Reduced Physiologically-Based Pharmacokinetic Model of Repaglinide: Impact of OATP1B1 and CYP2C8 Genotype and Source of In Vitro Data on the Prediction of Drug-Drug Interaction Risk
Reduced Physiologically-Based Pharmacokinetic Model of Repaglinide: Impact of OATP1B1 and CYP2C8 Genotype and Source of In Vitro Data on the Prediction of Drug-Drug Interaction Risk
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DOI：
10.1007/s11095-014-1333-3
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发表时间：
2014-09-01
影响因子：
3.7
通讯作者：
Galetin, Aleksandra
中科院分区：
文献类型：
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作者：
Gertz, Michael;Tsamandouras, Nikolaos;Galetin, Aleksandra
采用基于生理的药代动力学（PBPK）模型，研究OATP1B1基因型作为一个变量对瑞格列奈药代动力学和药物-药物相互作用（ddi）风险的影响。在NONMEM v.7.2中，采用群体方法，使用29个SLCO1B1 C . 521t > C的平均血浆浓度-时间谱来估计不同基因型组的肝摄取清除率（cl摄取）。估计对SLCO1B1 c.521TT/TC和CC的瑞格列奈cl摄取分别对应于217和113 μ L/min/10(6)个细胞。OATP1B1基因型对cl2摄取有显著影响（与野生型相比，CC降低48%）。敏感性分析强调了CLmet和CLdiff不确定性对利用等离子体数据优化cl摄取的影响。这种不确定性的传播对瑞格列奈oatp1b1介导的DDI与环孢素的预测有边际影响；然而，瑞格列奈代谢DDI预测值的敏感性较高。此外，采用简化PBPK模型模拟评估CYP2C8*3和SLCO1B1 C . 521t > C对瑞格列奈暴露的影响；进行功率计算以指导前瞻性DDI和药物遗传学研究。简化PBPK模型用于参数优化的应用，以及与使用等离子体而不是组织剖面相关的该过程的局限性。
To investigate the effect of OATP1B1 genotype as a covariate on repaglinide pharmacokinetics and drug-drug interaction (DDIs) risk using a reduced physiologically-based pharmacokinetic (PBPK) model.Twenty nine mean plasma concentration-time profiles for SLCO1B1 c.521T > C were used to estimate hepatic uptake clearance (CLuptake) in different genotype groups applying a population approach in NONMEM v.7.2.Estimated repaglinide CLuptake corresponded to 217 and 113 mu L/min/10(6) cells for SLCO1B1 c.521TT/TC and CC, respectively. A significant effect of OATP1B1 genotype was seen on CLuptake (48% reduction for CC relative to wild type). Sensitivity analysis highlighted the impact of CLmet and CLdiff uncertainty on the CLuptake optimization using plasma data. Propagation of this uncertainty had a marginal effect on the prediction of repaglinide OATP1B1-mediated DDI with cyclosporine; however, sensitivity of the predicted magnitude of repaglinide metabolic DDI was high. In addition, the reduced PBPK model was used to assess the effect of both CYP2C8*3 and SLCO1B1 c.521T > C on repaglinide exposure by simulations; power calculations were performed to guide prospective DDI and pharmacogenetic studies.The application of reduced PBPK model for parameter optimization and limitations of this process associated with the use of plasma rather than tissue profiles are illustrated.