Dose schedule optimization and the pharmacokinetic driver of neutropenia.
PLoS One
; 9(10): e109892, 2014.
Article
em En
| MEDLINE
| ID: mdl-25360756
ABSTRACT
Toxicity often limits the utility of oncology drugs, and optimization of dose schedule represents one option for mitigation of this toxicity. Here we explore the schedule-dependency of neutropenia, a common dose-limiting toxicity. To this end, we analyze previously published mathematical models of neutropenia to identify a pharmacokinetic (PK) predictor of the neutrophil nadir, and confirm this PK predictor in an in vivo experimental system. Specifically, we find total AUC and Cmax are poor predictors of the neutrophil nadir, while a PK measure based on the moving average of the drug concentration correlates highly with neutropenia. Further, we confirm this PK parameter for its ability to predict neutropenia in vivo following treatment with different doses and schedules. This work represents an attempt at mechanistically deriving a fundamental understanding of the underlying pharmacokinetic drivers of neutropenia, and provides insights that can be leveraged in a translational setting during schedule selection.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Esquema de Medicação
/
Modelos Biológicos
/
Neutropenia
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article