Prediction of drug clearance in a smoking population: modeling the impact of variable cigarette consumption on the induction of CYP1A2
Prediction of drug clearance in a smoking population: modeling the impact of variable cigarette consumption on the induction of CYP1A2
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DOI：
10.1007/s00228-011-1189-y
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发表时间：
2012-06-01
影响因子：
2.9
通讯作者：
Yeo, Karen Rowland
中科院分区：
文献类型：
--
作者：
Plowchalk, David R.;Yeo, Karen Rowland
得出 CYP1A2 丰度的估计值作为每日香烟消费量的函数，并使用这些值来预测吸烟者 CYP1A2 底物的清除率。吸烟引起的肝脏 CYP1A2 丰度变化是根据报告的吸烟人群亚组的体内咖啡因清除率数据推断出来的，这些亚组根据每日香烟消费量进行分类。这些丰度值与基于 Simcyp 群体的模拟器中的体外体内外推法 (IVIVE) 一起用于预测吸烟者中咖啡因、茶碱和氯氮平的清除率。随后，在一项涉及 PF-2400013（一种由 CYP1A2 代谢的药物）的 1 期临床试验中，该模型被用来预测吸烟者和非吸烟者队列之间口腔清除率的差异。对于吸烟 0、1-5、6-10 岁的受试者，估计肝脏 CYP1A2 丰度值为 52、64、79、90 和 94 pmol/mg 微粒体蛋白。分别为 11-20 支和 > 20 支/天。相对于非吸烟者，吸烟者咖啡因、茶碱和氯氮平口服清除率的预测倍数增加与观察到的数据一致。经过验证的模型能够恢复吸烟引起的 PF-2400013 口腔清除率的增加；男性非吸烟者和吸烟者的预测和观察平均值 (CV%) 分别为 90 L/h (40%) 和 141 L/h (34%)，以及 100 L/h (58%) 和 131 L/h (33%)。 这项研究表明，使用基于每日香烟消费量的 CYP1A2 丰度的定量估计，可以预测吸烟人群中 CYP1A2 底物的清除率。与 IVIVE 方法结合。
To derive estimates of CYP1A2 abundance as a function of daily cigarette consumption and use these values to predict the clearances of CYP1A2 substrates in smokers.Smoking-induced changes in hepatic CYP1A2 abundance were extrapolated from reported in vivo caffeine clearance data for sub-groups of a smoking population that were categorized according to their daily cigarette consumption. These abundance values together with in vitro-in vivo extrapolation (IVIVE) within the Simcyp population-based Simulator were used to predict the clearances of caffeine, theophylline, and clozapine in smokers. The model was used subsequently to predict differences in oral clearance between smoker and non-smoker cohorts in a Phase 1 clinical trial involving PF-2400013, a drug metabolized by CYP1A2.Estimated hepatic CYP1A2 abundance values were 52, 64, 79, 90, and 94 pmol/mg microsomal protein for subjects smoking 0, 1-5, 6-10, 11-20, and > 20 cigarettes/day respectively. Predicted -fold increases in oral clearance of caffeine, theophylline and clozapine in smokers relative to non-smokers were consistent with observed data. The validated model was able to recover the smoking-induced increase in oral clearance of PF-2400013; predicted and observed mean (CV%) values in male nonsmokers and smokers were 90 L/h (40%) and 141 L/h (34%) respectively, and 100 L/h (58%) and 131 L/h (33%) respectively.This study demonstrates that it may be possible to predict the clearance of CYP1A2 substrates in smoking populations using quantitative estimates of CYP1A2 abundance based on daily cigarette consumption in conjunction with an IVIVE approach.