Janssen Research & Development, Beerse, Belgium.
Janssen Research & Development, San Diego, California, USA.
Clin Pharmacol Ther. 2016 Nov;100(5):548-557. doi: 10.1002/cpt.419. Epub 2016 Aug 27.
Based on ibrutinib pharmacokinetics and potential sensitivity towards CYP3A4-mediated drug-drug interactions (DDIs), a physiologically based pharmacokinetic approach was developed to mechanistically describe DDI with various CYP3A4 perpetrators in healthy men under fasting conditions. These models were verified using clinical data for ketoconazole (strong CYP3A4 inhibitor) and used to prospectively predict and confirm the inducing effect of rifampin (strong CYP3A4 inducer); DDIs with mild (fluvoxamine, azithromycin) and moderate inhibitors (diltiazem, voriconazole, clarithromycin, itraconazole, erythromycin), and moderate (efavirenz) and strong CYP3A4 inducers (carbamazepine), were also predicted. Ketoconazole increased ibrutinib area under the curve (AUC) by 24-fold, while rifampin decreased ibrutinib AUC by 10-fold; coadministration of ibrutinib with strong inhibitors or inducers should be avoided. The ibrutinib dose should be reduced to 140 mg (quarter of maximal prescribed dose) when coadministered with moderate CYP3A4 inhibitors so that exposures remain within observed ranges at therapeutic doses. Thus, dose recommendations for CYP3A4 perpetrator use during ibrutinib treatment were developed and approved for labeling.
基于依鲁替尼的药代动力学和对 CYP3A4 介导的药物相互作用（DDI）的潜在敏感性，开发了一种基于生理学的药代动力学方法，以在空腹条件下从机制上描述健康男性中各种 CYP3A4 引发剂的 DDI。这些模型使用酮康唑（强 CYP3A4 抑制剂）的临床数据进行了验证，并用于前瞻性预测和确认利福平（强 CYP3A4 诱导剂）的诱导作用；还预测了与中度抑制剂（氟西汀、阿奇霉素）和中度（地尔硫卓、伏立康唑、克拉霉素、伊曲康唑、红霉素）以及中度（依法韦仑）和强 CYP3A4 诱导剂（卡马西平）的 DDI。酮康唑使依鲁替尼的 AUC 增加了 24 倍，而利福平使依鲁替尼的 AUC 减少了 10 倍；应避免依鲁替尼与强抑制剂或诱导剂联合使用。当与中度 CYP3A4 抑制剂联合使用时，依鲁替尼的剂量应减少至 140mg（最大推荐剂量的四分之一），以使暴露量在治疗剂量下仍处于观察范围内。因此，制定并批准了 CYP3A4 引发剂使用期间依鲁替尼治疗的剂量建议以用于标签。
