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Modelling the influence of MDR1 polymorphism on digoxin pharmacokinetic parameters. |
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| auteur(s) : |
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Emmanuelle Comets ( ) 1, Céline Verstuyft 2, 3, Marc Lavielle 4, Patrice Jaillon 5, Laurent Becquemont 2, 3, 6, France Mentré 1, 7 |
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| laboratoire : |
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| résumé : |
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OBJECTIVES: Digoxin is a well-known probe for the activity of P-glycoprotein. The objective of this work was to apply different methods for covariate selection in non-linear mixed-effect models to study the relationship between the pharmacokinetic parameters of digoxin and the genotype for two major exons located on the multi-drug-resistance 1 (MDR1) gene coding for P-glycoprotein. METHODS: Thirty-two healthy volunteers were recruited in three pharmacokinetic drug interaction studies. The data after a single oral administration of digoxin alone were pooled. All subjects were genotyped for the MDR1 C3435T and G2677T/A genotypes. The concentration-time profile of digoxin was established using 12-16 blood samples taken between 15 min and 72 h after administration. We modelled the pharmacokinetics of digoxin using non-linear mixed-effect models. Parameter estimation was performed using the stochastic approximation EM method (SAEM). We used three methods to select the covariate model: selection from a full model using Wald tests, forward inclusion using the log-likelihood ratio test and model selection using the Bayesian Information Criterion. RESULTS: The three covariate inclusion methods led to the same final model. Carriers of two T alleles for the C3435T polymorphism in exon 26 of MDR1 had a lower apparent volume of distribution than carriers of a C allele. The only other covariate effect was a shorter absorption time-lag in women. CONCLUSION: The apparent volume of distribution of digoxin is lower in TT subjects, probably reflecting differences in bioavailability. Non-linear mixed-effect models can be useful for detecting the influence of covariates on pharmacokinetic parameters. |
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| type de publication : |
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Articles dans des revues avec comité de lecture |
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| domaine : |
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Sciences du Vivant/Bio-Informatique, Biostatistique
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langue du texte
intégral : |
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Anglais |
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| ISSN : |
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0031-6970 |
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| journal : |
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| European Journal of Clinical Pharmacology (Eur J Clin Pharmacol) |
| Publisher |
Springer Verlag (Germany) |
| ISSN |
0031-6970 (eISSN : 1432-1041) |
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| date de publication : |
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05/2007 |
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date de publication
électronique : |
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13/03/2007 |
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| volume : |
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63 |
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| numéro : |
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5 |
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| page, identifiant, ... : |
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437-49 |
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| mots-clés auteur : |
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digoxin – population pharmacokinetics – pharmacogenetics – P-glycoprotein |
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