Document Detail


Mycophenolate pharmacokinetics and association with response to acute graft-versus-host disease treatment from the Blood and Marrow Transplant Clinical Trials Network.
MedLine Citation:
PMID:  19925875     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Pamala A Jacobson; Jiayin Huang; Juan Wu; Miae Kim; Brent Logan; Amin Alousi; Michael Grimley; Javier Bolaños-Meade; Vincent Ho; John E Levine; Daniel Weisdorf
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Publication Detail:
Type:  Clinical Trial, Phase II; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation     Volume:  16     ISSN:  1523-6536     ISO Abbreviation:  Biol. Blood Marrow Transplant.     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-02-15     Completed Date:  2010-05-28     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  9600628     Medline TA:  Biol Blood Marrow Transplant     Country:  United States    
Other Details:
Languages:  eng     Pagination:  421-9     Citation Subset:  IM    
Copyright Information:
Copyright (c) 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00224874
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MeSH Terms
Descriptor/Qualifier:
Adrenal Cortex Hormones / therapeutic use
Adult
Area Under Curve
Communicable Diseases / complications
Drug Therapy, Combination
Glucuronides / blood
Graft vs Host Disease / complications,  drug therapy*,  pathology
Humans
Immunosuppressive Agents / administration & dosage,  pharmacology,  therapeutic use
Liver / pathology
Lower Gastrointestinal Tract / pathology
Middle Aged
Mycophenolic Acid / administration & dosage,  analogs & derivatives*,  blood,  pharmacokinetics,  therapeutic use
Remission Induction
Skin / pathology
Survival Analysis
Treatment Outcome
Grant Support
ID/Acronym/Agency:
K23 CA096622/CA/NCI NIH HHS; K23 CA096622-05/CA/NCI NIH HHS; U10 HL069290/HL/NHLBI NIH HHS; U10 HL069330/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Adrenal Cortex Hormones; 0/Glucuronides; 0/Immunosuppressive Agents; 0/mycophenolic acid glucuronide; 9242ECW6R0/mycophenolate mofetil; HU9DX48N0T/Mycophenolic Acid
Comments/Corrections

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