Mao Jialin, Tay Suzanne, Khojasteh Cyrus S, Chen Yuan, Hop Cornelis E C A, Kenny Jane R
Department of Drug Metabolism and Pharmacokinetics, Genentech, A Member of the Roche Group, 1 DNA Way, South San Francisco, California, 94080, USA.
Pharm Res. 2016 May;33(5):1204-19. doi: 10.1007/s11095-016-1865-9. Epub 2016 Feb 11.
To evaluate an alternative in vitro system which can provide more quantitatively accurate drug drug interaction (DDI) prediction for 10 protein kinase inhibitors for which DDI risk was over-predicted by inhibition data generated in human liver microsomes (HLM).
Three cryopreserved human hepatocyte (hHEP) systems: 1) plated hHEPs; 2) hHEPs suspended in Dulbecco's Modified Eagle Medium (DMEM) and 3) hHEPs suspended in human plasma (plasma hHEPs) were developed to detect CYP3A time dependent inhibition, and the static mechanistic model was used to predict clinical outcomes.
A general trend was observed in the CYP3A inactivation potency (k inact /K I, app ) as HLM > plated > DMEM ≥ plasma hHEPs. Using the static mechanistic model, DDIs predicted using parameters estimated from plated, DMEM and plasma hHEPs had 84, 74 and 95% accuracy (out of 19 clinical interaction studies) within 2-fold of the reported interaction, respectively. They demonstrated significant improvement compared to the DDIs predicted using parameters estimated from HLMs where 58% accuracy was obtained.
Based on 19 DDIs, plasma hHEPs demonstrate a more reliable clinical DDI prediction for 10 protein kinase inhibitors and prototypical CYP3A time dependent inhibitors.
评估一种体外替代系统，该系统可为10种蛋白激酶抑制剂提供更定量准确的药物-药物相互作用（DDI）预测，这些抑制剂的DDI风险在人肝微粒体（HLM）中产生的抑制数据中被过度预测。
开发了三种冷冻保存的人肝细胞（hHEP）系统：1）接种的hHEP；2）悬浮在杜氏改良 Eagle 培养基（DMEM）中的hHEP和3）悬浮在人血浆中的hHEP（血浆hHEP）以检测CYP3A时间依赖性抑制，并使用静态机制模型预测临床结果。
观察到CYP3A失活效力（k inact /K I, app）的一般趋势为HLM>接种的>DMEM≥血浆hHEP。使用静态机制模型，使用从接种的、DMEM和血浆hHEP估计的参数预测的DDI在已报道相互作用的2倍范围内分别具有84%、74%和95%的准确性（在19项临床相互作用研究中）。与使用从HLM估计的参数预测的DDI相比，它们有显著改善，后者的准确性为58%。
基于19种DDI，血浆hHEP对10种蛋白激酶抑制剂和典型的CYP3A时间依赖性抑制剂表现出更可靠的临床DDI预测。
