Development of a Physiologically-Based Pharmacokinetic Model for Sirolimus: Predicting Bioavailability Based on Intestinal CYP3A Content.
Development of a Physiologically-Based Pharmacokinetic Model for Sirolimus: Predicting Bioavailability Based on Intestinal CYP3A Content.
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DOI：
10.1038/psp.2013.33
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发表时间：
2013-07-24
影响因子：
3.5
通讯作者：
Vinks, A A
中科院分区：
文献类型：
--
作者：
Emoto, C;Fukuda, T;Cox, S;Christians, U;Vinks, A A
西罗莫司是哺乳动物雷帕霉素靶蛋白（mTOR）的抑制剂，越来越多地用于移植和癌症治疗。西罗莫司口服生物利用度低，药代动力学变异性大。这种变异性的潜在机制尚未在很大程度上得到探索。西罗莫司代谢通过体外固有清除率估计进行表征。途径贡献排序为CYP3A4 > CYP3A5 > CYP2C8。采用充分搅拌和Qgut模型，西罗莫司生物利用度预测为15%。生物利用度的个体间差异可归因于可变的肠道CYP3A表达。在Simcyp中开发的基于生理学的药代动力学（PBPK）模型预测西罗莫司在脂肪组织中的分布较高，并且除CYP介导的代谢外还有另一种消除途径。在剂量递增研究中，PBPK模型预测性能可接受，Cmax和曲线下面积（AUC）估计值在观察数据的20%范围内。该模型还显示出评估肝损害和药物相互作用（DDI）对西罗莫司药代动力学的影响的潜力。
Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) and is increasingly being used in transplantation and cancer therapies. Sirolimus has low oral bioavailability and exhibits large pharmacokinetic variability. The underlying mechanisms for this variability have not been explored to a large extent. Sirolimus metabolism was characterized by in vitro intrinsic clearance estimation. Pathway contribution ranked from CYP3A4 > CYP3A5 > CYP2C8. With the well stirred and Qgut models sirolimus bioavailability was predicted at 15%. Interindividual differences in bioavailability could be attributed to variable intestinal CYP3A expression. The physiologically-based pharmacokinetics (PBPK) model developed in Simcyp predicted a high distribution of sirolimus into adipose tissue and another elimination pathway in addition to CYP-mediated metabolism. PBPK model predictive performance was acceptable with Cmax and area under the curve (AUC) estimates within 20% of observed data in a dose escalation study. The model also showed potential to assess the impact of hepatic impairment and drug–drug interaction (DDI) on sirolimus pharmacokinetics.