Laboratory of Clinical Pharmacology, Yokohama University of Pharmacy, Yokohama-shi, Kanagawa, Japan.
Datascience Division, A2 Healthcare Corporation, Tokyo, Japan.
Clin Transl Sci. 2024 Oct;17(10):e70047. doi: 10.1111/cts.70047.
The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (LNG) exhibits target-mediated drug disposition (TMDD) in clinical settings, characterized by saturable binding to plasma soluble DPP-4 (sDPP-4) and tissue transmembrane DPP-4 (tDPP-4). Previous studies have indicated that saturable renal reabsorption of LNG contributes to its nonlinear urinary excretion observed in humans and wild-type mice, but not in Dpp-4 knockout mice. To elucidate the mechanisms underlying these complex phenomena, including DPP-4-related renal reabsorption of LNG, we employed physiologically-based pharmacokinetic (PBPK) modeling combined with a cluster Gauss-Newton method (CGNM). The CGNM facilitated the exploration of parameters in rat and human PBPK models for LNG and the determination of parameter identifiability. Through PBPK-CGNM analysis using reported autoradiography data ([C]-LNG) in wild-type and Dpp-4-deficient rats, DPP-4-specific distributions of LNG in various tissues were clearly differentiated from nonspecific parts. By fitting to human plasma concentrations and urinary and fecal excretions of LNG after intravenous and oral administrations, multiple unknown PBPK parameters were simultaneously estimated by the CGNM. Notably, the amount of tDPP-4 and the reabsorption clearance for LNG-DPP-4 complexes were identifiable, indicating their critical role in explaining the complex nonlinear pharmacokinetics of LNG. Compared with previous PBPK analyses, the CGNM allowed us to incorporate greater model complexity (e.g., consideration of tDPP-4 expressions and in vitro binding kinetics), ultimately resulting in a more accurate reproduction of LNG's TMDD. In conclusion, by considering LNG as a high-affinity probe for DPP-4, comprehensive PBPK-CGNM analyses suggested a dynamic whole-body distribution of DPP-4, including its involvement in the renal reabsorption of LNG.
二肽基肽酶-4（DPP-4）抑制剂利那列汀（LNG）在临床环境中表现出靶介导的药物处置（TMDD），其特征为与血浆可溶性 DPP-4（sDPP-4）和组织跨膜 DPP-4（tDPP-4）呈饱和结合。先前的研究表明，LNG 的可饱和肾重吸收导致其在人类和野生型小鼠中观察到的非线性尿排泄，但在 Dpp-4 敲除小鼠中则不然。为了阐明这些复杂现象的机制，包括与 DPP-4 相关的 LNG 肾重吸收，我们采用了基于生理学的药代动力学（PBPK）建模结合群高斯-牛顿方法（CGNM）。CGNM 有助于探索 LNG 在大鼠和人类 PBPK 模型中的参数，并确定参数可识别性。通过使用在野生型和 Dpp-4 缺陷型大鼠中报告的放射性自显影数据 ([C]-LNG）进行 PBPK-CGNM 分析，可将 LNG 在各种组织中的 DPP-4 特异性分布与非特异性部分清楚地区分开来。通过拟合静脉内和口服给予 LNG 后人体血浆浓度以及尿和粪便排泄，CGNM 可同时估计多个未知的 PBPK 参数。值得注意的是，tDPP-4 的量和 LNG-DPP-4 复合物的重吸收清除率是可识别的，这表明它们在解释 LNG 的复杂非线性药代动力学方面起着关键作用。与以前的 PBPK 分析相比，CGNM 允许我们纳入更大的模型复杂性（例如，考虑 tDPP-4 表达和体外结合动力学），最终更准确地再现 LNG 的 TMDD。总之，通过将 LNG 视为 DPP-4 的高亲和力探针，全面的 PBPK-CGNM 分析表明 DPP-4 具有全身动态分布，包括其参与 LNG 的肾重吸收。
