Effect of Hepatic Impairment on the Pharmacokinetics of Itacitinib
The Journal of Clinical Pharmacology 2021, 0(0) 1–7 © 2021, The American College of Clinical Pharmacology
DOI: 10.1002/jcph.1814
April M. Barbour, PhD1, Kevin Rockich, PhD1, Evan Cimino, BS1, Gongfu Zhou, PhD1, Caterina Leonetti-Whalen, MPH1, Xuejun Chen, PhD1, Swamy Yeleswaram, PhD1, Noam Epstein, MD1,2, and Naresh Punwani, PhD1
Abstract
Itacitinib is a potent, selective JAK-1 inhibitor currently in development for the treatment of chronic graft-vs-host-disease in combination with corticosteroids. Itacitinib is primarily eliminated via cytochrome P450 3A metabolism with minimal renal elimination. The purpose of this open-label study was to investigate the effect of hepatic impairment, as determined by Child-Pugh grade, on itacitinib pharmacokinetics. All participants received a single 300-mg dose of itacitinib orally in the fasted state. Blood samples were collected serially through 96 hours after dosing; 4 hours after dosing, an additional sample was collected for protein binding determination.
Participants with moderate hepatic impairment (N = 8) had an approximate 2.5-fold increase in total exposure (area under the plasma concentration–time curve from time 0 to infinity [AUC0-∞]) and an approximate 2-fold increase in maximal exposure (Cmax) compared to those with normal hepatic function (N = 8) (geometric mean ratio, 2.51 [90% confidence interval (CI), 1.54-4.08] for AUC0-∞ and 1.95 [90%CI, 1.14-3.35] for Cmax). Participants with severe hepatic impairment (N = 6) had an approximate 4-fold increase in total exposure (AUC0-∞) and an approximate 3.5-fold increase in maximal exposure compared to participants with normal hepatic function (geometric mean ratio, 4.08 [90%CI, 2.41-6.89] for AUC0-∞ and 3.48 [90%CI, 1.94-6.23] for Cmax). Protein binding was similar between participants with moderate or severe hepatic impairment and participants with normal hepatic function, with average unbound fractions (percent free) of 25.7%, 31.5%, and 25.6%, respectively. There were no serious or fatal treatment-related adverse events. The results of this study combined with exposure, efficacy, and safety data from the pivotal study in the relevant patient population will inform final dosing recommendations.
Keywords : graft-vs-host disease, hepatic impairment, itacitinib, JAK-1, pharmacokinetics
Following allogeneic hematopoietic stem cell transplan- tation, prophylactic treatment to prevent graft-vs-host disease (GVHD) is typically administered. In patients with matched related or unrelated donors and bone marrow or peripheral blood as the source, prophylactic treatment typically consists of a calcineurin inhibitor (tacrolimus or cyclosporine) and an antimetabolite (methotrexate or mycophenolate mofetil depending on the conditioning regimen).1 In matched related or unre- lated donors when using peripheral blood as the source, rabbit antithymocyte globulin is also incorporated into the prophylactic regimen.1 Despite GVHD prophylaxis, acute GVHD (aGVHD) or chronic GVHD (cGVHD) hypertension, and osteoporosis. Similarly, recently ap- proved second-line therapies, such as ruxolitinib in aGVHD or ibrutinib in cGVHD, leave opportunity for new therapies with improved risk-benefit profiles given treatment associated adverse events (AEs).10,11 Despite numerous ongoing studies to reduce the incidence of aGVHD and cGVHD with prophylaxis and emerging second-line treatments, there remains an unmet medical need for safe and effective treatment options in both GVHD prophylaxis and treatment.
