DataSheet1_Population pharmacokinetic model for oral ORIN1001 in Chinese patients with advanced solid tumors.PDF

Background: ORIN1001, a first-in-class oral IRE1-α endoribonuclease inhibitor to block the activation of XBP1, is currently in clinical development for inhibiting tumor growth and enhancing the effect of chemical or targeted therapy. Early establishment of a population pharmacokinetic (PopPK) model could characterize the pharmacokinetics (PK) of ORIN1001 and evaluate the effects of individual-specific factors on PK, which will facilitate the future development of this investigational drug.
Methods: Non-linear mixed effect model was constructed by Phoenix NLME software, utilizing the information from Chinese patients with advanced solid tumors in a phase I clinical trial (Register No. NCT05154201). Statistically significant PK covariates were screened out by a stepwise process. The final model, after validating by the goodness-of-fit plots, non-parametric bootstrap, visual predictive check and test of normalized prediction distribution errors, was further applied to simulate and evaluate the impact of covariates on ORIN1001 exposure at steady state up to 900 mg per day as a single agent.
Results: A two-compartment model with first-order absorption (with lag-time)/elimination was selected as the best structural model. Total bilirubin (TBIL) and lean body weight (LBW) were considered as the statistically significant covariates on clearance (CL/F) of ORIN1001. They were also confirmed to exert clinically significant effects on ORIN1001 steady-state exposure after model simulation. The necessity of dose adjustments based on these two covariates remains to be validated in a larger population.
Conclusion: The first PopPK model of ORIN1001 was successfully constructed, which may provide some important references for future research.

背景：ORIN1001是全球首款口服IRE1-α核糖核酸内切酶抑制剂，可阻断XBP1的激活，目前正处于临床开发阶段，用于抑制肿瘤生长并增强化疗或靶向治疗的疗效。早期构建群体药代动力学（population pharmacokinetic, PopPK）模型，能够表征ORIN1001的药代动力学（pharmacokinetics, PK）特征，并评估个体特异性因素对药代动力学的影响，可为该在研药物的后续开发提供助力。

方法：本研究依托Phoenix NLME软件构建非线性混合效应模型，数据来源于一项针对中国晚期实体瘤患者的I期临床试验（登记号：NCT05154201）。通过逐步筛选流程筛选出具有统计学意义的药代动力学协变量。最终模型经拟合优度图、非参数Bootstrap法、可视化预测检验及标准化预测分布误差检验验证后，进一步被用于模拟评估以单药形式每日给药最高900mg时，各协变量对ORIN1001稳态暴露量的影响。

结果：最终选定带滞后时间的一级吸收/消除二室模型为最优结构模型。总胆红素（total bilirubin, TBIL）与瘦体重（lean body weight, LBW）被确定为影响ORIN1001清除率（CL/F）的具有统计学意义的协变量。模型模拟结果进一步证实，二者对ORIN1001稳态暴露量具有临床层面的显著影响。基于这两项协变量调整给药剂量的必要性，仍需在更大规模人群中开展验证。

结论：本研究成功构建了首个ORIN1001的群体药代动力学模型，可为该药物的后续研究提供重要参考依据。