Abstract：
BI 187004, a selective small-molecule inhibitor of 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1), displayed complex nonlinear pharmacokinetics (PK) in humans. Following nine single oral doses, BI 187004 exhibited nonlinear PK at low doses and linear PK at higher doses. Notably, substantial hepatic 11β-HSD1 inhibition (50%) was detected in a very low-dose group, achieving a consistent 70% hepatic enzyme inhibition in subsequent ascending doses without any dose-dependent effects. The unusual PK and PD profiles of BI 187004 suggest the presence of pharmacological target-mediated drug disposition (TMDD), arising from the saturable binding of BI 187004 compound to its high-affinity and low-capacity target 11β-HSD1. The non-intuitive dose, exposure, and response relationship for BI 187004 pose a significant challenge in rational dose selection. This study aimed to construct a TMDD model to explain the complex nonlinear PK behavior and underscore the importance of recognizing TMDD in this small-molecule compound. Among the various models explored, the best model was a two-compartment TMDD model with three transit absorption components. The final model provides insights into 11β-HSD1 binding-related parameters for BI 187004, including the total amount of 11β-HSD1 in the liver (estimated to be 8000 nmol), the second order association rate constant (estimated to be 0.102 nM-1h-1), and the first-order dissociation rate constant (estimated to be 0.11 h-1). Our final population PK model successfully characterized the intricate nonlinear PK of BI 187004 across a wide dose range. This modeling work serves as a valuable reference for the rational selection of the dose regimens for BI 187004\'s future clinical trials.
摘要：
BI187004，11β-羟基类固醇脱氢酶-1（11β-HSD1）的选择性小分子抑制剂，在人体中表现出复杂的非线性药代动力学（PK）。在九次单次口服剂量后，BI187004在低剂量下表现出非线性PK,在较高剂量下表现出线性PK。值得注意的是,在极低剂量组中检测到大量肝脏11β-HSD1抑制（50％），在随后的递增剂量中实现一致的70％肝酶抑制，而没有任何剂量依赖性作用。BI187004的不寻常的PK和PD谱表明存在药理学靶标介导的药物处置（TMDD），源于BI187004化合物与其高亲和力和低容量靶标11β-HSD1的饱和结合。非直觉剂量，暴露,BI187004的反应关系对合理剂量选择构成了重大挑战。本研究旨在构建TMDD模型来解释复杂的非线性PK行为，并强调在这种小分子化合物中识别TMDD的重要性。在探索的各种模式中，最佳模型是具有三个运输吸收组件的两室TMDD模型。最终模型提供了对BI187004的11β-HSD1结合相关参数的见解，包括肝脏中11β-HSD1的总量（估计为8000nmol），二阶缔合速率常数(估计为0.102nM-1h-1)，和一阶解离速率常数(估计为0.11h-1)。我们的最终种群PK模型成功地表征了宽剂量范围内BI187004的复杂非线性PK。这项建模工作为未来BI187004临床试验剂量方案的合理选择提供了有价值的参考。
