The Population Pharmacokinetics of High-Dose Methotrexate in Infants with Acute Lymphoblastic Leukemia Highlight the Need for Bedside Individualized Dose Adjustment: A Report from the Children's Oncology Group.
Clin Pharmacokinet
; 58(7): 899-910, 2019 07.
Article
em En
| MEDLINE
| ID: mdl-30810947
ABSTRACT
BACKGROUND:
Infants with acute lymphoblastic leukemia (ALL) treated with high-dose methotrexate may have reduced methotrexate clearance (CL) due to renal immaturity, which may predispose them to toxicity.OBJECTIVE:
The aim of this study was to develop a population pharmacokinetic (PK) model of methotrexate in infants with ALL.METHODS:
A total of 672 methotrexate plasma concentrations were obtained from 71 infants enrolled in the Children's Oncology Group (COG) Clinical Trial P9407. Infants received methotrexate 4 g/m2 intravenously for four cycles during weeks 4-12 of intensification. A population PK analysis was performed using NONMEM® version 7.4. The final model was evaluated using a non-parametric bootstrap and a visual predictive check. Simulations were performed to evaluate methotrexate dose and the utility of a bedside algorithm for dose individualization.RESULTS:
Methotrexate was best characterized by a two-compartment model with allometric scaling. Weight was the only covariate included in the final model. The coefficient of variation for interoccasion variability (IOV) on CL was relatively high at 25.4%, compared with the interindividual variability for CL and central volume of distribution (10.7% and 13.2%, respectively). Simulations identified that 21.1% of simulated infants benefitted from bedside dose adjustment, and adjustment of methotrexate doses during infusions can avoid supratherapeutic concentrations.CONCLUSION:
Infants treated with high-dose methotrexate demonstrated a relatively high degree of IOV in methotrexate CL. The magnitude of IOV in the CL of methotrexate suggests that use of a bedside algorithm may avoid supratherapeutic methotrexate concentrations resulting from high IOV in methotrexate CL.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Metotrexato
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Leucemia-Linfoma Linfoblástico de Células Precursoras
/
Modelos Biológicos
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Antimetabólitos Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Female
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Humans
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Infant
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Male
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article