Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
Drug Metab Dispos. 2022 Mar;50(3):214-223. doi: 10.1124/dmd.121.000720. Epub 2021 Dec 22.
Idasanutlin is a potent inhibitor of the p53-MDM2 interaction that enables reactivation of the p53 pathway, which induces cell cycle arrest and/or apoptosis in tumor cells expressing functional p53. It was investigated for the treatment of solid tumors and several hematologic indications such as relapsed/refractory acute myeloid leukemia, polycythemia vera, or non-Hodgkin lymphoma. For safety reasons, it cannot be given in healthy volunteers for drug-drug interaction (DDI) explorations. This triggered the need for in silico explorations on top of the one available CYP3A clinical DDI study with posaconazole in solid tumor patients. Idasanutlin's clearance is dependent on CYP3A4/2C8 forming its major circulating metabolite M4, with contributions from UGT1A3 and biliary excretion. Idasanutlin and M4 have low permeability, very low clearance, and extremely low unbound fraction in plasma (<0.001), which makes in vitro data showing inhibition on CYP3A4/2C8 enzymes challenging to translate to clinical relevance. Physiologically-based pharmacokinetic models of idasanutlin and M4 have been established to simulate perpetrator and victim DDI scenarios and to evaluate whether further DDI studies in oncology patients are necessary. Modeling indicated that idasanutlin and M4 would show no or weak clinical inhibition of selective CYP3A4/2C8 substrates. Co-administered strong CYP3A and CYP2C8 inhibitors might lead to weak or moderate idasanutlin exposure increases, and the strong inducer rifampicin might cause moderate exposure reduction. As the simulated idasanutlin systemic exposure changes would be within the range of observed intrinsic variability, the target population can take co-medications that are either CYP2C8/3A4 inhibitors or weak/moderate CYP2C8/3A4 inducers without dose adjustment. SIGNIFICANCE STATEMENT: Clinical trials for idasanutlin are restricted to cancer patients, which imposes practical, scientific, and ethical challenges on drug-drug interaction investigations. Furthermore, idasanutlin and its major circulating metabolite have very challenging profiles of absorption, distribution, metabolism and excretion including high protein binding, low permeability and a combination of different elimination pathways each with extremely low clearance. Nonetheless, physiologically-based pharmacokinetic models could be established and applied for drug-drug interaction risk assessment and were especially useful to provide guidance on concomitant medications in patients.
伊达沙林是一种有效的 p53-MDM2 相互作用抑制剂，能够重新激活 p53 通路，导致表达功能性 p53 的肿瘤细胞发生细胞周期停滞和/或细胞凋亡。它被研究用于治疗实体瘤和几种血液学适应症，如复发性/难治性急性髓系白血病、真性红细胞增多症或非霍奇金淋巴瘤。出于安全原因，它不能在健康志愿者中用于药物相互作用（DDI）研究。这引发了在现有的与固体肿瘤患者中酮康唑的 CYP3A 临床 DDI 研究之上，进行计算机模拟探索的需要。伊达沙林的清除依赖于 CYP3A4/2C8 形成其主要的循环代谢物 M4，UGT1A3 和胆汁排泄也有贡献。伊达沙林和 M4 的跨膜渗透性低、清除率非常低、血浆中未结合分数极低（<0.001），这使得体外数据显示对 CYP3A4/2C8 酶的抑制作用难以转化为临床相关性。已经建立了伊达沙林和 M4 的基于生理学的药代动力学模型，以模拟加害人/受害者 DDI 情况，并评估是否需要对肿瘤患者进行进一步的 DDI 研究。模型表明，伊达沙林和 M4 对选择性 CYP3A4/2C8 底物不会显示出或仅有微弱的临床抑制作用。同时使用强 CYP3A 和 CYP2C8 抑制剂可能导致伊达沙林暴露量轻微或中度增加，而强诱导剂利福平可能导致中度暴露量减少。由于模拟的伊达沙林全身暴露变化将在观察到的内在变异性范围内，目标人群可以使用既是 CYP2C8/3A4 抑制剂又是弱/中度 CYP2C8/3A4 诱导剂的联合药物，而无需调整剂量。意义：伊达沙林的临床试验仅限于癌症患者，这对药物相互作用研究提出了实际、科学和伦理方面的挑战。此外，伊达沙林及其主要循环代谢物在吸收、分布、代谢和排泄方面具有非常具有挑战性的特征，包括高蛋白结合率、低通透性和不同消除途径的组合，每种途径的清除率都极低。尽管如此，仍可以建立并应用基于生理学的药代动力学模型进行药物相互作用风险评估，并且特别有助于为患者提供伴随药物治疗的指导。