Itacitinib is a selective Janus kinase 1 inhibitor being developed for the treatment of cGVHD. A sustained- release (SR) formulation of itacitinib is being used occur in ∼20% to 65% of patients (but has been reported to be as low as 12% for cGVHD), depending on multiple factors such as donor type and source, con- ditioning regimen, and prophylactic regimen.2–7 Corti- costeroids, systemic and/or local depending on disease severity and organs impacted, are the first-line therapy in GVHD.1 In aGVHD, steroids had a 66% response rate in a large pivotal study with itacitinib.8 However, long-term steroid treatment of cGVHD is suboptimal9 and associated with significant adverse effects such as glucose intolerance, cataracts, sleep disturbances,in clinical trials for GVHD. In a pivotal study in patients with aGVHD, itacitinib plus corticosteroids did not result in a statistically significant improvement in aGVHD overall response rate at day 28 compared with placebo plus corticosteroids (74% vs 66%; P .08).8 Itacitinib is primary metabolized by cytochrome P450 (CYP) 3A,12 with 8.4% of the drug eliminated as parent compound in the urine.13 Following a sin- gle 300-mg SR dose of itacitinib in participants with
severe renal impairment, itacitinib total (area under the plasma concentration–time curve [AUC0-∞]) and maximal exposure (Cmax) were increased by 2.23-fold and 1.65-fold compared to participants with normal renal function. There were no clinically meaningful
changes in exposure in participants with end-stage renal disease on hemodialysis as compared to participants with normal renal function, geometric mean ratios (GMRs) of 0.81 to 0.95 for AUC0-∞ and 0.71 to 0.83 for Cmax depending on the time of dialysis.14 Following
a single 200-mg SR itacitinib dose in healthy volun- teers, itacitinib exposure was increased nearly 5-fold when coadministered with the strong CYP3A inhibitor itraconazole and decreased nearly 80% when coadmin- istered with the strong CYP3A4 inducer rifampin.12 However, in patients with aGVHD, coadministration with the strong CYP3A inhibitor posaconazole in- creased exposure only 2-fold.15 The purpose of this study was to characterize itacitinib exposure in partic- ipants with hepatic impairment. Final dosing recom- mendations in patients with hepatic impairment will be based on the totality of exposure, safety, and efficacy data.
Methods
Clinical Study
This study was conducted in accordance with the In- ternational Conference on Harmonization Guidelines for Good Clinical Practice, including the archiving of essential documents, the principles of the Declaration of Helsinki, and other applicable local ethical and legal requirements. Informed consent was obtained from each participant before protocol-specific screening as- sessments were performed. The study was conducted at 4 US sites, and institutional review board approval was obtained for this study from the Midlands Independent Review Board (Overland Park, Kansas).
This was an open-label, parallel-group study in par- ticipants with normal hepatic function and participants with varying degrees of hepatic impairment. All par- ticipants received a single itacitinib dose of 300 mg (3 100 mg SR tablets) after an approximate 8-hour overnight fast. Food restriction continued for 4 hours after dosing, and water was also withheld 1 hour before and 1 hour after dosing with the exception of that consumed with dosing (240 mL). Up to 40 participants could have been enrolled in this study across 4 groups, with at least 6 participants completing the study per hepatic impairment group. There were 4 hepatic func- tion groups based on Child-Pugh scores at screening; mild hepatic impairment was Class A with 5 to 6 points (group 3), moderate hepatic impairment was Class B with 7 to 9 points (group 2), severe hepatic impairment was Class C with 10 to 14 points (group 1), with normal hepatic function defining the last group (group 4). The normal hepatic function group was matched to the moderate hepatic impairment group based on age ( 10 years), sex, and body mass index (BMI; 20%). The moderate hepatic impairment group and matched controls were enrolled first, given a previous population PK analysis that demonstrated no impact of mild hepatic impairment on exposure.16 After a review of interim data in moderate hepatic impairment, the decision was made that the severe impairment group would be enrolled.
Inclusion criteria included male or female (not pregnant or lactating) participants aged 18 to 80 years, with a BMI between 18 and 40 kg/m2 for participants with severe hepatic impairment and 18 and 38 kg/m2 for all other participants. Participants with normal hepatic function were in good health based on medical history, physical examination, vital signs, 12-lead electrocardiograms (ECGs), and clinical laboratory determinations. Key exclusion criteria included unstable, uncontrolled, or significant cardiovascular, respiratory, renal, gastrointestinal (including disease or surgery that may impact drug absorption), endocrine, hematopoietic, psychiatric, and/or neurological disease; chronic or active infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment; current treatment or treatment with strong or moderate inducers or inhibitors of CYP3A, P-glycoprotein, or breast cancer resistance protein within 30 days or 5 half-lives (whichever is longer) of study drug admin- istration; hemoglobin <9 g/dL and anemia symptoms deemed clinically significant by the investigator or platelets <35 000/μL at screening or check-in; absolute neutrophil count 1500 cells/μL at screening or check- in; participants who used prescription drugs within 14 days (with the exception of stable treatment of hepatic disease) or nonprescription medicines/products within 7 days of study drug administration; participants in groups 1 through 3 who had a history of paracentesis within 3 months of check-in; participants in groups 1 through 3 who required a new medication for hepatic encephalopathy within 3 months before check-in; participants in groups 1 through 3 with evidence of hepatorenal syndrome or creatinine clearance <60 mL/min calculated with the Cockcroft-Gault equation; participants with a portal systemic shunt; participants in groups 1 through 3 with unstable diabetes mellitus (hemoglobin A1c 10.0%); participants in groups 1 through 3 who smoke >10 cigarettes per day or equivalent use of other tobacco or nicotine-containing products and were unwilling to refrain from use on day 1 and abide by clinical research unit restrictions.
