Modelling the influence of MDR1 polymorphism on digoxin pharmacokinetic parameters.
OBJECTIVE
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.


CONCLUSIONS
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.
Comets
Emmanuelle
E
INSERM, U738, Paris, France. emmanuelle.comets@bichat.inserm.fr
Verstuyft
Céline
C
Lavielle
Marc
M
Jaillon
Patrice
P
Becquemont
Laurent
L
Mentré
France
F
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000483:Alleles; D001499:Bayes Theorem; D001682:Biological Availability; D004077:Digoxin / Q000493:pharmacokinetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D012737:Sex Factors; D013269:Stochastic Processes; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004077:Digoxin