Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplant (HCT)

NCT04645667 | Completed DMC

• 2 other identifiers: LCCC2034IRB 19-3328
• Study Type: observational
• Target: 38
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this research study is to evaluate tacrolimus plasma concentrations in patients who will undergo an allogeneic hematopoietic stem cell transplant (HCT). The study aims to identify associations between plasma concentrations, baseline demographic characteristics, clinical lab parameters, and genetic factors. These associations will help clinicians determine the best starting dose for tacrolimus in order to minimize risks of aGVHD and tacrolimus-induced toxicities.

Conditions

Acute GVHD

Keywords

tacrolimus; aGVHD; pharmacokinetics; pharmacodynamics; pharmacogenomics; CYP3A5 genetic polymorphisms

Outcome Measures

Primary Outcomes (1)

• Tacrolimus clearance

  Patient's clearance calculated after the first day on tacrolimus and patient's clearance calculated after 5-6 doses of tacrolimus after they reach steady-state

  Day +1 of tacrolimus administration to Day +4 of tacrolimus administration

Secondary Outcomes (4)

• Incidence and severity of aGVHD

  Day +21 to Day +100 from HCT

• Incidence of tacrolimus-induced toxicities

  Day -3 to Day +100 from HCT

• Time to aGVHD

  Day +21 to Day +100 from HCT

• Time to tacrolimus-induced toxicities (AKI, hypertension, metabolic panel abnormalities)

  Day -3 to Day +100 from HCT

Study Arms (1)

Adult patients of allogeneic hematopoietic HCT

Patients who receive their first allogeneic HCT transplant and who receive tacrolimus for aGVHD prophylaxis per standard of care.

Drug: Tacrolimus

Interventions

Tacrolimus DRUG

Patients will be enrolled into this group if they receive tacrolimus per standard of care. This is an observational study and no interventions will be made.

Also known as: Prograf

Adult patients of allogeneic hematopoietic HCT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

This study is a single-center prospective observational study that seeks to characterize steady-state tacrolimus pharmacokinetics pharmacodynamics in adult recipients of their first allogeneic HCT. Adult subjects who receive prophylactic tacrolimus for aGVHD prevention, and who receive active follow-up surveillance at our institution, are eligible for enrollment. The study population will consist of subjects treated in the Inpatient Bone Marrow Transplant Unit at the University of North Carolina Medical Center. A total of 50 subjects will be enrolled.

You may qualify if:

• ≥18 years of age
• Patients who will undergo their first HCT
• Patients who will start tacrolimus for aGVHD prophylaxis
• Patients who have provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information

You may not qualify if:

• Patients who have cognitive impairments that could affect informed decision-making
• Patients who are incarcerated
• Patients started on a strong CYP3A4 inhibitor (i.e. posaconazole)

Sponsors & Collaborators

• UNC Lineberger Comprehensive Cancer Center: lead
• University of North Carolina, Chapel Hill: collaborator

Study Sites (1)

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27514, United States

Location

Related Publications (25)

• Mahmoud HK, Elhaddad AM, Fahmy OA, Samra MA, Abdelfattah RM, El-Nahass YH, Fathy GM, Abdelhady MS. Allogeneic hematopoietic stem cell transplantation for non-malignant hematological disorders. J Adv Res. 2015 May;6(3):449-58. doi: 10.1016/j.jare.2014.11.001. Epub 2014 Nov 7.

  PMID: 26257943 BACKGROUND

• Broder MS, Quock TP, Chang E, Reddy SR, Agarwal-Hashmi R, Arai S, Villa KF. The Cost of Hematopoietic Stem-Cell Transplantation in the United States. Am Health Drug Benefits. 2017 Oct;10(7):366-374.

  PMID: 29263771 BACKGROUND

• Yalniz FF, Murad MH, Lee SJ, Pavletic SZ, Khera N, Shah ND, Hashmi SK. Steroid Refractory Chronic Graft-Versus-Host Disease: Cost-Effectiveness Analysis. Biol Blood Marrow Transplant. 2018 Sep;24(9):1920-1927. doi: 10.1016/j.bbmt.2018.03.008. Epub 2018 Mar 14.

