Real-Life Assessment of the Safety and Effectiveness of the New Tablet and Intravenous Formulations

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1 AAC Accepted Manuscript Posted Online 15 May 2017 Antimicrob. Agents Chemother. doi: /aac Copyright 2017 American Society for Microbiology. All Rights Reserved Real-Life Assessment of the Safety and Effectiveness of the New Tablet and Intravenous Formulations of Posaconazole in the Prophylaxis of Invasive Fungal Infections: Analysis of 343 courses 3 4 Frank P. Tverdek 1 ; Sang Taek Heo 2,& ; Samuel L. Aitken 1 ; Bruno Granwehr 2, Dimitrios P Kontoyiannis Department of Clinical Pharmacy Programs; 2 Department of Infectious Diseases, Infection Control, and Employee Health; The University of Texas MD Anderson Cancer Center, Houston, TX, USA Keywords: Posaconazole, hematologic malignancy; prophylaxis; cancer; antifungal Running title: Real-life Assessment of New Formulations of Posaconazole *Person to whom correspondence should be addressed: Dimitrios P. Kontoyiannis, M.D., Sc.D., PhD (Hon), Division of Internal Medicine, University of Texas MD Anderson Cancer Center, 1400 Pressler Street, FCT , Unit 1463, Houston, TX 77030, USA, Phone: , Fax: dkontoyi@mdanderson.org & Current author address: Department of Infectious Diseases, Jeju National University School of Medicine, Jeju, Korea 1

2 2 20 Abstract Background: Posaconazole is the preferred mold-active azole for prophylaxis against invasive fungal infection (IFI) in patients with hematologic malignancy (HM). Delayed release tablet and intravenous formulations of posaconazole have recently become available, but clinical data are limited. We sought to examine the real-world pharmacokinetics and prophylactic effectiveness of the new formulations of posaconazole given as prophylaxis in patients with HM. Methods: A retrospective cohort of all consecutive adult inpatients with HM who received 3 days of posaconazole as tablet or intravenous from 12/1/ /31/2015 for primary IFI prophylaxis at MD Anderson Cancer center. Clinical information were collected and correlated with low posaconazole serum levels (<700ng/mL). Rates of invasive fungal infections as well as safety events were assessed. Results: 1,321 courses of posaconazole were administered at MD Anderson Cancer Center during the study time period, with 343 patient courses assessed for prophylactic safety and effectiveness. Seventynine patient (23%) courses had posaconazole serum levels available for interpretation. Acute myelogenous leukemia was the primary malignancy (62%) with 20% of all patients having previously received a stem cell transplant. Median posaconazole level was 1,380ng/ml (IQR ). A low posaconazole level (< 700ng/mL) was observed in 14 (18%) of patients. Proven or probable breakthrough IFI occurred in 8 patients (2%), 6 of whom had posaconazole TDM performed, all with levels above 700ng/mL. Overall, 19% of patients experienced grade 3/4 liver injury, primarily manifesting as hyperbilirubinemia and correlated with a serum level >1,830. 2

3 Conclusions: Although hepatotoxicity in a small percentage of patients is of concern, posaconazole tablets appeared to be generally safe and effective. As all breakthrough IFI in whom TDM was performed occurred in patients with levels >700ng/mL and a PCZ level >1,830ng/mL correlated with grade 3/4 liver toxicity, further studies are needed to assess the role of therapeutic drug monitoring Downloaded from on July 8, 2018 by guest 3

4 4 51 Introduction Invasive fungal infections (IFIs) continue to be a significant cause of morbidity and mortality in patients with hematologic malignancy.(1) The triazole posaconazole (PCZ) has in vitro, preclinical, and clinical activity against a variety of yeasts and molds.(2) Since its introduction 15 years ago, PCZ has been widely used as for the prevention and treatment of IFI in patients with leukemia and hematopoietic stem cell transplant (HCT) recipients. Suboptimal absorption of the PCZ suspension in patients with mucositis, nausea and vomiting, or poor oral intake, or with gastric acid suppression therapy has been well documented and often limits its clinical effectiveness.(3, 4) The recent availability of the intravenous (IV) and delayed-release (DR) tablet formulations of PCZ results in significantly higher serum PCZ concentrations and increased attainment of traditional pharmacokinetic targets when compared to the PCZ suspension.(5, 6) Additionally, DR formulation has been demonstrated to provide more consistent absorption and is minimally affected by gastric ph and motility.(7, 8) At MD Anderson Cancer Center (MDACC), patients with hematologic malignancy were nearly universally transitioned from PCZ suspension to DR tablets. The IV formulation was utilized if they were unable to tolerate oral medications. As the hematologic malignancy population is quite complex in terms of comorbidities, the question remains whether the new formulations of PCZ perform as well in real life scenarios in unselected patients as compared to the registration studies. The tablet and intravenous formulations were approved on the basis of safety and pharmacokinetic data, with corresponding Phase III data for the tablet formulation recently being published. (9) To date, several small, single-center studies have reviewed the initial implementation of PCZ tablets, focusing mainly on pharmacokinetic endpoints.(5, 6, 10-12) In agreement with our early experience, these reports also have shown that PCZ tablets yield 4

