Dosage Recommendations for Off-label Use of Mycophenolate Mofetil in Pediatric Patients with Thalassemia Undergoing Hematopoietic Stem Cell Transplantation: An Approach Based on Population Pharmacokinetic Studies.

Abstract

Background and objectives: As an immunosuppressant, mycophenolate mofetil (MMF) is used to prevent graft versus host disease (GVHD) in patients after hematopoietic stem cell transplantation (HCT). This study aimed to establish a population pharmacokinetic model and simulate the dosage protocol in HCT patients with thalassemia (TM) to fill the gap of lacking MMF dosing regimen.

Methods: The mycophenolic acid (MPA) plasma concentrations were obtained from HCT patients with TM after using MMF. The population pharmacokinetic (PPK) parameters were obtained by NONMEM (Version VII, Level 2.0; ICON Development Solutions, Ellicott City, MD, USA) program. Monte Carlo simulations were used to determine the optimal dosing.

Results: A total of 239 blood samples from 31 pediatric patients were available, the PPK of MPA was described as a two-compartment model. The typical values for MPA clearance (CL), central distribution volume (V₂), peripheral distribution volume (V₃), intercompartmental clearance (Q), and absorption rate constant (Ka) were 14.9 L/h, 83.5L, 141L, 3.13 L/h, and 1.37/h respectively. The inter-individual variability (IIV) of CL and V₂ were 35% and 41%, respectively. Simulation results suggested that, as the patient's body surface area (BSA) value increased, MMF dosage initiated from 500 mg twice daily was effective.

Conclusions: A 'tiered' dosage regimen including patient urea and with doses stratified across BSA quartiles, rather than a 'one dose fits all' regimen, would help individualize MMF therapy in this population.