  PMID: 29550629 BACKGROUND

• Thomson AW, Bonham CA, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit. 1995 Dec;17(6):584-91. doi: 10.1097/00007691-199512000-00007.

  PMID: 8588225 BACKGROUND

• Ganetsky A, Shah A, Miano TA, Hwang WT, He J, Loren AW, Hexner EO, Frey NV, Porter DL, Reshef R. Higher tacrolimus concentrations early after transplant reduce the risk of acute GvHD in reduced-intensity allogeneic stem cell transplantation. Bone Marrow Transplant. 2016 Apr;51(4):568-72. doi: 10.1038/bmt.2015.323. Epub 2015 Dec 21.

  PMID: 26691423 BACKGROUND

• Kuypers DR, Claes K, Evenepoel P, Maes B, Vanrenterghem Y. Clinical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long-term pharmacokinetics in de novo renal allograft recipients. Clin Pharmacol Ther. 2004 May;75(5):434-47. doi: 10.1016/j.clpt.2003.12.009.

  PMID: 15116056 BACKGROUND

• Przepiorka D, Devine S, Fay J, Uberti J, Wingard J. Practical considerations in the use of tacrolimus for allogeneic marrow transplantation. Bone Marrow Transplant. 1999 Nov;24(10):1053-6. doi: 10.1038/sj.bmt.1702032.

  PMID: 10578154 BACKGROUND

• Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2004;43(10):623-53. doi: 10.2165/00003088-200443100-00001.

  PMID: 15244495 BACKGROUND

• Birdwell KA, Decker B, Barbarino JM, Peterson JF, Stein CM, Sadee W, Wang D, Vinks AA, He Y, Swen JJ, Leeder JS, van Schaik R, Thummel KE, Klein TE, Caudle KE, MacPhee IA. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther. 2015 Jul;98(1):19-24. doi: 10.1002/cpt.113. Epub 2015 Jun 3.

  PMID: 25801146 BACKGROUND

• Hesselink DA, Bouamar R, Elens L, van Schaik RH, van Gelder T. The role of pharmacogenetics in the disposition of and response to tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2014 Feb;53(2):123-39. doi: 10.1007/s40262-013-0120-3.

  PMID: 24249597 BACKGROUND

• Provenzani A, Santeusanio A, Mathis E, Notarbartolo M, Labbozzetta M, Poma P, Provenzani A, Polidori C, Vizzini G, Polidori P, D'Alessandro N. Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients. World J Gastroenterol. 2013 Dec 28;19(48):9156-73. doi: 10.3748/wjg.v19.i48.9156.

  PMID: 24409044 BACKGROUND

• Astellas Pharma US. Prograf (tacrolimus) [package insert]. U. S. Food and Drug Administra-tion website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/050709s031lbl.pdf. Revised May 2018. Accessed Feburary 7, 2020.

  BACKGROUND

• Bremer S, Vethe NT, Skauby M, Kasbo M, Johansson ED, Midtvedt K, Bergan S. NFAT-regulated cytokine gene expression during tacrolimus therapy early after renal transplantation. Br J Clin Pharmacol. 2017 Nov;83(11):2494-2502. doi: 10.1111/bcp.13367. Epub 2017 Aug 16.

  PMID: 28686294 BACKGROUND

• Venkataramanan R, Swaminathan A, Prasad T, Jain A, Zuckerman S, Warty V, McMichael J, Lever J, Burckart G, Starzl T. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet. 1995 Dec;29(6):404-30. doi: 10.2165/00003088-199529060-00003.

  PMID: 8787947 BACKGROUND

• Undre NA. Pharmacokinetics of tacrolimus-based combination therapies. Nephrol Dial Transplant. 2003 May;18 Suppl 1:i12-5. doi: 10.1093/ndt/gfg1029.

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• Wallemacq PE, Verbeeck RK. Comparative clinical pharmacokinetics of tacrolimus in paediatric and adult patients. Clin Pharmacokinet. 2001;40(4):283-95. doi: 10.2165/00003088-200140040-00004.

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• Moller A, Iwasaki K, Kawamura A, Teramura Y, Shiraga T, Hata T, Schafer A, Undre NA. The disposition of 14C-labeled tacrolimus after intravenous and oral administration in healthy human subjects. Drug Metab Dispos. 1999 Jun;27(6):633-6.

