Modelling the influence of MDR1 polymorphism on digoxin pharmacokinetic parameters
Modelling the influence of MDR1 polymorphism on digoxin pharmacokinetic parameters
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DOI：
10.1007/s00228-007-0269-5
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发表时间：
2007-05-01
影响因子：
2.9
通讯作者：
Mentre, France
中科院分区：
文献类型：
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作者：
Comets, Emmanuelle;Verstuyft, Celine;Mentre, France
目的：地高辛是一种已知的P-糖蛋白活性探针。本工作的目的是应用不同的方法进行协变量选择的非线性混合效应模型，研究地高辛的药代动力学参数和基因型之间的关系位于多药耐药1（MDR 1）基因编码的P-糖蛋白。方法：32名健康志愿者被招募在三个药代动力学药物相互作用研究。汇总地高辛单次口服给药后的数据。对所有受试者进行MDR 1 C3435 T和G2677 T/A基因型分型。使用给药后15 min至72 h采集的12-16份血样建立地高辛的浓度-时间曲线。我们使用非线性混合效应模型模拟地高辛的药代动力学。使用随机近似EM方法（SAEM）进行参数估计。我们使用了三种方法来选择协变量模型：选择从一个完整的模型，使用Wald检验，向前包含使用对数似然比检验和模型选择使用贝叶斯信息Criterion.Results：三种协变量包含方法导致相同的最终模型。携带两个T等位基因的C3435 T多态性在MDR 1的外显子26有一个较低的表观分布容积比携带者的C等位基因。唯一的其他协变量的影响是一个较短的吸收时间滞后women.Conclusion：地高辛的表观分布容积较低TT受试者，可能反映了生物利用度的差异。非线性混合效应模型可用于检测协变量对药代动力学参数的影响。
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.