5 higher serum concentrations than the previous suspension formulation and appear to be safe.(5) Whether there is a subset of patients who have low PCZ levels, despite use of the new PCZ formulations, remains unclear. In one small study, a subgroup of patients with increased body weight and diarrhea were found to have PCZ levels less than 700ng/ml. (10) However, more information is needed regarding the real-life effectiveness of new formulations of PCZ as an invasive fungal infection prophylaxis strategy. Specifically, the frequency and type of breakthrough IFI during prophylaxis with the new PCZ formulations have not been well described. Additionally, the safety of PCZ tablets outside of a selected study population merits further evaluation. Finally, as the drug-exposure profile of new PCZ formulations differs in comparison to PCZ suspension, the role of therapeutic drug monitoring(tdm), if any, warrants re-evaluation.(13) Specifically, the previously defined trough value of <700ng/ml established with the suspension formulation as the prophylactic threshold for increased risk of breakthrough IFI. Additionally, the potential toxicities associated with the consistently higher serum levels of the new PCZ formulations and an upper therapeutic limit are unknown.(14, 15) To that end, we sought to describe the real-life safety and effectiveness (incidence and type of breakthrough IFI) for patients receiving primary antifungal prophylaxis with PCZ in a large number of unselected high risk patients with leukemia and/or HCT at MDACC, a major tertiary care oncology center. Additionally, we sought to explore any associations with PCZ serum levels and efficacy or safety in the subset of patients who had TDM performed. Methods 5

6 Patients We retrospectively identified all patients hospitalized with leukemia and/or HSCT who had received PCZ DR tablets or IV prophylaxis (monotherapy) at MDACC from 12/1/ /31/2015. Patients were initially identified using a pharmacy database of all patients receiving PCZ DR or IV, regardless of indication. Patients were subsequently included if they had a diagnosis of leukemia or HCT. Additionally, patients must have received PCZ as an inpatient for 3 days for an indication of IFI prophylaxis. In order to limit the population to those truly receiving primary antifungal prophylaxis (PAP), patients with any prior medical record documentation of fungal infection, regardless of timing, were excluded. Additionally patients less than 18 years of age and those receiving PCZ outpatient were excluded. Evaluation for breakthrough IFI during the patients clinical course continued until death, discharge or the patient stopped receiving PCZ for more than 7 days. Patient records were additionally reviewed at 42 and 84 days regardless of length of prophylaxis to assess for death or IFI status. IFI was defined according to consensus criteria of the European Organization for Research and Treatment of Cancer/Infectious Disease Group and the National Institute of Allergy and Infectious Diseases Mycosis Study Group (EORTC/MSG).(16) Data collected included patient demographics, details of antifungal therapy, and clinical outcomes. Patient records were screened for potential PCZ-associated toxicities, including hepatotoxicity, neurotoxicity, bone pain, peripheral neuropathy and infusion reactions. Clinically relevant hepatotoxicity, mucositis, and diarrhea were defined according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0).(17) Hepatotoxicity was assessed according to standard National Cancer Institute (NCI) grading scales. Only Grade 3/4 hepatotoxicity was considered clinically significant. 6

7 Prolongation in the corrected QT interval (QTc) was assessed by comparing electrocardiograms (ECGs) obtained at baseline and during PCZ prophylaxis, when available Therapeutic Drug Monitoring (TDM) No institutionally-defined criteria for performing PCZ TDM for prophylaxis existed at MDACC during the time period of this study. In general, PCZ levels are obtained with morning laboratory testing and PCZ is administered at 0900 (a standard medication administration time), but this timing may vary. Therefore, plasma concentrations reported here may be assumed to be close to serum trough levels. Patients in this study had received PCZ serum level monitoring according to clinician preference. All serum PCZ levels were reviewed during the duration of PCZ prophylaxis until IFI, discharge, or death. Only the first recorded PCZ level obtained during prophylaxis was evaluated in the assessment of variability of PCZ levels and their relationship to clinical outcomes. At our center, PCZ levels are generally measured after five to seven days following initiation of PCZ. If more than one PCZ serum level was obtained during the prophylaxis phase, intra-patient variability was assessed in comparison to the initial level, provided no change in PCZ dose occurred between levels. An optimal PCZ serum level was defined as > 700ng/mL. Statistical Analysis Primary endpoints There were two primary endpoints of interest - development of proven/probable IFI according to EORTC criteria (primary effectiveness endpoint) and development of hepatotoxicity, defined as a new-onset grade 3/4 elevation to total bilirubin, alkaline phosphatase, and/or ALT (primary safety endpoint). Additionally, a primary pharmacokinetic endpoint, attainment of an optimal (e.g., 700ng/mL) was assessed. All patients were included in the primary effectiveness cohort. Groups with and without these 7

8 endpoints were compared using univariate statistics. Multivariate analyses were planned a priori but the low number of patients reaching the primary endpoints prevented any meaningful analyses from being completed. As weight and body mass index (BMI) have previously been shown to correlate with PCZ serum levels, these were specifically correlated with PCZ serum levels using linear regression.(10) Classification and regression tree (CART) analysis was used to determine what, if any, significant breakpoints existed with low PCZ serum levels and potential liver injury. Secondary endpoints Day 42 and 84 outcomes were the secondary effectiveness endpoints. Additionally, initiation of alternative antifungals (i.e., echinocandins or amphotericin B products) was assessed as a marker of clinical suspicion for IFI independently of EORTC criteria. QTc prolongation and other toxicities were the secondary safety endpoints. All safety endpoints are presented descriptively. All data were collected using REDCap data management tools (Vanderbilt University, Nashville, TN) hosted by MDACC. Statistical analyses were completed using Stata v14.1 software (StataCorp LP, College Station, TX). This study was approved by the institutional review board at MDACC with a waiver of the requirement for informed consent. Results A total of 1,321 courses of PCZ were provided to inpatients at MDACC during the study time period (Figure 1). After applying inclusion/exclusion criteria, a total of 343 primary IFI prophylaxis courses, in unique patients, were assessed for safety and effectiveness, while 79 patients (23%) had serum PCZ levels available for interpretation. The median age was 59 with 57% males. Patients were primarily 8

