Isavuconazole on the Plasma Concentrations of Tacrolimus among Solid Organ

Transcription

1 AAC Accepted Manuscript Posted Online 3 July 2017 Antimicrob. Agents Chemother. doi: /aac Copyright 2017 American Society for Microbiology. All Rights Reserved Title: Effects of Isavuconazole on the Plasma Concentrations of Tacrolimus among Solid Organ Transplant Patients Authors: 1. Ryan M Rivosecchi 1 2. Cornelius J Clancy 2,3,4 3. Ryan K Shields 2, 3 4. Christopher R Ensor 1,5 5. Michael A Shullo 1,5 6. Bonnie A Falcione 1,5 7. Raman Venkataramanan 6,7 8. # M. Hong Nguyen 2,3 Affiliations: 1. Department of Pharmacy & Therapeutics, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 2. Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 3. XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 4. VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 5. Department of Pharmacy & Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania 6. Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania 7. Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania Corresponding Author: M. Hong Nguyen Professor of Medicine Director, Transplant Infectious Diseases and Antimicrobial Management Program University of Pittsburgh, ID Division 3550 Fifth Avenue, Suite S872 Scaife Hall Pittsburgh, PA nguyenh@dom.pitt.edu 31 Running Title: Isavuconazole interaction with tacrolimus 32

2 2 33 Abbreviations: 34 Cytochrome P450: CYP 35 Intravenous: IV 36 Invasive fungal infections: IFI 37 Interquartile: IQ 38 Model of End-Stage Liver Disease: MELD 39 Pharmacokinetic: PK 40 Solid organ transplant: SOT Tacrolimus concentration to dose ratio: C/D University of Pittsburgh Medical Center: UPMC Downloaded from on April 8, 2018 by guest

3 3 44 Abstract We evaluated the interaction between isavuconazole and tacrolimus among 55 organ transplant recipients. After isavuconazole discontinuation, tacrolimus concentration/dose normalized by weight (C/D) was reduced by 16%. Liver transplant recipients experienced the largest C/D reduction. A 1.3-fold decrease in tacrolimus daily dose was required to maintain desired tacrolimus levels. There was considerable inter-patient variability in the magnitude of the drug interaction. Tacrolimus doses should not be adjusted uniformly, but rather guided by therapeutic drug monitoring. Downloaded from on April 8, 2018 by guest

4 Antifungal prophylaxis is commonly administered following solid organ transplant (SOT) to prevent invasive fungal infections.(1) Tacrolimus, a primary immunosuppressive agent in SOT, is a substrate of cytochrome P450 (CYP) 3A4. The triazole antifungals are inhibitors of CYP3A4, which have varying effects on tacrolimus metabolism.(2, 3) The manufacturers of voriconazole and posaconazole recommend an empiric 1/3 reduction in the daily tacrolimus dose; however in clinical practice, the required reduction is often substantially greater.(4, 5) Isavuconazole acts as both a substrate and inhibitor of CYP3A4.(6-8) Currently, there are no definitive dosing recommendations for tacrolimus in patients receiving isavuconazole. Following a cluster of mucormycosis cases among SOT recipients at the University of Pittsburgh Medical Center (UPMC), universal isavuconazole prophylaxis was instituted [Table 1]. The objective of this study was to evaluate the effects of isavuconazole on whole blood trough tacrolimus concentrations in various SOT populations. We performed a retrospective study of consecutive patients who underwent SOT at UPMC between September 15, 2015 and February 10, 2016, and who were initiated on isavuconazole prophylaxis for 21 days. Patients were required to receive tacrolimus, have follow-up for 40 days after isavuconazole was stopped, and have whole blood tacrolimus concentrations measured during and following isavuconazole prophylaxis. Patients were excluded if they were on tacrolimus or other azoles at the time of transplantation, or required renal replacement therapy beyond the first 5 days after transplantation Fifty-five SOT recipients were included [Table 2]. Tacrolimus levels were obtained during (n=1,098) or following (n=3,080) isavuconazole prophylaxis. Tacrolimus

5 concentration/dose (C/D) ratios were normalized for body weight, and calculated by: [tacrolimus trough level/(total tacrolimus daily dose/actual body weight)].(9) While on isavuconazole, the median tacrolimus C/D was highest on day 4, reflecting the effects of isavuconazole loading doses [Figure 1]. C/D stabilized by day 8. The median tacrolimus C/D was higher among liver recipients than other organ recipients (p=0.002). C/D distributions showed wide variations within each of the transplant groups [Table 2]. After discontinuation of isavuconazole, median tacrolimus C/D gradually decreased, and stabilized at approximately 28 days [Figure 1]. In comparing tacrolimus C/D while on and off isavuconazole, ratios were considered at days 8 to 21 and days 28 to 60, respectively; these time points were selected based on our data above data [Figure 1], and to account for the prolonged half-life of isavuconazole (~80 to 100 hours).(6) Overall, the median tacrolimus C/D was higher on isavuconazole than off (125 and 120 (ng/ml)/(mg/kg), respectively); p=0.037). On a per-patient basis, tacrolimus C/D was reduced by a mean of 13% after isavuconazole discontinuation. Liver transplant recipients experienced the largest per-patient tacrolimus C/D reduction (36% vs. 8% in heart, 3% in lung and 1% in kidney recipients; p=0.047) [Figure 2]. Differences in tacrolimus C/D were not evident between SOT groups off isavuconazole (p=0.59). The median daily tacrolimus doses on and off isavuconazole were 6 and 8 mg, respectively [Table 2]. The corresponding median tacrolimus levels were 11 and 9 µg/ml, respectively. To estimate the potential tacrolimus dose for individual patients after discontinuing isavuconazole, we calculated the estimated tacrolimus daily dose off

6 isavuconazole as: (daily tacrolimus dose while on isavuconazole/(tacrolimus level on isavuconazole*tacrolimus level off isavuconazole)). The calculated value for all patients was 6.1 mg. The ratio of the median actual tacrolimus dose taken by the patients off isavuconazole to the calculated estimated tacrolimus dose was 1.3. In other words, tacrolimus dose was increased by a median of 1.3 fold after isavuconazole was discontinued. Age, race, sex, use of proton pump inhibitor, and liver transplantation were evaluated in univariate analyses to determine the association with tacrolimus C/D. Liver transplant was the only factor that was significantly associated with tacrolimus C/D among patients receiving isavuconazole (p=0.001). This association was no longer present after isavuconazole was discontinued (linear regression p=0.68). We used Model of End-stage Liver Disease (MELD) scores to assess the degree the liver dysfunction among liver transplant patients, and defined liver dysfunction as MELD score >10. The MELD scores for liver transplant patients while on and off isavuconazole were 11 and 7, respectively (p=0.0007). Fifty-six percent (10/18) and 17% (3/18) of liver transplant recipients had MELD scores >10, respectively (p=0.035), while on and off isavuconazole. Results did not differ if C/D ratios were not normalized by weight. To our knowledge, this is the first study that characterizes the interaction between isavuconazole and tacrolimus among SOT recipients. We used a population-based approach to evaluate the impact of isavuconazole on tacrolimus concentrations, which was feasible because of the large number of tacrolimus blood levels. Our results support three important conclusions. First, isavuconazole was associated with small but significant increases in tacrolimus levels among SOT recipients. Second, there was marked inter-patient variability in

7 tacrolimus levels. Finally, the interaction between isavuconazole and tacrolimus was more prominent among liver transplant patients than other SOT recipients Overall, the per-patient tacrolimus C/D was reduced a median of 13%, and the daily median tacrolimus dose to maintain specific tacrolimus levels was increased by 1.3-fold after isavuconazole was discontinued. Groll and colleagues demonstrated a 2.25-fold increase in tacrolimus concentrations when tacrolimus was administered 2 days after isavuconazole loading dose in healthy volunteers.(10) Although both Groll et al. and our study demonstrated that a drug-drug interaction exists between isavuconazole and tacrolimus (presumably through the inhibition of CYP3A4 by isavuconazole), the degree of drug interaction differed. Notably, our analysis was performed with isavuconazole at steady state in contrast to the loading phase in the Groll study; studying the change in tacrolimus C/D while isavuconazole concentrations were at steady-state provided a more accurate depiction of the magnitude of the drug-drug interaction. Moreover, Groll included healthy, young (mean age: 35 years) volunteers who were on no other drugs, whereas our patients were older (mean age: 60 years), critically ill, and within a month of transplant. Our results, combined with the considerable inter-patient variability in the magnitude of the drug interaction,(11) suggest that tacrolimus should not be administered using uniform dose reductions among patients receiving isavuconazole, but rather guided by therapeutic drug monitoring. This conclusion differs from the standard dose reductions that are recommended when initiating or discontinuing voriconazole or posaconazole.(4, 5)

8 Our finding that the interaction between isavuconazole and tacrolimus differed by transplanted organ was novel. Indeed, the 13% decrease in tacrolimus C/D among our entire cohort following discontinuation of isavuconazole was driven largely by a 36% decrease among liver transplant patients; no other organ had a significant difference in tacrolimus C/D after isavuconazole was stopped. If liver transplant patients are removed from the cohort, the perpatient decrease in tacrolimus C/D was only 3%. MELD scores were higher within the first 4 weeks of liver transplantation (while patients were on isavuconazole prophylaxis) than thereafter (p=0.0007), suggesting that abnormal liver function may have accounted for the association with tacrolimus C/D. Indeed, metabolism of isavuconazole and tacrolimus through the CYP3A4 pathway, which is known to exhibit both inter- and intrapatient variability after liver transplantation, was likely impaired during the time the patients were receiving both agents.(12) Isavuconazole clearance is decreased in patients with moderate hepatic dysfunction, leading to a near doubling of half-life after a single dose.(13) Desai and colleagues demonstrated a doubling of mean isavuconazole trough levels in patients with mild or moderate hepatic dysfunction.(14) Of note, the difference in tacrolimus C/D between organs was no longer apparent 8 weeks after liver transplant, which may be attributable to recovery of hepatic function in the liver transplant patients. In the future, studies of isavuconazole pharmacokinetic (PK) following liver transplantation and other SOT are needed Isavuconazole is characterized by a large volume of distribution and prolonged half-life after multiple administrations.(15, 16) In a dose-finding PK study, Schmitt-Hoffmann and colleagues noted a ~4- to 5-fold accumulation factor between the first and final day (day 14 or 21) of isavuconazole administration, and steady-state volume of distribution of 308 to 542

9 liters.(17) Based on a systemic clearance of 2.4 to 4.1 liters/hour in healthy volunteers, effects of isavuconazole would be expected to last for 75 to 226 hours after discontinuation.(17) Our SOT patients had persistently elevated tacrolimus C/D ratios >600 hours after stopping isavuconazole (Figure 1). The differences between our data and those of Schmitt-Hoffmann could be due to the longer course of isavuconazole in this study, with all patients receiving the drug for 1 month. We acknowledge that our results may not be generalizable to patient populations other than SOT recipients, or to SOT recipients at other centers. Since isavuconazole levels were not evaluated, we were unable to determine if differences in isavuconazole concentrations may have been responsible for variations in tacrolimus C/D. In conclusion, the interaction between isavuconazole and tacrolimus is most significant following liver transplantation, and relatively modest following other SOT. However, the impact of isavuconazole on tacrolimus levels varies significantly between individuals undergoing each type of transplant. In our program, we currently recommend against standardized tacrolimus dose reductions. Rather, we advocate close tacrolimus TDM until levels are stable, and such time that isavuconazole levels are likely to have reached steady state (~7 days). Programs should devise their own protocols for tacrolimus therapeutic drug monitoring (TDM) upon initiation of isavuconazole, based on types of organ transplant and local experience. A complete PK analysis, including isavuconazole levels, is warranted to further define drug interactions Acknowledgements. The authors would like to acknowledge the assistance of Lloyd Clark. C. J. C. receives support from the U. S. Department of Veterans Affairs (1IO1BX001955) and National

10 Institutes of Health (AI111037, AI121555, AI126157). R. K. S. (K08AI114883) and M. H. N. (AI107290, AI128338) receive support from the National Institutes of Health. All authors contributed to the design, data collection, analysis, and manuscript preparation Disclosures. This project was funded by investigator-initiated research grants to C. J. C. and M. H. N. from Astellas Pharma, Inc. C. J. C. and M. H. N. have participated in an advisory board for Astellas Pharma, Inc. Downloaded from on April 8, 2018 by guest