  PMID: 10348790 BACKGROUND

• Dai Y, Hebert MF, Isoherranen N, Davis CL, Marsh C, Shen DD, Thummel KE. Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro. Drug Metab Dispos. 2006 May;34(5):836-47. doi: 10.1124/dmd.105.008680. Epub 2006 Feb 24.

  PMID: 16501005 BACKGROUND

• Hebert MF. Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery. Adv Drug Deliv Rev. 1997 Sep 15;27(2-3):201-214. doi: 10.1016/s0169-409x(97)00043-4.

  PMID: 10837558 BACKGROUND

• Anglicheau D, Verstuyft C, Laurent-Puig P, Becquemont L, Schlageter MH, Cassinat B, Beaune P, Legendre C, Thervet E. Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients. J Am Soc Nephrol. 2003 Jul;14(7):1889-96. doi: 10.1097/01.asn.0000073901.94759.36.

  PMID: 12819250 BACKGROUND

• Furlong T, Storb R, Anasetti C, Appelbaum FR, Deeg HJ, Doney K, Martin P, Sullivan K, Witherspoon R, Nash RA. Clinical outcome after conversion to FK 506 (tacrolimus) therapy for acute graft-versus-host disease resistant to cyclosporine or for cyclosporine-associated toxicities. Bone Marrow Transplant. 2000 Nov;26(9):985-91. doi: 10.1038/sj.bmt.1702639.

  PMID: 11100278 BACKGROUND

• US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). 5.0. National Institutes of Health; 2017. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf

  BACKGROUND

• Center for International Blood and Marrow Transplant Research Transplant Activity Report Covering 2010-2014.

  BACKGROUND

• Dunlap TC, Zhu J, Weiner DL, Kemper RM, DeVane SC, Ma F, Nguyen V, Coghill JM, Dang V, Grgic T, Jamieson K, Miller J, Myers J, Patel T, Riches M, Serody JS, Trepte M, Vincent BG, Wood WA, Ptachcinski JR, Shaw JR, Weimer E, Armistead PM, Crona DJ. A Tacrolimus Population Pharmacokinetic Model for Adult Allogeneic Hematopoietic Cell Transplant Recipients Provides Clinical Opportunities for Precision Dosing. Clin Pharmacokinet. 2025 Nov;64(11):1621-1637. doi: 10.1007/s40262-025-01529-w. Epub 2025 Aug 12.

  PMID: 40794300 DERIVED

• Zhu J, Campagne O, Torrice CD, Flynn G, Miller JA, Patel T, Suzuki O, Ptachcinski JR, Armistead PM, Wiltshire T, Mager DE, Weiner DL, Crona DJ. Evaluation of the performance of a prior tacrolimus population pharmacokinetic kidney transplant model among adult allogeneic hematopoietic stem cell transplant patients. Clin Transl Sci. 2021 May;14(3):908-918. doi: 10.1111/cts.12956. Epub 2021 Jan 27.

  PMID: 33502111 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Blood will be collected at baseline prior to the first dose of tacrolimus, and will will consist of 2 tubes of 5 mL blood (one for PK and one pharmacogenetics). Then, serial blood sampling will occur at 0.5, 1, 2, 4, 6, and 10h after the first tacrolimus dose. On Day -2 and Day -1, blood will be collected prior to the morning dose for the 24h and 48h estimates. On Day 0, blood will again be collected at 0.5, 1, 2, 4, 6, and 10. Also, 10 mL of blood on Day +1, Day +8, and Day +15 (30 mL total) for PD biomarker analysis. For haplo-transplant patients, blood sampling will be similar but will occur on Day +5, Day +6, Day +7, and Day +8 once tacrolimus is initiated, and blood for PD biomarkers will occur on Day +9, Day +16, and Day +23.

MeSH Terms

Interventions

Tacrolimus

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Daniel J Crona, PharmD, PhD

  UNC Lineberger Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 18, 2020
• First Posted: November 27, 2020
• Study Start: February 1, 2021
• Primary Completion: October 15, 2023
• Study Completion: October 15, 2023
• Last Updated: October 17, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)