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Modelling the influence of MDR1 polymorphism on digoxin pharmacokinetic parameters.

Abstract : 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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https://www.hal.inserm.fr/inserm-00146888
Contributor : Emmanuelle Comets <>
Submitted on : Tuesday, May 15, 2007 - 4:55:38 PM
Last modification on : Wednesday, September 16, 2020 - 5:21:01 PM
Long-term archiving on: : Wednesday, April 7, 2010 - 12:55:44 AM

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Emmanuelle Comets, Céline Verstuyft, Marc Lavielle, Patrice Jaillon, Laurent Becquemont, et al.. Modelling the influence of MDR1 polymorphism on digoxin pharmacokinetic parameters.. European Journal of Clinical Pharmacology, Springer Verlag, 2007, 63 (5), pp.437-49. ⟨10.1007/s00228-007-0269-5⟩. ⟨inserm-00146888⟩

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