11 References 1. Singh N Antifungal prophylaxis in solid-organ transplant recipients: considerations for clinical trial design. Clin Infect Dis 39 Suppl 4:S Nivoix Y, Ubeaud-Sequier G, Engel P, Leveque D, Herbrecht R Drug-drug interactions of triazole antifungal agents in multimorbid patients and implications for patient care. Curr Drug Metab 10: Zhang S, Pillai VC, Mada SR, Strom S, Venkataramanan R Effect of voriconazole and other azole antifungal agents on CYP3A activity and metabolism of tacrolimus in human liver microsomes. Xenobiotica 42: Anonymous. VFend(R)[Package Insert]. Roerig/Pzifer Inc, New York, NY; Accessed 5. Anonymous. Noxafil(R)[Package Insert] Merck & Co, INC., Whitehouse Station, NJ; Accessed 6. Anonymous. Cresemba(R) [Package Insert] Astellas Pharma US, Inc., Northbrook, IL; Marty FM, Ostrosky-Zeichner L, Cornely OA, Mullane KM, Perfect JR, Thompson GR, 3rd, Alangaden GJ, Brown JM, Fredricks DN, Heinz WJ, Herbrecht R, Klimko N, Klyasova G, Maertens JA, Melinkeri SR, Oren I, Pappas PG, Racil Z, Rahav G, Santos R, Schwartz S, Vehreschild JJ, Young JA, Chetchotisakd P, Jaruratanasirikul S, Kanj SS, Engelhardt M, Kaufhold A, Ito M, Lee M, Sasse C, Maher RM, Zeiher B, Vehreschild MJ, Vital, FungiScope Mucormycosis I Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis 16: Maertens JA, Raad, II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, Bow EJ, Rahav G, Neofytos D, Aoun M, Baddley JW, Giladi M, Heinz WJ, Herbrecht R, Hope W, Karthaus M, Lee DG, Lortholary O, Morrison VA, Oren I, Selleslag D, Shoham S, Thompson GR, 3rd, Lee M, Maher RM, Schmitt-Hoffmann AH, Zeiher B, Ullmann AJ Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet 387: Mori T, Aisa Y, Kato J, Nakamura Y, Ikeda Y, Okamoto S Drug interaction between voriconazole and calcineurin inhibitors in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 44: Groll AH, Desai A, Han D, Howieson C, Kato K, Akhtar S, Kowalski D, Lademacher C, Lewis W, Pearlman H, Mandarino D, Yamazaki T, Townsend R Pharmacokinetic Assessment of Drug-Drug Interactions of Isavuconazole With the Immunosuppressants Cyclosporine, Mycophenolic Acid, Prednisolone, Sirolimus, and Tacrolimus in Healthy Adults. Clin Pharmacol Drug Dev doi: /cpdd Kim T, Jancel T, Kumar P, Freeman AF Drug-drug interaction between isavuconazole and tacrolimus: a case report indicating the need for tacrolimus drug-level monitoring. J Clin Pharm Ther doi: /jcpt Thummel KE, Shen DD, Podoll TD, Kunze KL, Trager WF, Bacchi CE, Marsh CL, McVicar JP, Barr DM, Perkins JD, et al Use of midazolam as a human cytochrome P450 3A probe: II. Characterization of inter- and intraindividual hepatic CYP3A variability after liver transplantation. J Pharmacol Exp Ther 271: Schmitt-Hoffmann A, Roos B, Spickermann J, Heep M, Peterfai E, Edwards DJ, Stoeckel K Effect of mild and moderate liver disease on the pharmacokinetics of isavuconazole after intravenous and oral administration of a single dose of the prodrug BAL8557. Antimicrob Agents Chemother 53:

12 Desai A, Schmitt-Hoffmann AH, Mujais S, Townsend R Population Pharmacokinetics of Isavuconazole in Subjects with Mild or Moderate Hepatic Impairment. Antimicrob Agents Chemother 60: Schmitt-Hoffmann A, Roos B, Maares J, Heep M, Spickerman J, Weidekamm E, Brown T, Roehrle M Multiple-dose pharmacokinetics and safety of the new antifungal triazole BAL4815 after intravenous infusion and oral administration of its prodrug, BAL8557, in healthy volunteers. Antimicrob Agents Chemother 50: Cornely OA, Bohme A, Schmitt-Hoffmann A, Ullmann AJ Safety and pharmacokinetics of isavuconazole as antifungal prophylaxis in acute myeloid leukemia patients with neutropenia: results of a phase 2, dose escalation study. Antimicrob Agents Chemother 59: Schmitt-Hoffmann A, Roos B, Heep M, Schleimer M, Weidekamm E, Brown T, Roehrle M, Beglinger C Single-ascending-dose pharmacokinetics and safety of the novel broadspectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200 milligrams) and oral administrations (100, 200, and 400 milligrams) of its prodrug, BAL8557, in healthy volunteers. Antimicrob Agents Chemother 50: Wallemacq PE, Verbeeck RK Comparative clinical pharmacokinetics of tacrolimus in paediatric and adult patients. Clin Pharmacokinet 40:

13 Table 1. Tacrolimus dosing protocols and duration of isavuconazole prophylaxis according to organ transplant Initial target Duration of Initial dosage of concentration range of isavuconazole tacrolimus tacrolimus 1 prophylaxis Kidney transplant 2 mg every 12 hours 8 to 12 ng/ml 1 month Liver transplant 1 mg every 12 hours 8 to 10 ng/ml 1 month Heart transplant 2 mg every 12 hours 10 to 12 ng/ml 1 month Lung transplant 0.5 mg every 12 hours 12 to 15 ng/ml 3 to 4 months This table summarizes standard recommendations at UPMC at the time of this study. Isavuconazole was dosed according to manufacturer recommendations.(6) 1 There were no changes in target tacrolimus levels throughout the study period. Tacrolimus levels were measured using high-performance liquid chromatography mass spectrometry.