9 white (72%). Acute myeloid leukemia was the primary malignancy (62%) with 20% of patients having previously received a stem cell transplant (Table 1) Patients received the PCZ loading dosing of 300mg BID on the first day in 62% of cases and 300mg daily maintenance dose in 99% of cases. Patients received PCZ for a median length of 8 days (range days). Fifty percent of patients received courses 8 days or longer 29% received courses longer than 14 days. Eleven patients initially received the IV formulation, their clinical details are described in Table 2. Therapeutic Drug Monitoring (TDM) There were 79 patients (23%) who had serum PCZ levels drawn during therapy, with a median value of 1,380 (IQR ). Levels were drawn a median of 10 (IQR ) days after initiation of therapy. A low PCZ level (<700ng/mL) was observed in 14 (18%) of patients. A relationship between a low serum PCZ level and younger age, history of HSCT and certain malignancies were identified (Table 3) in univariate analysis. Other factors, including graft versus host disease (GVHD) grade, obesity status, BMI, and actual body weight did not yield any significant associations (Table 3). Mean intra-patient variability in 15 patients with multiple PCZ levels was 48%. No correlation was observed between serum levels and the use of H 2 antagonists or proton pump inhibitors (Table 3). Effectiveness Proven or probable breakthrough IFI occurred in 8 (2%) patients. (Table 4) Possible breakthrough IFI occurred in another 16 (4%) of patients. In patients with TDM performed with proven/probable IFIs (6 of 8), all IFIs occurred in patients with serum PCZ levels in excess of 700ng/mL. Independently of EORTC criteria, echinocandins were initiated in 68% of patients and liposomal amphotericin B in 13%. 9

10 At the 42 day assessment, 81% of patients in the study were alive with no IFI identified and 14% of patients had died. By day 84, 5% were being treated for IFI while 72% of patients were alive with no IFI Safety Patient characteristics based on the presence of hepatotoxicity are presented in Table 5. Three hundred sixteen (92%) patients had a baseline liver assessment at the start of prophylaxis. Of these, 144 (46%) patients had a baseline elevation of ALT (24%), alkaline phosphatase (20%), and/or bilirubin (21%) preceding PCZ therapy. Twenty-three (16%) of these 144 patients had grade 3/4 liver injury at baseline (23 [100%] with bilirubin abnormalities and one [4%] with additional alkaline phosphatase abnormalities). In the 172 (54%) patients with no liver injury, 109 (63%) of patients had at least one elevation of bilirubin or liver enzymes during prophylaxis. Among patients without baseline liver injury, 25 (15%) experienced at least one grade 3/4 liver injury (23 [13%] with bilirubin abnormalities and 3 [2%] with ALT abnormalities). In these patients, 18/25 (72%) had resolution of liver function abnormalities. (11 within 7 days, the remainder within 14 days). Sixteen of 25 (64%) had PCZ discontinued in response to the liver toxicity, five of whom who had no resolution of LFT abnormalities. Among these 5, two had confirmed liver GVHD, one had hemophagocytic lymphohistiocytosis, one had received pre-transplant chemotherapy with inotuzomab, and one was receiving an investigational chemotherapeutic agent with an as-yet unknown adverse effect profile as potential alternative causes of liver toxicity. In the remaining 12 patients who had PCZ discontinued and had resolution of liver abnormalities, only one case appeared to have a clear alternative explanation of liver abnormalities haemolytic anemia induced by rasburicase administration in a patient with glucose-6-phosphate dehydrogenase deficiency. Of the remaining nine patients who remained on PCZ, two patients failed to have resolution of liver abnormalities, one of whom died with HSCT graft failure on the day toxicity was noted and another who died two days 10

11 following identification of toxicity and subsequent PCZ dose modification (from 300mg to 100mg) with refractory AML. The remaining seven patients experienced complete resolution of liver abnormalities within seven days and without dose modification. In these 25 patients, nine had PCZ serum levels available for assessment with a median value of 2,130ng/mL (range 982 4,540). Two patients had repeated PCZ serum levels available, one of whom had an increase in value from 4,540ng/mL to 5,740ng/mL following a dose reduction, the other had a slight decrease from 3,940ng/mL to 3,240ng/mL with resolution of liver abnormalities despite continued therapy. Among the 121 patients with baseline liver injury but no grade 3/4 abnormalities, a total of 34 (28%) experienced grade 3/4 liver injury during prophylaxis (30 [25%] with bilirubin abnormalities and 6 [5%] with ALT abnormalities). Overall, 19% (59/316) patients in the primary safety cohort experienced new-onset grade 3/4 liver injury. Among the 66 patients with at least one PCZ serum level and no baseline grade 3/4 liver injury, there was no statistical difference in the median serum PCZ level in patients with and without new grade 3/4 liver injury (1,765 ng/ml vs 1,310 ng/ml, p = 0.06). No association between grade 3/4 liver injury was seen in logistic regression analysis, using each ng/ml increase in PCZ serum levels as the independent variable (p=0.158). However, CART analysis identified a PCZ serum level of 1,830 ng/ml as a significant correlate of new grade 3/4 liver injury (59% vs. 20%, OR 5.6, 95% [CI] , p = 0.005). The area under the receiver operating curve (AUC ROC) for the CART-derived breakpoint showed a modest predictive capability, with a value of 0.67 (95% CI ). The PCZ serum level was obtained before the maximum observed liver test value in 55% of patients with grade 3/4 liver injury versus 59% of those without (p = 0.50). ECG monitoring was performed prior to and during PCZ therapy in 79 (23%) patients. The median duration of prophylaxis was significantly longer in patients with serial ECG monitoring (13 [IQR 8 22] vs 6 [IQR 3 14] days, p < 0.001). The median time to follow-up ECG was 17 (IQR 7 39) days. The mean 11

