title: Pharmacokinetic Variability of Mycophenolic Acid in Pediatric and Adult Patients With Hematopoietic Stem Cell Transplantation.
abstract: The aim of this study was to evaluate the pharmacokinetic variations of mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), in both pediatric and adult patients following hematopoietic stem cell transplantation (HSCT). Twenty pediatric patients with a median age of 3 years (range 0.2-12 years) and 13 adult patients with a median age of 54 years (range 18-63 years) were enrolled. Blood samples were collected on days 0, 7, 14, 21, and 30 after allogeneic HSCT. Total and free (unbound) MPA as well as MPA 7-O-glucuronide (MPAG) were quantified using a validated LC-MS/MS assay. The plasma protein binding of MPA and MPAG did not change significantly in pediatric patients over the 1-month sampling period post-HSCT. However, it increased in adult patients from day 7 to day 30 post-HSCT, from 97.3 ± 0.8% to 98.3 ± 0.6% for MPA (P < .05), and 74.6 ± 9.4% to 82.9 ± 8.1% for MPAG (P < .05). The plasma protein binding of MPA was significantly higher in males compared to females in both pediatric (98.3 ± 1.1% vs 97.4 ± 1.1%) and adult (98.1 ± 0.7% vs 97.4 ± 1.2%) patients (P < .05). The MPAG/MPA ratios on a milligram-per-kilogram dose basis in adult patients were significantly higher than those in pediatric patients (4.3 ± 3.4 vs 2.4 ± 2.6; P < .05). Time-dependent plasma protein binding and age-related differences in MPA metabolism at least in part impact the reported large intra- and interindividual variability in MPA pharmacokinetics. These patient and pharmacologic factors, if incorporated into MMF regimen design and modification, may contribute to the rational dose selection of MMF in HSCT patients.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX, USA. dzhang11@uh.edu.
authors.forename: Daping
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Renbarger
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX, USA.
authors.forename: Diana S-L
authors.initials: DS
authors.lastname: Chow
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D018380:Hematopoietic Stem Cell Transplantation / Q000639:trends*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics; D007223:Infant; D007262:Infusions, Intravenous; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics; D012709:Serum Albumin / Q000378:metabolism; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D012709:Serum Albumin; D009173:Mycophenolic Acid
keywords: hematopoietic stem cell transplantation; metabolism; mycophenolate mofetil; mycophenolic acid; pediatric and adult patients; protein binding