Area-under-the-Curve-Based Mycophenolate Mofetil Dosage May Contribute to Decrease the Incidence of Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients

Abstract

Acute graft-versus-host disease (GvHD) remains the second leading cause of death, after disease relapse, in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). The medical records of 112 pediatric patients who underwent allo-HSCT from matched unrelated and haploidentical donors were analyzed. Patients were divided into two groups, according to the GvHD prophylactic regimen used. In the control group, GvHD prophylaxis consisted of cyclosporine A (CsA) and methotrexate (MTX) or CsA and mycophenolate mofetil (MMF) at a standard daily dose of 30 mg/kg. All subjects in the study group received tacrolimus (FK506) and MMF. In this group, MMF was subjected to therapeutic drug monitoring (TDM) through mycophenolic acid (MPA) area under the curve AUC0–12. We found a statistically significant difference in both overall acute GvHD (p < 0.0001) and overall chronic GvHD (p < 0.05) incidence between the study and the control group. The initial daily MMF dose and the age at transplant in the study group proved to be inversely correlated (r = −0.523, p < 0.0001). The children under six years of age required a significantly higher daily MMF dose (p < 0.008). This study showed that pharmacological monitoring of MPA AUC0–12 concentration allowed a reduction in the incidence of acute and chronic GvHD. MMF showed age-dependent pharmacokinetics due to greater drug clearance in younger children.

A Systematic Review of Multiple Linear Regression-Based Limited Sampling Strategies for Mycophenolic Acid Area Under the Concentration–Time Curve Estimation

“…Van Hest et al [ 43 ] checked the utility of MPA LSS established for patients without diabetes in patients with diabetes and showed LSS suitability in the latter group. The LSS developed by Weber et al [ 65 ] was applied to calculate MPA AUC 0–12 and to obtain the optimal MMF dose in children after allogeneic hematopoietic cell transplantation [ 83 ]. The authors [ 83 ] proved that pharmacological monitoring of MPA AUC 0–12 allowed a reduction in the incidence of acute and chronic graft-versus-host disease in patients who were undergoing prophylactic treatment with Tac and MMF.…”

“…The LSS developed by Weber et al [ 65 ] was applied to calculate MPA AUC 0–12 and to obtain the optimal MMF dose in children after allogeneic hematopoietic cell transplantation [ 83 ]. The authors [ 83 ] proved that pharmacological monitoring of MPA AUC 0–12 allowed a reduction in the incidence of acute and chronic graft-versus-host disease in patients who were undergoing prophylactic treatment with Tac and MMF. The MPA AUC 0–12 was calculated using the LSS developed by Yamaguchi et al [ 29 ] to evaluate the effects of UDP-glucuronosyltransferases polymorphisms on the pharmacokinetics of MMF in Chinese renal transplant recipients [ 84 ].…”

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

“…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]…”

“…Those LSSs that include MPA concentrations within 2-3 h after drug administration might facilitate TDM. Some LSSs have been applied in clinical practice to adjust MMF dose, e.g., Berger et al [75] conducted TDM-adjusted MMF dosing in children after renal transplantation based on LSS-calculated AUC and Carlone et al [88] applied LSS for MPA AUC 0-12 estimation and adjusted MMF oral dose to achieve target MPA AUC 0-12 in children treated with MMF and Tac after HSCT.…”

“…In children after HSCT, treated with MMF and Tac, it was proved that adjusting MMF dose to achieve MPA AUC 0-12 within 30-60 µg•h/mL allowed a reduction in the incidence of acute and chronic GvHD [88]. Windreich et al [87] proved that individualized MMF dosing by targeting MPA AUC was feasible, safe, and effective in the early phase after allo-HCT in children treated with MMF and CsA.…”