12 increase in QTc from baseline to the highest measured QTc during therapy was 13.37ms (+/-35.25). One patient was identified as experiencing an episode of life threatening Torsades des pointes, with a QTc of 437ms (no baseline assessment documented.) The patient was receiving PCZ tablets and did not have a concurrent PCZ serum level checked. The patient was also receiving an additional known QT prolonging medication, ondansetron. This patient recovered with supportive care and discontinuation of both ondansetron and PCZ. One patient was identified as having bone pain after 3 days of PCZ therapy. There were no other identified medication causes of bone pain in the patient. No PCZ serum level was performed. The bone pain resolved once patient was switched to fluconazole. No episodes of encephalopathy, neurotoxicity or peripheral neuropathy were identified during chart review. All IV posaconazole doses were given through a central line and over 90 minutes- no infusion related reactions were identified. Discussion In this series of 343 high-risk patients with hematologic malignancy at a NCI-designated comprehensive cancer center, we found that the newer formulations of PCZ, given as primary prophylaxis, were both safe and effective. In the subset of patients who had PCZ levels drawn, serum levels were much higher than historically observed with the PCZ suspension and comparable to levels achieved in the Phase 3 studies (9). Interestingly, a high degree of intra-patient variability was seen in PCZ levels. In the small subset of patients the IV formulation was useful to bridge therapy or continue prophylaxis in patients that were unable to tolerate the oral tablet formulation though the number of patients was too small to make any generalizations. 12

13 PCZ was associated with a proven/probable breakthrough IFI rate of only 2%, comparable to the low rate of breakthrough infections seen in registry and real life data with both PCZ suspension and tablets.(2, 18) The types of organisms implicated in the breakthrough IFI were small in number and representative of the type of pathogens typically seen in the high-risk hematologic malignancy patient. Importantly, 6 of the 8 patients with proven/probable IFI had serum PCZ levels greater than 700ng/mL, calling the validity of this efficacy measure into question with the newer formulations of PCZ. The 700ng/mL threshold was first proposed by Jang and colleagues in an analysis of two pivotal trials of PCZ suspension prophylaxis.(15) Its relevance has been debated as the analysis included possible IFIs in its composite endpoint of prophylactic failure.(19) Our study did not include possible IFI in our definition of prophylactic failure and we did not identify any such trough threshold. Most breakthrough IFI in the prior studies were due to mold species, similar to our study. Lewis and colleagues, demonstrated that the AUC/MIC ratio was directly related to PCZ treatment efficacy in a mouse model of mold infection.(20) While it is unclear what PD parameter is relevant to prophylaxis against mold infection, the posaconazole tablets provide a much higher AUC than the suspension at the current FDA approved dosing due to improved absorption of the tablet.(13, 21) Comparing two patients taking FDA approved dosing, manifesting with steady state trough levels of 700ng/ml (one receiving the tablet, one receiving suspension), the AUC will be higher in the patient receiving the tablet formulation. At any given trough level, the AUC will always be larger if once daily PCZ tablets were used to reach that target, as compared to the fractionated and frequent dosing of the PCZ suspension, where the PK profile may approximate that of a continuous infusion at steady state.(22) As such, standard dosing of the tablet formulations, even when yielding low trough values, may achieve AUC values similar to those seen in patients with a troughs in excess of 700ng/ml on the suspension formulation. If an AUC target is relevant to prophylactic effectiveness and this target is nearly universally achieved by the tablets, irrespective of 13

14 trough level, then risk for IFI may instead be driven by non-pharmacological factors such as immunologic deficiencies or intense fungal exposure rather than pharmacokinetics.(23) Further study is needed to identify the mechanism by which breakthrough IFI occurs as well as any potential PCZ exposure relationships The development of liver abnormalities approached 20% in this cohort and was more frequently observed in patients with pre-existing liver injury, in agreement with prior data in hospitalized patients receiving triazole antifungals.(24) It is important to note that the primary liver injury observed was hyperbilirubinemia, which is frequently multifactorial in this population and may reflect physiologic phenomena rather than drug-induced liver injury.(25, 26) As a more specific marker to drug-induced liver injury, grade 3/4 elevations in ALT were observed in only 2% of patients without pre-existing liver injury and 5% of those with such abnormalities, similar to what was observed in the phase 3 clinical trial of posaconazole tablets.(9) Furthermore, as a retrospective study, a cause-effect relationship between PCZ serum levels and liver injury cannot be established or presumed. Patients with hepatic impairment experience higher overall exposures to PCZ compared to healthy subjects, and it is possible that patients pre-existing liver abnormalities had decreased clearance of PCZ and therefore, higher measured serum levels.(27) As many patients in our cohort experienced resolution of liver abnormalities without dose modification while others had progressive hepatic dysfunction despite PCZ discontinuation, it is likely that underlying disease status and concomitant medications are a significant contributor to the observed liver injury. Nevertheless, these findings warrant further investigation and consideration in light of the consistently higher serum concentrations attained with the new formulations of PCZ. As expected, a small portion of patients receiving PCZ prophylaxis had prolongation of the QTc interval, although the implications of this association are unclear. One patient experienced Torsades des Pointes during therapy and recovered following discontinuation of PCZ. The average duration of PCZ prophylaxis 14

15 was short in this study, with a median of 8 days, and therefore further studies are needed to assess for toxicities that may appear in patients receiving prolonged durations of PCZ Whether routine monitoring of PCZ levels is warranted in the setting of prophylaxis is debatable. On one hand, significant intra-patient variability and a sizable percent of patients with low levels was encountered, although this may reflect selection bias as levels may have been sent for patients with concern for adequate PCZ exposure. On the other hand, the rate of breakthrough IFIs in patients with TDM on PCZ tablets was occurred only in patients with levels >700ng/mL. We were not able to identify other contributing factors that have been identified in previous studies as associated with lower PCZ serum levels. In a study by Miceli et.al., obesity and diarrhea were associated with lower levels.(10) Due to limitations with the retrospective nature of the study and medical record documentation, the impact of diarrhea was unfortunately not assessed in this study. Diarrhea, and other potential gastrointestinal issues such as nausea and vomiting, at varying times during the prophylaxis course may account for the large intra-patient variability seen in some of the patients PCZ serum levels. Patient weight, obesity, or higher BMI were not associated with the low levels of PCZ in our patients. We identified younger age as being associated with lower PCZ levels. The reasons for this association cannot be ascertained from our data, however, younger patients may more rapidly metabolize PCZ. Similar associations with younger age and low serum levels have been reported with voriconazole.(28) The associations of low level and certain malignancy subtypes is unclear and may be a spurious result given the small numbers and multiple statistical analyses performed, as well as the possible collinearity of younger patients and stem cell transplant given the screening process for stem cell transplant. Associations of low PCZ levels in patients with history of stem cell transplant are consistent with potential issues of absorption in patients with a high rate of mucositis and warrant further exploration. 15

16 This study has several limitations. First, the retrospective nature of the data collection limited our ability to identify all potential adverse events and their causality. Second, patient records were only reviewed for toxicities during the initial inpatient prophylaxis episode. Many patients may have continued on PCZ upon discharge and again during subsequent admissions. However, once the patient leaves the hospital it becomes difficult to attribute clinical outcomes to PCZ therapy due to issues with patient adherence and the possibility of overlapping antifungal prophylaxis strategies. Third, the subgroup analyses and low observed event rates limited the ability to perform adjusted analyses for toxicity or effectiveness, and the univariate analyses should be considered underpowered and exploratory. The TDM analysis presented herein is limited in that not all patients had a measured serum level. Nonetheless, all patients with breakthrough IFI were represented in the TDM subgroup. Conclusions We found that the newer formulations of PCZ were safe and effective as IFI prophylaxis in a high-risk population with hematologic cancer. Significant breakthrough IFI manifested as primarily mold infections and were not associated with PCZ serum levels. Potentially serious adverse events occurred rarely, mainly hepatotoxicity and QTc prolongation. Serum PCZ monitoring identified a potential association between elevated serum PCZ levels and liver injury. In the context of the current study, PCZ TDM does not appear to be useful to optimize efficacy, while further research is needed to clarify the association between serum levels and hepatotoxicity. Re-evaluation of the clinical significance of the 700ng/ml threshold for prophylaxis is warranted. Supported in part by funding from Merck, Inc. DPK acknowledges the Frances King Black Endowment for Cancer Research. We thank Russell E Lewis for useful discussions. 16

17 Disclosures: D.P.K. has received research support from Pfizer, Astellas, and has received honoraria from Merck, Astellas, Pfizer, Cidara, Inc, Amplyx, Inc and F2G, Inc. BG: Has received research support from Merck and Gilead. FT: Scientific advisory board(astellas) and speakers board (Merck). SA: Scientific advisory board (Astellas) and speakers board (Merck). Heo: STH acknowledges the research grant from Jeju National University in Downloaded from on July 8, 2018 by guest 17

18 References 1. Pagano L, Caira M The role of primary antifungal prophylaxis in patients with haematological malignancies. Clin Microbiol Infect 20 Suppl 6: Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, Helfgott D, Holowiecki J, Stockelberg D, Goh YT, Petrini M, Hardalo C, Suresh R, Angulo-Gonzalez D Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 356: Dolton MJ, Ray JE, Chen SC, Ng K, Pont L, McLachlan AJ. Multicenter study of posaconazole therapeutic drug monitoring: exposure-response relationship and factors affecting concentration. Antimicrob Agents Chemother 56: Dolton MJ, Ray JE, Marriott D, McLachlan AJ. Posaconazole exposure-response relationship: evaluating the utility of therapeutic drug monitoring. Antimicrob Agents Chemother 56: Jung DS, Tverdek FP, Kontoyiannis DP Switching from posaconazole suspension to tablets increases serum drug levels in leukemia patients without clinically relevant hepatotoxicity. Antimicrob Agents Chemother 58: Pham AN, Bubalo JS, Lewis JS, 2nd Comparison of posaconazole serum concentrations from haematological cancer patients on posaconazole tablet and oral suspension for treatment and prevention of invasive fungal infections. Mycoses doi: /myc Kraft WK, Chang PS, van Iersel ML, Waskin H, Krishna G, Kersemaekers WM Posaconazole tablet pharmacokinetics: lack of effect of concomitant medications altering gastric ph and gastric motility in healthy subjects. Antimicrob Agents Chemother 58: Krishna G, Ma L, Martinho M, Preston RA, O'Mara E A new solid oral tablet formulation of posaconazole: a randomized clinical trial to investigate rising single- and multiple-dose pharmacokinetics and safety in healthy volunteers. J Antimicrob Chemother 67: Cornely OA, Duarte RF, Haider S, Chandrasekar P, Helfgott D, Jimenez JL, Candoni A, Raad I, Laverdiere M, Langston A, Kartsonis N, Van Iersel M, Connelly N, Waskin H Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease. J Antimicrob Chemother 71: Miceli MH, Perissinotti AJ, Kauffman CA, Couriel DR Serum posaconazole levels among haematological cancer patients taking extended release tablets is affected by body weight and diarrhoea: single centre retrospective analysis. Mycoses 58: Pham AN, Bubalo JS, Lewis JS, 2nd Experience Utilizing 400 mg Daily of Posaconazole Tablet Formulation in Order to Achieve Desired Minimum Serum Concentrations in Adult Patients with a Hematologic Malignancy or Stem Cell Transplant. Antimicrob Agents Chemother doi: /aac

19 Durani U, Tosh PK, Barreto JN, Estes LL, Jannetto PJ, Tande AJ Retrospective Comparison of Posaconazole Levels in Patients Taking the Delayed-Release Tablet versus the Oral Suspension. Antimicrob Agents Chemother 59: insert] Np Merck & Co., Inc., Whitehouse Station, NJ, USA. 14. Dolton MJ, Ray JE, Chen SC, Ng K, Pont L, McLachlan AJ Multicenter study of posaconazole therapeutic drug monitoring: exposure-response relationship and factors affecting concentration. Antimicrob Agents Chemother 56: Jang SH, Colangelo PM, Gobburu JV Exposure-response of posaconazole used for prophylaxis against invasive fungal infections: evaluating the need to adjust doses based on drug concentrations in plasma. Clin Pharmacol Ther 88: De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, Pappas PG, Maertens J, Lortholary O, Kauffman CA, Denning DW, Patterson TF, Maschmeyer G, Bille J, Dismukes WE, Herbrecht R, Hope WW, Kibbler CC, Kullberg BJ, Marr KA, Munoz P, Odds FC, Perfect JR, Restrepo A, Ruhnke M, Segal BH, Sobel JD, Sorrell TC, Viscoli C, Wingard JR, Zaoutis T, Bennett JE, European Organization for R, Treatment of Cancer/Invasive Fungal Infections Cooperative G, National Institute of A, Infectious Diseases Mycoses Study Group Consensus G 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 46: Institute NC Common terminology criteria for adverse events v4.0. NIH publication :NCI, NIH, DHHS, Washington, DC. 18. Cumpston A, Caddell R, Shillingburg A, Lu X, Wen S, Hamadani M, Craig M, Kanate AS Superior Serum Concentrations with Posaconazole Delayed-Release Tablets Compared to Suspension Formulation in Hematological Malignancies. Antimicrob Agents Chemother 59: Cornely OA, Ullmann AJ Lack of evidence for exposure-response relationship in the use of posaconazole as prophylaxis against invasive fungal infections. Clin Pharmacol Ther 89: Lewis RE, Albert ND, Kontoyiannis DP Comparative pharmacodynamics of posaconazole in neutropenic murine models of invasive pulmonary aspergillosis and mucormycosis. Antimicrob Agents Chemother 58: Duarte RF, Lopez-Jimenez J, Cornely OA, Laverdiere M, Helfgott D, Haider S, Chandrasekar P, Langston A, Perfect J, Ma L, van Iersel ML, Connelly N, Kartsonis N, Waskin H Phase 1b study of new posaconazole tablet for prevention of invasive fungal infections in high-risk patients with neutropenia. Antimicrob Agents Chemother 58: Heinz WJ, Zirkel J, Kuhn A, Schirmer D, Lenker U, Keller D, Klinker H Relevance of timing for determination of posaconazole plasma concentrations. Antimicrob Agents Chemother 55: Bochud PY, Chien JW, Marr KA, Leisenring WM, Upton A, Janer M, Rodrigues SD, Li S, Hansen JA, Zhao LP, Aderem A, Boeckh M Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med 359:

20 Lo Re V, 3rd, Carbonari DM, Lewis JD, Forde KA, Goldberg DS, Reddy KR, Haynes K, Roy JA, Sha D, Marks AR, Schneider JL, Strom BL, Corley DA Oral Azole Antifungal Medications and Risk of Acute Liver Injury, Overall and by Chronic Liver Disease Status. Am J Med 129: e Hogan WJ, Maris M, Storer B, Sandmaier BM, Maloney DG, Schoch HG, Woolfrey AE, Shulman HM, Storb R, McDonald GB Hepatic injury after nonmyeloablative conditioning followed by allogeneic hematopoietic cell transplantation: a study of 193 patients. Blood 103: Tverdek FP, Kofteridis D, Kontoyiannis DP Antifungal agents and liver toxicity: a complex interaction. Expert Rev Anti Infect Ther 14: Lipp HP Clinical pharmacodynamics and pharmacokinetics of the antifungal extended-spectrum triazole posaconazole: an overview. Br J Clin Pharmacol 70: Dolton MJ, Ray JE, Chen SC, Ng K, Pont LG, McLachlan AJ Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring. Antimicrob Agents Chemother 56: Downloaded from on July 8, 2018 by guest 20

