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Evaluation of systemic concentrations of budesonide in patients treated for gastrointestinal graft-versus- host disease and the potential interaction with fluconazole or voriconazole Lindsay Stansfield, PharmD1; Thomas E. Hughes, PharmD1; Scott Penzak, PharmD1; Juan Gea-Banacloche, MD2; Richard Childs, MD3
The National Institutes of Health Clinical Center,1 The National Cancer Institute,2 Hematology Branch, National Heart, Lung and Blood Institute,3 Bethesda, Maryland, U.S.A.
Pharmacokinetic Sampling
Blood samples on days 7 and 14 in all cohorts
Drug interactions in the blood and marrow stem cell transplant (BMT) setting
Treatment of GI GVHD
Institutional Review Board approval will be obtained prior to study
Budesonide Cmin 15 minutes before 08:00 dose & Cmax 4.5 hours after
are common. Fluconazole (Diflucan®, Pfizer, New York, NY) and voriconazole
First-line treatment for moderate to severe acute & chronic GVHD is high-
08:00 dose
(Vfend ®, Pfizer, New York, NY) are triazole antifungals that are frequently
dose systemic corticosteroids5
All patients will provide written informed consent prior to enrollment
Voriconazole Cmin drawn on day 14 in Cohort 1 & on day 7 in Cohort 2
prescribed for prophylaxis and treatment of fungal infections in BMT
Nonabsorbable corticosteroids act locally on the GI tract3
Patients will enroll in 1 of 3 cohorts based on the preference of the primary
Samples analyzed via mass spectrometry & high-performance liquid
recipients.1,2 Budesonide (Entocort® EC, AstraZeneca, Wilmington, DE), an
Budesonide undergoes extensive first-pass metabolism by CYP3A43
clinical team and/or current (or lack thereof) antifungal therapy
oral non-absorbable corticosteroid, is FDA-approved for mild to moderate
Budesonide’s metabolites have 1/100th the corticosteroid activity of
GI GVHD diagnosis will be made by the primary clinical team
active Crohn’s disease involving the ileum and/or ascending colon, and for
Data Collection
Drug Dosing and Administration
maintenance of clinical remission of mild to moderate Crohn’s disease for up
Systemic bioavailability of budesonide is 12% in healthy subjects & 21% in
At baseline
Dosing is continuous
to 3 months.3 Since acute gastrointestinal (GI) graft-versus-host (GVHD)
patients with Crohn’s disease, for whom it is FDA-approved6
Treatment must be at least 14 days unless subject withdraws consent or
disease shares a similar pathogenic background with Crohn’s disease and
Immunologic source (autologous, allogeneic, syngeneic)
experiences toxicity that requires removal from study
oral topical corticosteroids are effective in Crohn’s, budesonide is often used
Systemic Antifungal Therapy
Anatomic source (bone marrow, peripheral blood, umbilical cord or
Budesonide will be administered as Entocort® EC 3 mg given p.o. every 8
in conjunction with systemic steroids, or for milder GI GVHD, as systemic
Immunosuppression with corticosteroids is a significant risk factor for
hours, starting on day 0 (first day of budesonide)
steroid-sparing therapy.4 Fluconazole and voriconazole, which are moderate
invasive fungal infections7
Matching status for allogeneic transplants
Cohorts 1 & 2: Voriconazole 200 mg p.o. every 12 hours (loading dose of
and strong inhibitors of cytochrome P4503A4 (CYP3A4), respectively, may
Triazoles and echinocandins have largely replaced amphotericin B and its
Recipient & donor factors
400 mg p.o. every 12 hours x 2 doses in Cohort 1 only)
inhibit the metabolism of budesonide, which normally undergoes extensive
lipid formulations for prophylaxis due to less toxicity and equivalent
Throughout the study
Cohort 3: Fluconazole 400 mg p.o. once daily (no loading dose)
first-pass metabolism by CYP3A4.1-3 Increased systemic concentrations of
Serum creatinine and hepatic panel
Cohorts 2 & 3: Micafungin 100 mg I.V. once daily starting on day 8 (if
budesonide may result in hypercorticism and adrenal suppression.3 Our aim
Since triazole antifungals inhibit the CYP3A4 pathway drug interactions can
Fecal output
clinically indicated)
is to determine the pharmacokinetic (PK) effects of fluconazole and
be problematic1,2
Fluconazole dose-adjusted for renal impairment based on Cockroft-Gault
voriconazole on the trough (Cmin) and peak (Cmax) of budesonide.
Micafungin is metabolized by arylsulfatase; hydroxylation by CYP3A is not
Coefficient of variation of 71% was assumed for budesonide Cmax based on
