A Pharmacokinetic and Pharmacogenetic Analysis of Osteosarcoma Patients Treated With High-Dose Methotrexate: Data From the OS2006/Sarcoma-09 Trial.
J Clin Pharmacol
; 58(12): 1541-1549, 2018 12.
Article
em En
| MEDLINE
| ID: mdl-29791011
ABSTRACT
Growing evidence suggests that polymorphisms of genes coding for transporters or enzymes may partially explain the large between subject variability reported for methotrexate (MTX) pharmacokinetics (PK). This prospective study aimed to develop a population PK-pharmacogenetic model to evaluate the part of between-subject variability due to single-nucleotide polymorphisms (SNPs) in transporters and enzyme genes implicated in MTX distribution and elimination. MTX concentrations and 54 SNPs (located in ABCB1, ABCC1, ABCC2, ABCC3, ABCC4, ABCG2, SLC19A1, SLCO1B1, and UGT1A1 genes) were analyzed in patients treated with MTX included in the OS2006/sarcoma-09 trial (a multicenter, open-label, phase III trial, ClinicalTrials.gov. Identifier NCT00470223). PK data were analyzed using the nonlinear mixed-effect modeling software program Monolix. The influence of each SNP was evaluated using a stepwise procedure under additive, recessive, or dominant genetic model. The likelihood ratio test was used to test the effect of each SNP on PK parameters. Overall, 187 patients with 7898 MTX blood concentrations were included in the PK-pharmacogenetic analysis. A 2-compartment model adequately described the data. Although high-dose MTX dosing recommendations in pediatric patients are currently based on body surface area, body weight was more predictive of clearance between-subject variability than body surface area. The most significant polymorphism associated with MTX clearance was rs13120400 (on the ABCG2 gene) under the recessive genetic model (P < .0001). GG genotype carriers for rs13120400 appeared to have a moderate decrease in MTX exposure compared to AA or GA carriers.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Ósseas
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Proteínas de Transporte
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Osteossarcoma
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Metotrexato
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Antimetabólitos Antineoplásicos
Tipo de estudo:
Clinical_trials
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Guideline
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Adolescent
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Child
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Female
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Humans
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Male
Idioma:
En
Revista:
J Clin Pharmacol
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
França