Dataset Information

Optimizing drug therapy in pediatric SCT: focus on pharmacokinetics.

ABSTRACT: Given age-related differences in drug metabolism and indications for hematopoietic SCT (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 post-grafting immunosuppression, presented at the First Annual Pediatric Bone Marrow Transplant Consortium (PBMTC) 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, CY, fludarabine and alemtuzumab as HSCT conditioning in children. For post-grafting 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.

SUBMITTER: McCune JS

PROVIDER: S-EPMC5996991 | biostudies-other | 2015 Feb

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Optimizing drug therapy in pediatric SCT: focus on pharmacokinetics.

McCune J S JS Jacobson P P Wiseman A A Militano O O

Bone marrow transplantation 20141027 2

Given age-related differences in drug metabolism and indications for hematopoietic SCT (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 post-grafting immunosuppression, presented at the First Annual Pediatric Bone Marrow Transplant Consortium (PBMTC) meeting in April 2013. Person ...[more]

PMID: 25347008

Similar Datasets

Project description:A prospective multicenter study was conducted to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of fludarabine plasma (f-ara-a) and intracellular triphosphate (f-ara-ATP) in children undergoing hematopoietic cell transplantation (HCT) and receiving fludarabine with conditioning. Plasma and peripheral blood mononuclear cells (PBMCs) were collected over the course of therapy for quantitation of f-ara-a and f-ara-ATP. Nonlinear mixed-effects modeling was used to develop the PK model, including identification of covariates impacting drug disposition. Data from a total of 133 children (median age, 5 years; range, .2 to 17.9) undergoing HCT for a variety of malignant and nonmalignant disorders were available for PK-PD modeling. The implementation of allometric scaling of PK parameters alone was insufficient to describe drug clearance, particularly in very young children. Renal impairment was predicted to increase drug exposure across all ages. The rate of f-ara-a entry into PBMCs (expressed in pmoles per million cells) decreased over the course of therapy, resulting in 78% lower f-ara-ATP after the fourth dose (1.7 pmoles/million cells [range, .2 to 7.2]) compared with first dose (7.9 pmoles/million cells [range, .7 to 18.2]). The overall incidence of treatment-related mortality (TRM) was low at 3% and 8% at days 60 and 360, respectively, and no association with f-ara-a exposure and TRM was found. In the setting of malignancy, disease-free survival was highest at 1 year after HCT in subjects achieving a systemic f-ara-a cumulative area under the curve (cAUC) greater than 15 mg*hour/L compared to patients with a cAUC less than 15 mg*hour/L (82.6% versus 52.8% P = .04). These results suggest that individualized model-based dosing of fludarabine in infants and young children may reduce morbidity and mortality through improved rates of disease-free survival and limiting drug-related toxicity. ClinicalTrials.gov Identifier: NCT01316549.

Dataset Information

Optimizing drug therapy in pediatric SCT: focus on pharmacokinetics.

Publications

Optimizing drug therapy in pediatric SCT: focus on pharmacokinetics.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets