Optimizing drug therapy in pediatric stem cell transplantation: Focus on pharmacokinetics

摘要

Given age-related differences in drug metabolism and indications for hematopoietic stem cell transplantation (HSCT), personalized drug dosing of the conditioning regimen and post-transplant immunosuppression may reduce graft rejection, relapse rates, and toxicity in pediatric HSCT recipients. This manuscript summarizes the pharmacokinetic/dynamic data of HSCT conditioning and postgrafting immunosuppression, presented at the First Annual Pediatric Bone Marrow Transplant Consortium meeting in April 2013. Personalized dosing of BU to a target plasma exposure reduces graft rejection in children and improves relapse/toxicity rates in adults. Current weight-based dosing achieves the target BU exposure in only a minority (24.3%) of children. The initial BU dose should be based on the European Medicines Agency nomogram or population pharmacokinetic models to improve the numbers of children achieving the target exposure. There are limited pharmacokinetic data for treosulfan, cyclophosphamide, fludarabine, and alemtuzumab as HSCT conditioning in children. For postgrafting immunosuppression, mycophenolic acid (MPA) clearance may be increased in younger children (< 12 years). The preferred MPA pharmacokinetic monitoring parameters and target range are still evolving in HSCT recipients. Multi-institutional trials incorporating properly powered pharmacokinetic/dynamic studies are needed to assess the effect of variability in the plasma exposure of drugs/metabolites on clinical outcomes in pediatric HSCT recipients.