Simcyp (a Certara Company), Sheffield, UK.
Clin Pharmacol Ther. 2013 Aug;94(2):260-8. doi: 10.1038/clpt.2013.79. Epub 2013 Apr 10.
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.
细胞因子水平升高已知会下调细胞色素 P450 酶（CYPs）的表达和抑制其活性。用于治疗炎症或感染的细胞因子调节治疗性蛋白（TPs）可能会逆转抑制作用，表现为 TP-药物相互作用（TP-DDIs）。使用基于生理学的药代动力学模型来定量预测白细胞介素-6（IL-6）对敏感 CYP3A4 底物的影响。在虚拟类风湿关节炎（RA）患者中，100 pg/ml 的 IL-6 可使辛伐他汀的血浆浓度-时间曲线下面积（AUC）升高，这与观察到的临床数据相当（59 比 58%）。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，与观察到的数据也非常吻合（45 比 39%）。在另一组接受环孢素治疗的 BMT 患者中，IL-6 与环孢素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初步步骤。