21 Table 1. Baseline characteristics in patients with posaconazole prophylaxis Characteristics All patients (n=343), N (%) Age (years), median (IQR) 59 (43-70) Male 194 (57) Weight (kg), median (IQR) 76 (65-92) BMI (kg/m 2 ), median (IQR) 27.6 ( ) Race White 246 (72) Black 24 (7) Hispanic 50 (15) Asian 15 (4) Unknown 8 (2) Malignancy AML 212 (62) ALL 50 (15) CML 18 (5) CLL 9 (3) MM 2 (1) MDS 28 (8) Lymphoma 17 (5)

22 Other a 7 (2) Active malignancy 270 (79) History of HSCT 70 (20) GVHD II or more c 25 (30) Abbreviation: BMI, body mass index; AML, acute myeloid leukemia; ALL, acute lymphocytic leukemia; CML, chronic myeloid leukemia; CLL, chronic lymphocytic leukemia; MM, multiple myeloma; MDS, myelodysplastic syndrome; HSCT, hematopoietic stem cell transplantation; GVHD, graft versus host disease; IQR, interquartile range. a Others included myelofibrosis (n=4), mycosis fungoides, aplastic anemia, and blastic plasmacytoid dendritic neoplasm (n=1 each) b Assessed among patients with prior HSCT. Downloaded from on July 8, 2018 by guest

23 Table 2. Clinical features of 11 patients having received intravenous posaconazole formulation Pati ent Age Sex Hematologic malignancy Type of SCT GVHD Mucositis Dose Total duration of IV POSA serum level (ng/ml) 42 days Outcome 84 days outcome 1 27 F ALL Haplo Yes Yes 300 mg daily 7 2,080 Death M ALL Haplo Yes Yes 300 mg daily 6 None Alive and no IFI identified Alive and no IFI identified 3 58 F MDS Cord Yes Yes 300 mg daily 8 2,690 Death M AML Haplo No Yes 300 mg daily Alive and no IFI identified 5 46 F MDS MUD Yes Yes 300 mg daily 3 None Clinical worsening of IFI 6 88 M CLL None - Yes 300 mg daily 2 None Alive and no IFI identified Alive and no IFI identified Clinical improvement of IFI Alive and no IFI identified 7 56 M AML MUD Yes Yes 300 mg daily 2 None Death M MM MUD Yes Yes 300 mg daily 13 1,490 Death F MDS MRD No Yes 300 mg daily 3 None Alive and no IFI identified M ALL Cord No Yes 300 mg daily 11 1,140 Alive and no IFI identified Alive and no IFI identified Alive and no IFI identified F Lymphoma MUD Yes Yes 300 mg daily 15 2,360 Death - Abbreviation: BMI, body mass index; AML, acute myeloid leukemia; ALL, acute lymphocytic leukemia; CLL, chronic lymphocytic leukemia; MM, multiple myeloma; MDS, myelodysplastic syndrome; SCT, Stem cell transplantation; GVHD, graft versus host disease; IQR, interquartile range.

24 Table 3. Comparison of clinical characteristics according to level of therapeutic drug monitoring of posaconazole in patients with posaconazole prophylaxis Characteristics Age (years), median (IQR) Total patients (n= 76), N (%) Posaconazole <700 ng/ml (n=14), N (%) Posaconazole 700 ng/ml (n=62), N (%) 60 (51 67) 48 (31-61) 62 (54-68) 0.03 Male 47 (62) 10 (71) 37 (60) 0.41 Weight (kg), median (IQR) BMI (kg/m 2 ), median (IQR) 81 (66 95) 84 (69-108) 79 (66-93) (23 32) 27 (25-32) 28 (23-32) 0.83 Race 0.88 White 57 (75) 10 (71) 47 (76) Black 8 (11) 2 (14) 6 (10) Hispanic 8 (11) 8 (14) 6 (10) Asian 1 (1) 0 1 (2) Unknown 2 (3) 0 2 (3) Malignancy AML 42 (55) 3 (21) 39 (63) 0.01 ALL 9 (12) 2 (14) 7 (11) 0.75 CML 6 (8) 4 (29) 2 (3) <0.01 p-value a

25 CLL 1 (1) 0 1 (1) 0.63 MM 1 (1) 0 1 (1) 0.63 MDS 9 (12) 2 (14) 7 (11) 0.75 Lymphoma 7 (9) 2 (14) 5 (8) 0.47 Other 1 (1) 1 (7) 0 Malignancy status 0.24 Active 56 (74) 8 (57) 48 (77) Remission 15 (20) 5 (38) 10 (16) Unknown 5 (7) 1 (7) 4 (6) History of HCT 14 (18) 5 (11) 9 (28) 0.06 GVHD II or more b 13/32 (41) 4/9 (44) 9/23 (39) 0.78 Concomitant drug H 2 antagonists 11 (14) 3 (21) 8 (13) 0.41 PPI 48 (63) 8 (57) 40 (65) 0.61 Abbreviation: BMI, body mass index; AML, acute myeloid leukemia; ALL, acute lymphocytic leukemia; CML, chronic myeloid leukemia; CLL, chronic lymphocytic leukemia; MM, multiple myeloma; MDS, myelodysplastic syndrome; HCT, hematopoietic stem cell transplantation; GVHD, graft versus host disease; PPI, proton pump inhibitor; IQR, interquartile range. a P values of tests comparing posaconazole < 700 ng/ml versus posaconazole 700 ng/ml groups. b Assessed among patients with prior HCT.