Pharmacokinetic Sampling and Bioanalytical Methods Blood samples for pharmacokinetic (PK) analysis of itacitinib included day 1 before dosing and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours after dosing on days 1 to 5. A blood sample for the determination of plasma protein binding was obtained 4 hours after dosing.
Plasma sample concentrations of itacitinib were determined using a validated liquid chromatography– tandem mass spectrometry method as described previously.12 The assay range was 5 to 5000 nM with an accuracy (percent bias) of –2.5% to 1.6% and precision (coefficient of variation) of 0.8% to 1.9% for the quality control samples during analysis of the plasma samples from this study. Plasma protein binding was analyzed by a non–GLP assay using equilibrium dialysis followed by liquid chromatography–tandem mass spectrometry as described previously.14
Pharmacokinetic and Statistical Analysis
The sample size for each cohort was based on precedent set by other initial safety and tolerability studies of similar nature and regulatory recommendations (ie, a minimum of 8 evaluable subjects in the control and moderate impairment arms17) and was not based on statistical power calculation. Standard noncompart- mental PK methods were used to analyze itacitinib plasma concentrations using Phoenix WinNonlin ver- sion 8.0 (Certara USA Inc, Princeton, New Jersey). PK parameters of Cmax, time to maximum concentration
(tmax), half-life, AUC from time 0 to last observed concentration at time t (AUC0-t), AUC0-∞, apparent clearance, and apparent volume of distribution were calculated as described previously.12 All estimated PK parameters were summarized descriptively. The log-
transformed primary end points of Cmax, AUC0-t, and AUC0-∞ were also analyzed using a 1-way analysis of variance (ANOVA) with calculation of the GMR and 90% confidence interval (CI) to compare itacitinib exposures when administered to patients with normal
hepatic function (reference group) and patients with moderate or severe hepatic impairment. The statistical significance of the median tmax was examined using the Wilcoxon signed-rank test comparing participants with normal hepatic function and either patients with moderate or severe hepatic impairment separately. The ANOVA and Wilcoxon signed-rank test were per- formed using SAS Enterprise Guide version 7.1 (SAS Institute, Cary, North Carolina).
Safety Assessment and Analysis
Safety was assessed through AEs, physical exams, vital signs, and ECGs, along with laboratory assessments including hematology, serum chemistry, and urinalysis. AEs were tabulated by the Medical Dictionary for Regulatory Activities version 21.1 preferred term and system organ class. Severity of AEs was based on the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials.18
Safety was monitored from the time the participant signed the informed consent form through 30 days after the itacitinib dose or the date of the follow-up phone call (33 3 days after the itacitinib dose) or until toxicities resolved, returned to baseline, or were deemed irreversible, whichever was longer.
Results
Subjects’ Disposition
A total of 22 participants were enrolled and completed the study per protocol; 6 participants with severe hep- atic impairment, 8 participants with moderate hepatic impairment, and 8 participants with normal hepatic function. Overall, the mean for age and BMI were 57.5 (range, 42-74) years and 30.11 (range, 20.5-38.0) kg/m2. Males comprised 77.3% of participants, and most participants were White (86.4%). Demographics were similar across groups (Table 1).
