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 thirteen 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 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 one 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 <0.05), and 74.6±9.4% to 82.9±8.1% for MPAG (P <0.05). 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 <0.05). The MPAG/MPA ratios on an mg/kg dose basis in adult patients were significantly higher than those in pediatric patients

Recent Advances in Therapeutic Drug Monitoring of Voriconazole, Mycophenolic Acid, and Vancomycin: A Literature Review of Pediatric Studies

“…In pediatric patients after HSCT, MPA as well as MPAG plasma protein binding was significantly higher in boys compared to girls (98.3% ± 1.1% vs. 97.4% ± 1.1% for MPA; 78.7% ± 8.7% vs. 73.3% ± 9.4% for MPAG). Consequently, lower percentages of unbound forms were observed in pediatric males than females (1.7% ± 1.1% vs. 2.6% ± 1.1% for MPA; 21.3% ± 8.7% vs. 26.7% ± 9.4% for MPAG) [85].…”

“…Zhang et al [85] also observed gender-related differences in pharmacokinetics. In pediatric patients after HSCT, MPA as well as MPAG plasma protein binding was significantly higher in boys compared to girls (98.3% ± 1.1% vs. 97.4% ± 1.1% for MPA; 78.7% ± 8.7% vs. 73.3% ± 9.4% for MPAG).…”

“…Nakaseko et al [109] found in juvenile patients with autoimmune diseases that the actual measured MPA AUC 0-12 and the AUC 0-12 corrected for dose per body weight and time to reach maximum concentration (C max ) were lower in young patients, whereas the AUC 0-12 corrected for dose per body surface area and C max were comparable among all the groups. Although Harnicar et al [85] did not identify an age effect, they concluded that young children were potentially at special risk as patients <16 years of age had lower troughs over the 6-week period, as expected given their faster MMF metabolism. Kim et al [84] indicated that for children <10 kg, higher doses may be required to achieve exposure similar to that in adults known to prevent acute GVHD.…”

“…MPA TDM is recommended in pediatric patients, but it is still not a routine practice although numerous studies proved the advantage of dose adjustment based on TDM [66][67][68][69][70][71][72][73]. Our review includes studies on the MPA TDM in children after renal transplantation [67,[74][75][76][77][78][79][80][81], other organ transplantation such as heart [82,83], liver [72], or intestine [65], children after hematopoietic stem cell transplantation [84][85][86][87][88][89] or cord blood transplantation [90], and children with lupus [71,73,[91][92][93][94][95][96], nephrotic syndrome [69,70,[97][98][99][100][101][102][103][104][105]…”

A Limited Sampling Strategy for Therapeutic Drug Monitoring of Mycophenolate Mofetil for Prophylaxis of Acute Graft-Versus-Host Disease in Allogeneic Stem Cell Transplantation

“…Combination regimens that include MMF have shown that it permits a reduction in dose of cyclosporine, tacrolimus, or corticosteroid without increasing the chances of acute rejections 7 – 9 . The systemic exposure of MPA is unpredictable and wide variations in pharmacokinetics have been reported 2 , 10 – 13 . Thus, therapeutic drug monitoring (TDM) of MMF is routinely practiced in solid organ transplants to target a specified area under the concentration–time curve (AUC) based on exposure–effect relationship.…”