title: Mycophenolate pharmacokinetics and association with response to acute graft-versus-host disease treatment from the Blood and Marrow Transplant Clinical Trials Network.
abstract: There are limited data as to the effectiveness of mycophenolate mofetil (MMF) plus high-dose corticosteroids for the treatment of acute graft-versus-host disease (aGVHD), and even less data regarding the pharmacokinetic disposition and exposure-response relationship of MMF in individuals with GVHD. MMF pharmacokinetics were studied in a multicenter Blood and Marrow Transplant Clinical Trials Network randomized phase II trial evaluating the effectiveness of MMF as one of 4 agents added to corticosteroids as treatment of aGVHD. Thirty-two of the patients randomized to receive MMF underwent pharmacokinetic sampling in weeks 1 and 2 were studied. Mean age was 41 +/- 13.6 years. Twenty one (65.6%), 5 (15.6%), 6 (18.8%) patients had a complete response (CR), partial response (PR) or lesser response by day 28, respectively. Twenty-five (78.1%), 2 (6.3%), 5 (15.6%) patients had a CR, PR, or other response by day 56 to treatment, respectively. Mycophenolic acid (MPA) pharmacokinetic measurements from weeks 1 and 2 did not correlate with CR at either day 28 or day 56 (P > .07); however, if the mean of weeks 1 and 2 total MPA troughs was >0.5 microg/mL or that of an unbound trough was >0.015 microg/mL, then a significantly greater proportion achieved CR + PR at days 28 and 56. CR + PR at day 28 was observed in 19 of 19 patients (100%) with a mean total trough >0.5 mg/mL, but in only 7 of 13 (54%) with a mean total trough < or =0.5 microg/mL (P = .002). Similarly, CR + PR at day 28 was seen in 15 of 15 patients (100%) with an unbound trough concentration >0.015 microg/mL, but in only 11 of 17 (65%) with an unbound trough concentration < or =0.015 microg/mL (P = .02). There was no association between the pharmacokinetic measures and risk of infection by day 90 or overall survival (OS) at day 180 postrandomization. About one-half of subjects did not achieve the favorable MPA total and unbound trough concentrations. The current practice of MMF 1 gm twice daily dosing provides low plasma concentrations in many patients. Higher doses may improve the efficacy of MMF as aGVHD therapy.
authors.affiliation: Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN 55455, USA. jacob117@umn.edu
authors.forename: Pamala A
authors.initials: PA
authors.lastname: Jacobson
authors.forename: Jiayin
authors.initials: J
authors.lastname: Huang
authors.forename: Juan
authors.initials: J
authors.lastname: Wu
authors.forename: Miae
authors.initials: M
authors.lastname: Kim
authors.forename: Brent
authors.initials: B
authors.lastname: Logan
authors.forename: Amin
authors.initials: A
authors.lastname: Alousi
authors.forename: Michael
authors.initials: M
authors.lastname: Grimley
authors.forename: Javier
authors.initials: J
authors.lastname: Bolaños-Meade
authors.forename: Vincent
authors.initials: V
authors.lastname: Ho
authors.forename: John E
authors.initials: JE
authors.lastname: Levine
authors.forename: Daniel
authors.initials: D
authors.lastname: Weisdorf
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D019540:Area Under Curve; D003141:Communicable Diseases / Q000150:complications; D004359:Drug Therapy, Combination; D020719:Glucuronides / Q000097:blood; D006086:Graft vs Host Disease / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008099:Liver / Q000473:pathology; D041741:Lower Gastrointestinal Tract / Q000473:pathology; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D012074:Remission Induction; D012867:Skin / Q000473:pathology; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D020719:Glucuronides; D007166:Immunosuppressive Agents; C113145:mycophenolic acid glucuronide; D009173:Mycophenolic Acid