Pharmacokinetics
Exposures in participants with moderate hepatic im- pairment were higher than those in participants with normal hepatic function, while exposures in partici- pants with severe hepatic impairment were higher than those with moderate hepatic impairment (Figure 1). From Figure 1, it is apparent that 24 hours after dosing and beyond, concentrations are relatively low and a very low percentage of the total exposure is due to concentrations beyond 24 hours; the mean percentage extrapolated for each group is 1.29% in the severe impairment group, 2.21% in the moderate impairment group, and 3.35% in the normal hepatic function group with all subjects from all groups having
<9% of the AUC0-∞ estimated by extrapolation. Partic- ipants with moderate hepatic impairment had an ∼2.5- fold increase in AUC0-∞ and an 2-fold increase in Cmax compared to those with normal hepatic function (GMR, 2.51 [90%CI, 1.54-4.08] for AUC0-∞ and 1.95 [90%CI, 1.14-3.35] for Cmax; Table 2). Participants with severe hepatic impairment had an ∼4-fold increase in AUC0-∞ and an 3.5-fold increase in Cmax compared to participants with normal hepatic function (GMR, 4.08 [90%CI, 2.41-6.89] for AUC0-∞ and 3.48 [90%CI, 1.94-6.23] for Cmax; Table 2). GMRs (90%CIs) were similar for the PK end points of AUC0-∞ and AUC0-t. The increases in exposure between both the severe and moderate grades of hepatic impairment vs normal hepatic function were statistically significant given none of the GMR 90%CIs, based on the ANOVA, included 1. Tmax was not statistically different when comparing between participants with severe or moderate hepatic impairment and participants with normal hepatic function.
Figure 1. Mean ( standard deviation) concentration-time profiles for itacitinib following a single 300-mg dose in participants with normal hepatic function, moderate hepatic impairment, and severe hepatic impairment.
The protein binding of itacitinib was independent of hepatic function. The mean unbound fraction of itacitinib in moderate or severe hepatic impairment and participants with normal hepatic function was 25.7%, 31.5%, and 25.6%, respectively.
Safety
Two treatment-emergent AEs (TEAEs; headache) were reported by 2 participants (1 each grade 1 and grade 2) during the study, both of which were considered related to the study drug by the investigator and resolved before study end. No TEAEs were serious or fatal. There was no trend in TEAE incidence with increasing hepatic impairment. There were no treatment-emergent safety concerns or notable trends observed from clinical laboratory results, vital signs, or 12-lead ECGs.
Discussion
This was a multicenter, open-label study of 300-mg SR itacitinib administered orally as single doses to par- ticipants with normal hepatic function and moderate and severe hepatic impairment. The primary objective of this study was to characterize itacitinib exposure in participants with varying degrees of hepatic impair- ment. Participants with moderate hepatic impairment had an approximate 2.5 increase in total exposure. In a pilot study in participants with aGVHD, itacitinib exposures were increased 2 in patients concomi- tantly receiving a strong CYP3A4 inhibitor, mainly posaconazole, compared to patients not receiving a strong CYP3A4 inhibitor.15 Although the sample size was small in that pilot phase 1 study, an acceptable risk- benefit profile was observed with an overall response rate of 75.0% across all treatment-naive individuals, regardless of treatment with 200 or 300 mg itacitinib, and an adverse event profile as expected was observed in this patient population with itacitinib being well tolerated.15 Therefore, a dose adjustment is not cur- rently recommended in the ongoing cGVHD study in patients with moderate hepatic impairment as defined by the Child-Pugh classification of hepatic impairment. Given that no dose adjustment is currently rec- ommended in patients with moderate hepatic im- pairment, and given that population PK analysis supported that mild hepatic impairment, as defined by the National Cancer Institute (NCI) Organ Dysfunction Working Group criteria,19,20 has no impact on itacitinib exposure,16 patients with mild hepatic impairment were not enrolled in this study.
In participants with severe hepatic impairment, as defined by the Child-Pugh classification of hepatic function, total exposure was 4 higher than in participants with normal hepatic function. Currently, patients with severe hepatic impairment not due to dis- ease etiology are generally excluded from the ongoing cGVHD study given the exclusion criteria of a persis- tent bilirubin >2 mg/dL. Final dose recommendations will be based on the totality of data including exposure, safety, and efficacy data from the pivotal study in the target patient population.
Figure 2. Comparison of concentration-time profiles of participants with normal hepatic function within this study (red) compared to healthy participants from a previous study (black) following a single dose of 300 mg sustained-release itacitinib administered in the fasted state.