14 Table 2. Clinical characteristics of patients included in this study All patients (n=55) Kidney transplant (n=20) Liver transplant (n=18) Heart transplant (n=9) Lung transplant (n=8) P-value Median age in years (range) 60 (22-74) 53.5 (22-74) 60.5 (43-69) 64 (58-69) 66 (56-68) Male, n (%) 47 (85) 17 (85) 13 (72) 7 (78) 7 (88) 0.73 Race: white, n (%) Median weight in kilograms (range) Body mass index (range) Concomitant PPI, n (%) Duration of intravenous therapy, days 1 Median tacrolimus C/D 2 (interquartile range) Median tacrolimus daily dose in mg (IQ range) 46 (84) 16 (80) 15 (83) 7 (78) 7 (88) (52-180) 28 (13 41) 93 (65-146) 30 (25 41) 88 ( ) 30 (21 40) 77 ( ) 26 (19 31) 69 (60-74) 23 (17 27) (78) 16 (80) 14 (78) 5 (63) 8 (100) (0-21) 2 (0-4) 5 ( 0-18) 5 (3-21) 10 (6-21) < (94 188) On isavuconazole, day (76 181) 6 (4-10) 7.5 ( ) 192 ( ) 105 (84 150) 4 (2.75-6) 7.5 ( ) 106 (80 109) 8.5 (5.5-10) < Median tacrolimus trough levels in 10.5 ( ) 10.5 ( ) 8.5 ( ) 12 (9.7-14) 12.5 ( ) 0.001

15 15 ng/ml (IQ range) Off isavuconazole, day Median tacrolimus C/D (interquartile range) 120 (62 171) 154 (59 187) 101 (60 161) 103 (79 154) 87 (38 163) Median tacrolimus daily dose in mg (IQ range) Median tacrolimus trough levels in ng/ml (IQ range) Median actual tacrolimus dose taken off isavuconazole / calculated estimated tacrolimus dose 3 8 (5-10) 6.5 ( ) 9 (7-11_ 7 (6-9.5) 11 ( ) 1.3 ( ) 6 (4-8) 9.5 ( ) 11 ( ) 9.5 ( ) 11 ( ) 1.3 ( ) 1.9 ( ) 1.1 ( ) 1.4 ( ) 1 Patients initiated on oral therapy were considered to have zero days of intravenous therapy The patient s actual body weight on the day of isavuconazole initiation was used throughout the C/D analysis. The total daily dose was calculated as an average of doses (mg) for the day the tacrolimus level was assayed and two days prior; this calculation was chosen to account for the ~12 hour half-life of tacrolimus.(18) 3 The calculated estimated tacrolimus daily dose off isavuconazole was defined as (daily tacrolimus dose while on isavuconazole / (tacrolimus level on isavuconazole * tacrolimus level off isavuconazole)).(9) PPI = proton pump inhibitor, C/D = concentration to dose ratio (ng/ml)/(mg/kg) 0.28

16 Tacrolimus C/D ratio Tacrolimus C/D ratio Figure 1: Tacrolimus concentration/dose ratios of solid organ transplant patients. Individual diamonds represent median tacrolimus C/D ratio for all patients at indicated times. Tacrolimus C/D ratios were evaluated after the first full day of isavuconazole and tacrolimus therapy (i.e., post-operative day 2). Figure 1A: On isavuconazole prophylaxis Days after starting isavuconazole and tacrolimus Figure 1B: Off isavuconazole prophylaxis (stopped on day 0) Weeks after discontinuation of isavuconazole Figure 2. Tacrolimus C/D (median + interquartile range) on and off isavuconazole stratified by type of organ transplant.

17 C o n c e n tr a tio n /d o s e (n g /m L )/(m g /k g ) C o n c e n tr a tio n /d o s e (n g /m L )/(m g /k g ) Figure 2A: Tacrolimus C/D on isavuconazole. Tacrolimus C/D was higher among liver transplant patients (median: 191.8) than kidney (123.7, p=0.046), heart (104.7, p=0.02) and lung transplant patients (106.3, p=0.01) K id n e y L iv e r H e a r t L u n g s Figure 2B: Tacrolimus C/D off isavuconazole. There was no difference in tacrolimus C/D among types of organ transplant patients (p=0.59) K id n e y L iv e r H e a r t L u n g s 288

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