Eli Lilly and Company, Indianapolis, Indiana, USA.
J Clin Pharmacol. 2020 Jul;60(7):915-930. doi: 10.1002/jcph.1584. Epub 2020 Feb 20.
Abemaciclib, a selective inhibitor of cyclin-dependent kinases 4 and 6, is metabolized mainly by cytochrome P450 (CYP)3A4. Clinical studies were performed to assess the impact of strong inhibitor (clarithromycin) and inducer (rifampin) on the exposure of abemaciclib and active metabolites. A physiologically based pharmacokinetic (PBPK) model incorporating the metabolites was developed to predict the effect of other strong and moderate CYP3A4 inhibitors and inducers. Clarithromycin increased the area under the plasma concentration-time curve (AUC) of abemaciclib and potency-adjusted unbound active species 3.4-fold and 2.5-fold, respectively. Rifampin decreased corresponding exposures 95% and 77%, respectively. These changes influenced the fraction metabolized via CYP3A4 in the model. An absolute bioavailability study informed the hepatic and gastric availability. In vitro data and a human radiolabel study determined the fraction and rate of formation of the active metabolites as well as absorption-related parameters. The predicted AUC ratios of potency-adjusted unbound active species with rifampin and clarithromycin were within 0.7- and 1.25-fold of those observed. The PBPK model predicted 3.78- and 7.15-fold increases in the AUC of the potency-adjusted unbound active species with strong CYP3A4 inhibitors itraconazole and ketoconazole, respectively; and 1.62- and 2.37-fold increases with the concomitant use of moderate CYP3A4 inhibitors verapamil and diltiazem, respectively. The model predicted modafinil, bosentan, and efavirenz would decrease the AUC of the potency-adjusted unbound active species by 29%, 42%, and 52%, respectively. The current PBPK model, which considers changes in unbound potency-adjusted active species, can be used to inform dosing recommendations when abemaciclib is coadministered with CYP3A4 perpetrators.
阿贝西利是细胞周期蛋白依赖性激酶 4 和 6 的选择性抑制剂，主要通过细胞色素 P450（CYP）3A4 代谢。进行了临床研究以评估强抑制剂（克拉霉素）和诱导剂（利福平）对阿贝西利和活性代谢物暴露的影响。开发了一个包含代谢物的基于生理的药代动力学（PBPK）模型，以预测其他强和中度 CYP3A4 抑制剂和诱导剂的影响。克拉霉素使阿贝西利的血浆浓度-时间曲线下面积（AUC）和效力调整的未结合活性物质 3 的 AUC 分别增加了 3.4 倍和 2.5 倍。利福平分别使相应的暴露减少了 95%和 77%。这些变化影响了模型中通过 CYP3A4 代谢的部分。一项绝对生物利用度研究提供了肝和胃的可用性信息。体外数据和人体放射性标记研究确定了活性代谢物的形成分数和速率以及与吸收相关的参数。与利福平和克拉霉素相比，预测的效力调整的未结合活性物质的 AUC 比值在 0.7 至 1.25 倍之间。PBPK 模型预测，与强 CYP3A4 抑制剂伊曲康唑和酮康唑合用，效力调整的未结合活性物质的 AUC 分别增加 3.78 倍和 7.15 倍；与中度 CYP3A4 抑制剂维拉帕米和地尔硫卓合用，分别增加 1.62 倍和 2.37 倍。该模型预测莫达非尼、波生坦和依非韦伦将使效力调整的未结合活性物质的 AUC 分别减少 29%、42%和 52%。当前的 PBPK 模型考虑了未结合效力调整的活性物质的变化，可以用于在阿贝西利与 CYP3A4 制剂合用时提供给药建议。