26 Table 4. Clinical features of 8 patients with breakthrough invasive fungal infection Patien t Age Sex Hematologic malignancy Allo-HSCT Site Identified fungal organism Days after start of POSA prophyla xis POSA serum level (ng/ml) 1 56 M MM Yes Lung Not otherwise specified yeast 13 1, F CLL No Blood Rhodotorula spp. 7 None 42 days Outcome 84 days outcome Death, GI GVHD complications - Clinical improvement of IFI Clinical improvement of IFI 3 58 F MDS Yes Lung Penicillium spp. 9 1,400 Death, related IFI M AML No Lung Aspergillus flavus 5 57 F AML No Skin Fusarium spp. 3 None 14 1, F AML No Lung Positive galactomannan only 16 1, M AML Yes Blood Positive galactomannan only 46 1, M MDS No Lung Positive galactomannan only 12 1,810 Death, likely IFI related - Clinical improvement of IFI Clinical improvement of IFI Clinical improvement of IFI Clinical improvement of IFI Death, sepsis & GVHD - Clinical worsening of IFI Death, pneumonia

27 Table 5. Comparison of clinical characteristics according to hepatotoxicity in patients with posaconazole prophylaxis Characteristics Total patients (n=316), N (%) No hepatotoxicity (n=299), N (%) Hepatotoxicity (n=17), N (%) Age (years), median (IQR) 60 (44 71) 60 (43-70) 65 (44-73) 0.64 Male 179 (57) 168 (56) 11 (65) 0.49 Weight (kg), median (IQR) 76 (64 91) 76 (64-91) 76 (69-86) 0.41 BMI (kg/m 2 ), median (IQR) 27 (23 31) 26.4 (23-31) 27.5 (25-33) 0.27 Race 0.83 White 225 (71) 212 (71) 13 (76) Black 23 (7) 22 (7) 1 (6) Hispanic 46 (15) 43 (14) 3 (18) Asian 15 (5) 15 (5) 0 Unknown 7 (2) 7 (2) 0 Malignancy 0.23 AML 192 (61) 184 (62) 8 (47) ALL 46 (15) 42 (14) 4 (24) CML 16 (5) 13 (4) 3 (18) CLL 9 (3) 9 (3) 0 MM 2 (1) 2 (1) 0 MDS 29 (9) 26 (9) 2 (12) p-value a

28 Lymphoma 17 (5) 17 (6) 0 Other b 6 (2) 6 (2) 0 Malignancy status 0.83 Active 246 (78) 233 (78) 13 (76) Remission 43 (14) 40 (13) 3 (18) Unknown 27 (9) 26 (9) 1 (6) History of HSCT 66 (21) 62 (21) 4 (24) 0.78 GVHD II or more c 23/66 (35) 20/62 (32) 3/4 (75) 0.08 Abbreviation: BMI, body mass index; AML, acute myeloid leukemia; ALL, acute lymphocytic leukemia; CML, chronic myeloid leukemia; CLL, chronic lymphocytic leukemia; MM, multiple myeloma; MDS, myelodysplastic syndrome; HSCT, hematopoietic stem cell transplantation; GVHD, graft versus host disease; IQR, interquartile range. a P values of tests comparing hepatotoxicity versus non-hepatotoxicity groups. b Others included myelofibrosis (n=4), aplastic anemia, and blastic plasmacytoid dendritic neoplasm (n=1 each) c Assessed among patients with prior HSCT.

29 Table 5. Comparison of clinical characteristics according to hepatotoxicity in patients with posaconazole prophylaxis Characteristics Total patients (n=316), N (%) No hepatotoxicity (n=299), N (%) Hepatotoxicity (n=17), N (%) Age (years), median (IQR) 60 (44 71) 60 (43-70) 65 (44-73) 0.64 Male 179 (57) 168 (56) 11 (65) 0.49 Weight (kg), median (IQR) 76 (64 91) 76 (64-91) 76 (69-86) 0.41 BMI (kg/m 2 ), median (IQR) 27 (23 31) 26.4 (23-31) 27.5 (25-33) 0.27 Race 0.83 White 225 (71) 212 (71) 13 (76) Black 23 (7) 22 (7) 1 (6) Hispanic 46 (15) 43 (14) 3 (18) Asian 15 (5) 15 (5) 0 Unknown 7 (2) 7 (2) 0 Malignancy 0.23 AML 192 (61) 184 (62) 8 (47) ALL 46 (15) 42 (14) 4 (24) CML 16 (5) 13 (4) 3 (18) CLL 9 (3) 9 (3) 0 MM 2 (1) 2 (1) 0 MDS 29 (9) 26 (9) 2 (12) p-value a

30 Lymphoma 17 (5) 17 (6) 0 Other b 6 (2) 6 (2) 0 Malignancy status 0.83 Active 246 (78) 233 (78) 13 (76) Remission 43 (14) 40 (13) 3 (18) Unknown 27 (9) 26 (9) 1 (6) History of HSCT 66 (21) 62 (21) 4 (24) 0.78 GVHD II or more c 23/66 (35) 20/62 (32) 3/4 (75) 0.08 Abbreviation: BMI, body mass index; AML, acute myeloid leukemia; ALL, acute lymphocytic leukemia; CML, chronic myeloid leukemia; CLL, chronic lymphocytic leukemia; MM, multiple myeloma; MDS, myelodysplastic syndrome; HSCT, hematopoietic stem cell transplantation; GVHD, graft versus host disease; IQR, interquartile range. a P values of tests comparing hepatotoxicity versus non-hepatotoxicity groups. b Others included myelofibrosis (n=4), aplastic anemia, and blastic plasmacytoid dendritic neoplasm (n=1 each) c Assessed among patients with prior HSCT.

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