Optimizing drug therapy in pediatric SCT: Focus on pharmacokinetics

Abstract

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.

Haploidentical transplantation in children with unmanipulated peripheral blood stem cell graft: The need to look beyond post‐transplantation cyclophosphamide in younger children

“…The findings of our study might thus be explained by the reduced efficacy of PTCY in clearing alloreactive T cells in younger children coupled with variable MMF metabolism, which are probably attributable to the differing metabolisms of these drugs in younger children as exemplified in the PK studies . Unfortunately, PK data are not available in this cohort of patients as they were not a part of the original study.…”

“…The age of the children in this cohort varied between two and 15 yr. On the other hand, another PK study of high-dose CY in children above the age of 10 yr undergoing myeloablative conditioning for solid tumors did not reveal any impact of age on clearance or the volume of distribution of CY (21). It is possible that a dosing based on body weight might not be optimum in younger children (22). The other contributing factor could have been related to the PK s of MMF in younger children (23).…”

A Pilot Study of Continuous Infusion of Mycophenolate Mofetil for Prophylaxis of Graft-versus-Host-Disease in Pediatric Patients

“…MPA pharmacokinetics has been extensively studied in adult reduced-intensity transplants; however, the data in myeloablative transplants, especially in the pediatric age group, is very limited (reviewed in McCune et al [20]). Although retrospective studies have shown correlation between MPA levels and risk of aGVHD and there is a large inter-and intrapatient pharmacokinetic variability, MMF continues to be used on a fixed-dose schedule [21][22][23].…”

Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II

“…Proper characterization of age-dependent pharmacokinetics is particularly important to alloHCT as newborn screening techniques are leading to earlier diagnosis of immunodeficienicies and, in turn, younger alloHCT recipients. 171 The expression of drug clearance relative to BSA appears to be the most appropriate method for comparing clearance in children of varying ages. 172 The current practice of linearly dividing dose by body weight does not reflect the true nature of the relationship between clearance and dosing weight.…”