title: Pharmacodynamics of mycophenolate mofetil after nonmyeloablative conditioning and unrelated donor hematopoietic cell transplantation.
abstract: The immunosuppressive drug mycophenolate mofetil (MMF) is used after nonmyeloablative hematopoietic cell transplantation (HCT); however, limited pharmacodynamic data are available. We evaluated plasma concentrations of mycophenolic acid (MPA), the active metabolite of MMF, and outcomes in 85 patients with hematologic malignancies conditioned with fludarabine and 2 Gy total body irradiation followed by HLA-matched unrelated-donor HCT and postgrafting cyclosporine and MMF. The first 38 patients received MMF 15 mg/kg twice daily; the next 47 patients received MMF 3 times daily. MPA pharmacokinetics were determined on days 7 and 21. Comparing the twice-daily and 3-times-daily MMF groups, the mean total MPA concentration steady state (Css) was 1.9 and 3.1 microg/mL; the unbound Css was 18 and 36 ng/mL, respectively (P < .001). Sixteen patients with a total MPA Css less than 3 microg/mL had low (< 50%) donor T-cell chimerism (P = .03), and 6 patients with MPA Css less than 2.5 microg/mL had graft rejection. An elevated unbound Css was associated with cytomegalovirus reactivation (P = .03). There were no significant associations between MPA pharmacokinetics and acute graft-versus-host disease (GVHD) or relapse. We conclude that increased MPA Css's predicted higher degrees of donor T-cell chimerism after unrelated donor nonmyeloablative HCT and suggest that targeting MPA Css's greater than 2.5 microg/mL could prevent graft rejection.
authors.affiliation: Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D1-100, PO Box 19024, Seattle, WA 98109-1024, USA.
authors.forename: Luisa
authors.initials: L
authors.lastname: Giaccone
authors.forename: Jeannine S
authors.initials: JS
authors.lastname: McCune
authors.forename: Michael B
authors.initials: MB
authors.lastname: Maris
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Gooley
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Sandmaier
authors.forename: John T
authors.initials: JT
authors.lastname: Slattery
authors.forename: Scott
authors.initials: S
authors.lastname: Cole
authors.forename: Richard A
authors.initials: RA
authors.lastname: Nash
authors.forename: Rainer F
authors.initials: RF
authors.lastname: Storb
authors.forename: George E
authors.initials: GE
authors.lastname: Georges
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D046528:Chimerism; D003587:Cytomegalovirus / Q000502:physiology; D006084:Graft Rejection / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008099:Liver / Q000502:physiology; D008111:Liver Function Tests; D008875:Middle Aged; D009101:Multiple Myeloma / Q000473:pathology / Q000601:surgery; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D009325:Nausea / Q000150:complications; D009503:Neutropenia / Q000150:complications; D012008:Recurrence; D012709:Serum Albumin / Q000378:metabolism; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014775:Virus Activation
chemical_list: D012709:Serum Albumin; D009173:Mycophenolic Acid