...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Predicting Clinical Effects of CYP3A4 Modulators on Abemaciclib and Active Metabolites Exposure Using Physiologically Based Pharmacokinetic Modeling
【24h】

Predicting Clinical Effects of CYP3A4 Modulators on Abemaciclib and Active Metabolites Exposure Using Physiologically Based Pharmacokinetic Modeling

机译：用生理基于药代动力学建模预测CYP3A4调节剂CYP3A4调节剂的临床疗效和活性代谢物暴露

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

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.
机译：Abemaciclib是细胞周期素依赖性激酶4和6的选择性抑制剂，主要由细胞色素P450（CYP）3A4代谢。进行临床研究以评估强抑制剂（克拉霉素）和诱导剂（利福平）对阿贝马西林和活性代谢物暴露的影响。建立了一个包含代谢产物的生理药代动力学（PBPK）模型，以预测其他强效和中度CYP3A4抑制剂和诱导剂的作用。克拉霉素使阿贝马西林和效力调整的非结合活性物质的血浆浓度-时间曲线（AUC）下面积分别增加了3.4倍和2.5倍。利福平的相应暴露量分别减少了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报告了肝脏和胃的可用性。体外数据和人体放射性标记研究确定了活性代谢物的分数和形成速率以及吸收相关参数。使用利福平和克拉霉素调整效力的未结合活性物质的预测AUC比率在观察值的0.7倍和1.25倍以内。PBPK模型预测，使用强CYP3A4抑制剂伊曲康唑和酮康唑的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；同时使用中度CYP3A4抑制剂维拉帕米和地尔硫卓分别增加1.62倍和2.37倍。该模型预测莫达非尼、波生坦和依法韦伦将使经效价调整的未结合活性物质的AUC分别降低29%、42%和52%。当前的PBPK模型考虑了未结合效力调整活性物种的变化，可用于在阿贝马西利与CYP3A4合用时告知给药建议。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号