In participants with normal hepatic function, the exposure of itacitinib was slightly lower than that previously reported at the same dose and food status; that is, 300-mg single dose administered fasted; AUC0-∞ and Cmax were 2490 1830 nmol • h/L and 467 366 nmol/L (N 8), respectively, in this study com- pared to historical values of 2860 1450 nmol • h/L and 668 335 nmol/L, respectively (N 23, data on file). A comparison of individual concentration-time profiles of participants with normal hepatic function in this study to those from the previous study mentioned above demonstrated a similar range of distributions between the 2 data sets (Figure 2). Two subjects had differentiated profiles (Figure 2), with higher exposure than the other 6 from this study. With more subjects, it is possible that the distribution may become more normal than bimodal. The observed distribution is likely a function of the small sample rather than patient characteristics, as there is no notable difference between the characteristics of the 2 participants with the higher exposures and the other 6. Additionally, the following participant characteristics do not significantly impact exposure based on previous population PK analyses: sex, body weight, age, race, and ethnicity16 (data on file). In this study, hepatic function was categorized using the Child-Pugh criteria, as per regulatory guidance. How this translates to clinical application in an oncol- ogy setting is uncertain. The NCI Organ Dysfunction Working Group criteria for hepatic function classification may be a more clinically practical system for categorization.19,20 These 2 sets of categorization cri- teria, however, are not entirely aligned. The impact of hepatic function as characterized by the NCI criteria on itacitinib exposure will be explored using PK and clinical data from the pivotal study in the relevant patient population.
Patients with cGVHD may appear to have impaired hepatic function as a consequence of the disease, which impacts many organs including the liver. However, whether disease etiology within the liver may impact exposure should be investigated in the relevant patient population. In a PK study of posaconazole in patients with GVHD following allogeneic hematopoietic stem cell transplantation, there was no relationship between posaconazole exposure and markers of liver function— alanine aminotransferase, aspartate transaminase, or bilirubin21—of which alanine aminotransferase and bilirubin, along with alkaline phosphatase, also are included in cGVHD organ scoring.22 Whether the same would be demonstrated with itacitinib, that is, no change in exposure due to chronic GVHD pre- sentation in the liver, is uncertain given the differ- ences in metabolism and elimination with posaconazole undergoing metabolism via uridine diphosphate glu- curonidation and a majority (66%) of the dose excreted unchanged in the feces.23 Therefore, final dosing recom- mendations will be made on the basis of the totality of exposure, safety, and efficacy data with consideration of the risk-benefit profile in the relevant population, for example, cGVHD.
Conclusions
Participants with moderate hepatic impairment had an approximate 2.5-fold increase in AUC0-∞ and an ∼2-hepatic function. Participants with severe hepatic im- pairment had an 4-fold increase in AUC0-∞ and an 3.5-fold increase in Cmax compared to participants with normal hepatic function. Protein binding was similar between participants with moderate or severe hepatic impairment and participants with normal hepatic function.
Conflicts of Interest
All authors are current or former employees of Incyte and own stock in Incyte.
Funding
This study was sponsored by Incyte.
Data Sharing Statement
Access to individual subject-level data is not available for this study.
References
1. Penack O, Marchetti M, Ruutu T, et al. Prophylaxis and management of graft versus host disease after stem-cell trans- plantation for haematological malignancies: updated consen- sus recommendations of the European Society for Blood and Marrow Transplantation. Lancet Haematol. 2020;7(2): e157-e167.
2. Craddock C, Nagra S, Peniket A, et al. Factors predicting long- term survival after T-cell depleted reduced intensity allogeneic stem cell transplantation for acute myeloid leukemia. Haemato- logica. 2010;95(6):989-995.
3. Devillier R, Furst S, El-Cheikh J, et al. Antithymocyte globulin in reduced-intensity conditioning regimen allows a high disease-free survival exempt of long-term chronic graft- versus-host disease. Biol Blood Marrow Transplant. 2014;20(3): 370-374.
4. Finke J, Bethge WA, Schmoor C, et al. Standard graft-versus- host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10(9):855-864.
5. Moiseev IS, Pirogova OV, Alyanski AL, et al. Graft-versus- host disease prophylaxis in unrelated peripheral blood stem cell transplantation with post-transplantation cyclophosphamide, tacrolimus, and mycophenolate mofetil. Biol Blood Marrow Transplant. 2016;22(6):1037-1042.
6. Storb R, Deeg HJ, Pepe M, et al. Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial. Blood. 1989;73(6):1729-1734.
7. Tanaka Y, Kurosawa S, Tajima K, et al. Analysis of non-relapse mortality and causes of death over 15 years following allogeneic hematopoietic stem cell transplantation. Bone Marrow Trans- plant. 2016;51(4):553-559.
