GDC-0810 Pharmacokinetics and Transporter-Mediated Drug Interaction Evaluation with an Endogenous Biomarker in the First-in-Human, Dose Escalation Study
GDC-0810 Pharmacokinetics and Transporter-Mediated Drug Interaction Evaluation with an Endogenous Biomarker in the First-in-Human, Dose Escalation Study
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DOI：
10.1124/dmd.119.087924
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发表时间：
2019-09-01
影响因子：
3.9
通讯作者：
Liu, Lichuan
中科院分区：
文献类型：
--
作者：
Cheung, Kit Wun Kathy;Yoshida, Kenta;Liu, Lichuan
GDC-0810(Cheeti等人，2018年)是一种口服生物利用度、选择性雌激素受体(ER)降解剂，开发用于治疗ER阳性乳腺癌。对GDC-0810及其两种主要代谢物的药代动力学(PK)进行了首次人体剂量递增I期研究(n=41)。GDC-0810在每日1次给药100~600 mg范围内呈线性关系。单次600毫克剂量后的平均终端半衰期约为8小时。由于GDC-0810是一种高效的有机阴离子转运多肽(OATP1B1/3)的体外抑制物，因此对同一FIH研究中收集的一组血浆样本中具有前景的OATP1B1/3的内源性生物标志物--共比例卟啉I(CPI)的动力学特征进行了回顾分析。CPI显示GDC-0810呈剂量依赖性增加，提示体内抑制OATP1B转运蛋白。为了定量预测OATP1B介导的药物-药物相互作用(DDIS)与普伐他汀(已知的OATP1B底物)的相互作用的大小，首先使用一室模型估计体内无结合抑制常数，然后将其纳入基于生理的药代动力学模型。与临床DDI研究结果相比，该模型显示了对DDI大小的低估，而预测具有相对较大的不确定性，这是因为影响规模小、样本量有限以及CPI动力学的可变性。总之，这项研究描述了GDC-0810在乳腺癌患者中的药代动力学特征，并早在FIH研究中就证明了CPI在检测OATP1B介导的新分子实体DDIS方面的有效性。这是首次在人类研究中报道研究分子和转运体生物标记物之间的药代动力学相互作用的研究。观察到的相互作用和基于模型的分析和预测为在FIH临床研究早期定量预测转运体介导的DDIS的新方法提供了重要的见解。
GDC-0810 (Cheeti et al., 2018) is an orally bioavailable, selective estrogen receptor (ER) degrader developed to treat ER-positive breast cancer. A first-in-human (FIH) dose escalation phase I study (n = 41) was conducted to characterize the pharmacokinetics (PK) of GDC-0810 and its two major metabolites. GDC-0810 demonstrated linear PK from 100 to 600 mg given once daily. The mean terminal half-life following a single 600 mg dose was approximately 8 hours. Since GDC-0810 is a potent in vitro inhibitor of organic anion transporting polypeptide (OATP) 1B1/3, the kinetic profile of coproporphyrin I (CPI), a promising endogenous biomarker for OATP1B1/3, was analyzed retrospectively in a subset of the plasma samples collected in the same FIH study. CPI exhibited a GDC-0810 dose-dependent increase, suggesting in vivo inhibition of OATP1B transporters. To quantitatively predict the magnitude of OATP1Bmediated drug-drug interactions (DDIs) with pravastatin (a known OATP1B substrate), the in vivo unbound inhibition constant was first estimated using a one-compartment model, and then incorporated to a physiologically based pharmacokinetic model. The model showed some underestimation of the magnitude of the DDI when compared with a clinical DDI study result, while prediction had a relatively large uncertainty due to the small effect size, limited sample size, and variability in CPI kinetics. In conclusion, this study characterized the pharmacokinetic profiles of GDC-0810 in breast cancer patients and demonstrated the utility of CPI in detecting OATP1B-mediated DDIs of a new molecular entity as early as FIH study.SIGNIFICANCE STATEMENTEndogenous biomarkers of transporters have recently been shown to be promising tools in evaluating the risk of clinical transporter-mediated DDIs. This is the first study to report a pharmacokinetic interaction between an investigational molecule and a transporter biomarker in a first-in-human study. The observed interaction and model-based analysis and the prediction provide important insights on the novel approach to quantitatively predict transporter-mediated DDIs as early as FIH studies in the clinical development.