Incyte Corporation, Wilmington, Delaware, USA.
Clin Pharmacol Ther. 2015 Feb;97(2):177-85. doi: 10.1002/cpt.30. Epub 2014 Dec 15.
Physiologically based pharmacokinetic modeling was applied to characterize the potential drug-drug interactions for ruxolitinib. A ruxolitinib physiologically based pharmacokinetic model was constructed using all baseline PK data in healthy subjects, and verified by retrospective predictions of observed drug-drug interactions with rifampin (a potent CYP3A4 inducer), ketoconazole (a potent CYP3A4 reversible inhibitor) and erythromycin (a moderate time-dependent inhibitor of CYP3A4). The model prospectively predicts that 100-200 mg daily dose of fluconazole, a dual inhibitor of CYP3A4 and 2C9, would increase ruxolitinib plasma concentration area under the curve by ∼two-fold, and that as a perpetrator, ruxolitinib is highly unlikely to have any discernible effect on digoxin, a sensitive P-glycoprotein substrate. The analysis described here illustrates the capability of physiologically based pharmacokinetic modeling to predict drug-drug interactions involving several commonly encountered interaction mechanisms and makes the case for routine use of model-based prediction for clinical drug-drug interactions. A model verification checklist was explored to harmonize the methodology and use of physiologically based pharmacokinetic modeling.
基于生理的药代动力学模型被应用于描述鲁索替尼的潜在药物相互作用。使用健康受试者的所有基线 PK 数据构建了鲁索替尼基于生理的药代动力学模型，并通过与利福平（一种强效 CYP3A4 诱导剂）、酮康唑（一种强效 CYP3A4 可逆抑制剂）和红霉素（一种中度时间依赖性 CYP3A4 抑制剂）的药物相互作用的观察结果进行回顾性预测进行了验证。该模型前瞻性地预测，氟康唑（一种 CYP3A4 和 2C9 的双重抑制剂）的每日 100-200mg 剂量将使鲁索替尼的血浆浓度曲线下面积增加约两倍，并且作为肇事者，鲁索替尼不太可能对地高辛（一种敏感的 P-糖蛋白底物）产生任何明显的影响。这里描述的分析说明了基于生理的药代动力学模型预测涉及几种常见相互作用机制的药物相互作用的能力，并为临床药物相互作用的基于模型的预测的常规使用提供了依据。还探讨了模型验证清单，以协调基于生理的药代动力学模型的方法和使用。
