A Physiologically Based Pharmacokinetic Modeling Approach to Predict Disease-Drug Interactions: Suppression of CYP3A by IL-6
A Physiologically Based Pharmacokinetic Modeling Approach to Predict Disease-Drug Interactions: Suppression of CYP3A by IL-6
复制标题
DOI：
10.1038/clpt.2013.79
复制
发表时间：
2013-08-01
影响因子：
6.7
通讯作者：
Kenny, J. R.
中科院分区：
文献类型：
--
作者：
Machavaram, K. K.;Almond, L. M.;Kenny, J. R.
众所周知，细胞因子水平升高会下调细胞色素P450酶的表达并抑制其活性。细胞因子调节治疗蛋白(TPS)用于治疗炎症或感染可逆转抑制，表现为TP-药物-药物相互作用(TP-DDiS)。用生理学药代动力学模型定量预测白细胞介素6(IL-6)对细胞色素P3A4敏感底物的影响。虚拟类风湿性关节炎(RA)患者服用100pg/mlIL-6后，血浆浓度-时间曲线(AUC)下的辛伐他汀面积升高，与观察到的临床数据(59%对58%)相似。在虚拟骨髓移植(BMT)患者中，500 pg/ml的IL-6导致环孢素AUC增加，也与观察数据(45%比39%)一致。在另一组接受环孢素治疗的骨髓移植患者中，与IL-6的相互作用程度被低估了三倍。TP-DDiS的复杂性突出了需要考虑的潜在病理生理因素，但这些模拟为预测TP-DDI风险提供了有价值的第一步。
Elevated cytokine levels are known to downregulate expression and suppress activity of cytochrome P450 enzymes (CYPs). Cytokine-modulating therapeutic proteins (TPs) used in the treatment of inflammation or infection could reverse suppression, manifesting as TP-drug-drug interactions (TP-DDIs). A physiologically based pharmacokinetic model was used to quantitatively predict the impact of interleukin-6 (IL-6) on sensitive CYP3A4 substrates. Elevated simvastatin area under the plasma concentration-time curve (AUC) in virtual rheumatoid arthritis (RA) patients, following 100 pg/ml of IL-6, was comparable to observed clinical data (59 vs. 58%). In virtual bone marrow transplant (BMT) patients, 500 pg/ml of IL-6 resulted in an increase in cyclosporine AUC, also in good agreement with the observed data (45 vs. 39%). In a different group of BMT patients treated with cyclosporine, the magnitude of interaction with IL-6 was underpredicted by threefold. The complexity of TP-DDIs highlights underlying pathophysiological factors to be considered, but these simulations provide valuable first steps toward predicting TP-DDI risk.