8. Zieser R, Socie G, Schroeder MA, et al. Gravitas-301: a random- ized, double-blind phase 3 study of itacitinib or placebo in combi- nation with corticosteroids for initial treatment of patients with acute-graft-versus-host disease. Presented at: European Hema- tology Association Virtual Meeting; June 12, 2020. S256.
9. Lee SJ, Vogelsang G, Gilman A, et al. A survey of diagnosis,hepatic function. Participants with severe hepatic im- pairment had an 4-fold increase in AUC0-∞ and an 3.5-fold increase in Cmax compared to participants with normal hepatic function. Protein binding was similar between participants with moderate or severe hepatic impairment and participants with normal hep- atic function.
management, and grading of chronic GVHD. Biol Blood Mar- row Transplant. 2002;8(1):32-39.
10. Incyte Corporation. Highlights of prescribing information: Jakafi (ruxolitinib) tables, for oral use. https://www.accessdata. fda.gov/drugsatfda_docs/label/2020/202192Orig1s019Rpllbl. pdf. Published 2019. Accessed January 21, 2021.
11. Pharmacyclics LLC and Janssen Biotech. Highlights of prescribing information: Imbruvica (ibrutinib) capsules, for oral use, Imbruvica (ibrutinib) tablets, for oral use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/ 205552s033,210563s010lbl.pdf. Published 2018. Accessed January 21, 2021.
12. Barbour AM, Punwani N, Epstein N, et al. Effect of itra- conazole or rifampin on itacitinib pharmacokinetics when administered orally in healthy subjects. J Clin Pharmacol. 2019;59(12):1641-1647.
13. Boer J, Barbour A, Kennedy K, et al. Human absorption, metabolism and elimination of itacitinib in healthy male adult volunteers. Presented at: American College of Clinical Pharma- cology Annual Meeting; September 23-25, 2018; Bethesda, MD.
14. Srinivas N, Barbour AM, Epstein N, et al. The effect of renal impairment on the pharmacokinetics and safety of itacitinib. J Clin Pharmacol. 2020;60(8):1022-1029.
15. Schroeder MA, Khoury HJ, Jagasia M, et al. A phase 1 trial of itacitinib, a selective JAK1 inhibitor, in patients with acute graft-versus-host disease. Blood Adv. 2020;4(8):1656- 1669.
16. Barbour AM, Chen X, Yeleswaram S. Population pharmacoki- netic analysis of itacitinib, a select JAK-1 inhibitor. Biol Blood Marrow Transplant. 2019;25(3):S254.
17. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation, Center for Biologics Evaluation. Guidance for industry-pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labeling. https:
//www.fda.gov/regulatory-information/search-fda-guidance- documents/pharmacokinetics-patients-impaired-hepatic- function-study-design-data-analysis-and-impact-dosing-and. Published 2003. Accessed January 21, 2021.
18. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research. Guidance for industry: toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials additional. https:
//www.fda.gov/regulatory-information/search-fda-guidance- documents/toxicity-grading-scale-healthy-adult-and- adolescent-volunteers-enrolled-preventive-vaccine-clinical. Published 2007. Accessed January 21, 2021.
19. Ramalingam SS, Kummar S, Sarantopoulos J, et al. Phase I study of vorinostat in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dys- function Working Group study. J Clin Oncol. 2010;28(29):4507- 4512.
20. Shibata SI, Chung V, Synold TW, et al. Phase I study of pazopanib in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study. Clin Cancer Res. 2013;19(13):3631-3639.
21. Krishna G, Martinho M, Chandrasekar P, Ullmann AJ, Patino H. Pharmacokinetics of oral posaconazole in allogeneic hematopoietic stem cell transplant recipients with graft-versus- host disease. Pharmacotherapy. 2007;27(12):1627-1636.
22. Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 diagnosis and staging working group report. Biol Blood Marrow Trans- plant. 2015;21(3):389-401 e381.
23. Merck & Co. Inc. Highlights of Prescribing Information: Noxafil (posaconazole) injection 18 mg/mL, Noxafil (posaconazole) delayed-release tablets 100mg, Noxafil (posaconazole) oral suspension 40 mg/mL. https:
//www.accessdata.fda.gov/drugsatfda_docs/label/2020/ 022003Orig1s026,205053Orig1s010,205596Orig1s010lbl.pdf. INCB39110 Published 2015. Accessed January 21, 2021.