a major pathway for micafungin metabolism8
Voriconazole dose adjusted for hepatic impairment based on Child-Pugh
previous data9
Each subject will serve as his or her own control in this longitudinal cohort
score at baseline
With α set at 0.05, a sample size of 12 subjects was deemed necessary to
study to minimize the variation in absorption, distribution, metabolism and
I.V. fluconazole or voriconzole are permitted
provide 80% power to detect a 200% difference in budesonide Cmax before
elimination of oral budesonide that can occur from patient to patient, due to
Inclusion Criteria
No dose adjustments to budesonide are permitted
and after azole administration. Student’s paired t-test will be used to
genetic, anatomic or other unidentified differences. Subjects will be accrued
18 years of age and older
compare budesonide concentrations
into 1 of 3 cohorts depending upon the antifungal prophylaxis the subject is
Patients who have undergone a bone marrow, cord, haplo-cord or peripheral
P values < .05 will be accepted as statistically significant
Study Schematic
receiving at study entry and the preference of the medical team for continued
blood stem cell transplantation who have GI GVHD grade II to IV5
SYSTAT® Software (version 11, Richmond, CA) was used for sample size
antifungal coverage after the initiation of budesonide and/or systemic
Candidate for antifungal therapy
calculation and inferential statistics
corticosteroids. Subjects with milder GI GVHD who are not currently on
Budesonide PK
Budesonide PK
Exclusion Criteria
Sampling (A.M.)
Sampling (A.M.)
antifungal prophylaxis are eligible for enrollment in cohort 1. In all 3 cohorts,
March-April: Scientific Review Board/ IRB Approval
Inability to take oral medication
a budesonide Cmin and Cmax will be measured both in the presence and
May-August: Patient enrollment and data collection
Contraindication to an azole antifungal
absence of fluconazole or voriconazole therapy. A 7 day interval will be used
Current therapy with a prohibited medication
Stop fluconazole
September-November: Data synthesis and analysis
between interventions to allow steady state to occur prior to measurement of
within 24 hours Budesonide
Voriconazole (P.M.)
Allergy to budesonide, fluconazole, micafungin, or voriconazole
(if applicable)
December-February: Manuscript publication
budesonide serum concentrations. Micafungin, which is not expected to
ECOG performance status of ≥3
affect budesonide’s metabolism, will be initiated when clinically indicated to
Psychiatric disorder or mental deficiency that could interfere with patient’s
1. Diflucan [package insert]. New York, NY: Pfizer Inc; 2011.
provide antifungal coverage upon discontinuation of azole therapy.
2. Vfend [package insert]. New York, NY: Pfizer Inc; 2011.
Subject is on
Stop voriconazole
3. Entocort® EC [package insert] Wilmington, DE: AstraZeneca; 2011.
ability to comply with study procedures and requirements
Start micafungin
4. Bertz H, Afting M, Kreisel W, Duffner U, Greinwald R, Finke J. Feasibility and response to budesonide as topical
Inability to provide informed consent
(if clinically
corticosteroid therapy for acute intestinal GVHD. Bone Marrow Transplant 1999;24:1185–1189.
5. Ferrara JLM, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet 2009;373:1550–1561. Epub 11 March
Major anticipated illness or organ failure
2009. DOI 10.1016/S0140-6736(09)60237-3
6. Fedorak RN, Bistritz L. Targeted delivery, safety, and efficacy of oral enteric-coated formulations of budesonide. Adv
Drug Deliv Rev 2005;57:303–316. Epub 30 September 2004. DOI 10.1016/j.addr.2004.08.009

Current documented or suspected invasive fungal infection
7. Wingard JR. Antifungal chemoprophylaxis after blood and marrow transplantation. Clin Infect Dis 2002;34:1386–1390.
Epub 17 April 2002. DOI 10.1086/340263

Intensive care unit patient
Subject is on
Stop fluconazole
8. Mycamine [package insert]. Northbrook, IL: Astellas Pharma; 2012.
9. Micromedex Healthcare Series Website. Accessed
Start micafungin
Child-Pugh Class C hepatic impairment
February 2, 2013.
(if clinically
Study Day -1 0 7 8 14
I gratefully acknowledge the following individuals for their insight and contributions to this project: Thomas E. Hughes,
Scott Penzak, Richard Childs, Robert DeChristoforo, Barry Goldspiel, Dan Zlott, and Tracey Walsh-Chocolaad.


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