title: Nonrelapse mortality and mycophenolic acid exposure in nonmyeloablative hematopoietic cell transplantation.
abstract: We evaluated the pharmacodynamic relationships between mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and outcomes in 308 patients after nonmyeloablative hematopoietic cell transplantation. Patients were conditioned with total body irradiation ± fludarabine, received grafts from HLA-matched related (n = 132) or unrelated (n = 176) donors, and received postgrafting immunosuppression with MMF and a calcineurin inhibitor. Total and unbound MPA pharmacokinetics were determined to day 25; maximum a posteriori Bayesian estimators were used to estimate total MPA concentration at steady state (Css). Rejection occurred in 9 patients, 8 of whom had a total MPA Css less than 3 μg/mL. In patients receiving a related donor graft, MPA Css was not associated with clinical outcomes. In patients receiving an unrelated donor graft, low total MPA Css was associated with increased grades III to IV acute graft-versus-host disease and increased nonrelapse mortality but not with day 28 T cell chimerism, disease relapse, cytomegalovirus reactivation, or overall survival. We conclude that higher initial oral MMF doses and subsequent targeting of total MPA Css to greater than 2.96 μg/mL could lower grades III to IV acute graft-versus-host disease and nonrelapse mortality in patients receiving an unrelated donor graft.
authors: Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA 98195, USA.
authors: Cara L
authors: CL
authors: McDermott
authors: Brenda M
authors: BM
authors: Sandmaier
authors: Barry
authors: B
authors: Storer
authors: Hong
authors: H
authors: Li
authors: Donald E
authors: DE
authors: Mager
authors: Michael J
authors: MJ
authors: Boeckh
authors: Meagan J
authors: MJ
authors: Bemer
authors: Jennifer
authors: J
authors: Knutson
authors: Jeannine S
authors: JS
authors: McCune
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001499:Bayes Theorem; D015331:Cohort Studies; D005260:Female; D006086:Graft vs Host Disease / Q000139:chemically induced / Q000209:etiology* / Q000401:mortality; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D019172:Transplantation Conditioning / Q000379:methods; D055815:Young Adult
chemical_list: D009173:Mycophenolic Acid
keywords: Bayesian; Graft versus host disease; Hematopoietic cell transplant; Mycophenolic acid; Pharmacokinetics
references: Clin Pharmacokinet. 2007;46(1):13-58
references: 17201457
references: Transplantation. 1999 Feb 27;67(4):499-504
references: 10071016
references: Clin Transplant. 2011 Mar-Apr;25(2):222-7
references: 20201951
references: Clin Chem. 1995 Jul;41(7):1011-7
references: 7600680
references: Blood. 2001 Jun 1;97(11):3390-400
references: 11369628
references: J Clin Pharmacol. 2012 Nov;52(11):1654-64
references: 22174435
references: Bone Marrow Transplant. 2012 Apr;47(4):581-8
references: 21552302
references: Blood Rev. 2005 May;19(3):153-64
references: 15748963
references: Am J Transplant. 2007 Nov;7(11):2496-503
references: 17908276
references: Pharmacol Res. 2011 May;63(5):423-31
references: 21272643
references: Am J Transplant. 2004 Dec;4(12):2045-51
references: 15575908
references: Clin Transplant. 2000 Apr;14(2):121-6
references: 10770416
references: JAMA. 2011 Nov 2;306(17):1918-20
references: 22045771
references: Blood. 2004 Oct 15;104(8):2254-62
references: 15226174
references: Anal Chem. 2012 Jan 3;84(1):216-23
references: 22092180
references: Bone Marrow Transplant. 2008 Jul;42(2):113-20
references: 18362900
references: Biol Blood Marrow Transplant. 2010 Mar;16(3):333-43
references: 19835971
references: Biol Blood Marrow Transplant. 2005 Jul;11(7):495-505
references: 15983549
references: Biol Blood Marrow Transplant. 2010 Mar;16(3):421-9
references: 19925875
references: Blood. 2003 Sep 15;102(6):2021-30
references: 12791654
references: Biol Blood Marrow Transplant. 2007 Sep;13(9):1041-8
references: 17697966
references: Blood. 2005 Dec 15;106(13):4381-8
references: 16144801
references: Stat Med. 1999 Mar 30;18(6):695-706
references: 10204198
references: Biol Blood Marrow Transplant. 2004 Apr;10(4):246-58
references: 15077223
references: Clin Transplant. 2001 Jun;15(3):176-84
references: 11389708
references: Bone Marrow Transplant. 1995 Jun;15(6):825-8
references: 7581076
references: Clin Pharmacokinet. 2009;48(10):667-75
references: 19743888
references: Anal Chem. 2001 Jan 1;73(1):41-6
references: 11195509
references: Ther Drug Monit. 2010 Oct;32(5):606-14
references: 20720518
references: Semin Hematol. 1991 Jul;28(3):250-9
references: 1887253
references: J Chromatogr B Biomed Appl. 1996 Jan 12;675(1):119-29
references: 8634753
references: Biol Blood Marrow Transplant. 2009 Sep;15(9):1134-9
references: 19660728
references: Clin Pharmacol Ther. 2005 Nov;78(5):486-500
references: 16321615
references: JAMA. 2011 Nov 2;306(17):1874-83
references: 22045765
references: Transplantation. 1999 Jul 27;68(2):261-6
references: 10440399
references: J Clin Pharmacol. 2013 Apr;53(4):393-402
references: 23382105
references: Biol Blood Marrow Transplant. 2006 Apr;12(4):454-65
references: 16545729
references: Leukemia. 2006 Oct;20(10):1701-5
references: 16888618
references: Transplantation. 1974 Oct;18(4):295-304
references: 4153799
references: Clin Biochem. 2000 Apr;33(3):203-8
references: 10913519
references: Bone Marrow Transplant. 2001 Oct;28(8):743-51
references: 11781625
references: Blood. 2007 Oct 1;110(7):2744-8
references: 17595333
references: Clin Pharmacol Ther. 2009 Jun;85(6):615-22
references: 19295506
references: Biol Blood Marrow Transplant. 2012 Mar;18(3):414-22
references: 21875504
references: Bone Marrow Transplant. 2009 Dec;44(11):739-48
references: 19377515