Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, 115 S Grand Ave, Iowa City, Iowa, 52242, USA.
AAPS J. 2020 Sep 29;22(6):125. doi: 10.1208/s12248-020-00481-w.
Linagliptin demonstrates substantial nonlinear pharmacokinetics due to its saturable binding to its pharmacological target dipeptidyl peptide 4 (DPP-4), a phenomenon known as target-mediated drug disposition (TMDD). In the current study, we established a novel whole-body physiologically-based pharmacokinetic (PBPK)-TMDD model for linagliptin. This comprehensive model contains plasma and 14 tissue compartments, among which TMDD binding process was incorporated in 9 of them, namely the plasma, kidney, liver, spleen, lung, skin, salivary gland, thymus, and reproductive organs. Our final model adequately captured the concentration-time profiles of linagliptin in both plasma and various tissues in both wildtype rats and DPP4-deficient rats following different doses. The association rate constant (k) in plasma and tissues were estimated to be 0.943 and 0.00680 nM h, respectively, and dissociation rate constant (k), in plasma and tissues were estimated to be 0.0698 and 0.00880 h, respectively. The binding affinity of linagliptin to DPP-4 (Kd) was predicted to be higher in plasma (0.0740 nM) than that in tissue (1.29 nM). When scaled up to a human, this model captured the substantial and complex nonlinear pharmacokinetic behavior of linagliptin in human adults that is characterized by less-than dose-proportional increase in plasma exposure, dose-dependent clearance and volume of distribution, as well as long terminal half-life with minimal accumulation after repeated doses. Our modeling work is not only novel but also of high significance as the whole-body PBPK-TMDD model platform developed using linagliptin as the model compound could be applied to other small-molecule compounds exhibiting TMDD to facilitate their optimal dose selection. Graphical abstract.
由于其与药理学靶标二肽基肽酶 4（DPP-4）的饱和结合，即所谓的靶介导药物处置（TMDD），利拉利汀表现出明显的非线性药代动力学。在本研究中，我们建立了一种新型的利拉利汀全身生理药代动力学（PBPK）-TMDD 模型。该综合模型包含血浆和 14 个组织隔室，其中 TMDD 结合过程包含在其中 9 个隔室中，即血浆、肾脏、肝脏、脾脏、肺、皮肤、唾液腺、胸腺和生殖器官。我们的最终模型充分捕捉了不同剂量下野生型大鼠和 DPP4 缺陷型大鼠血浆和各种组织中利拉利汀的浓度-时间曲线。血浆和组织中的结合速率常数（k）分别估计为 0.943 和 0.00680 nM h，解离速率常数（k）分别估计为 0.0698 和 0.00880 h。利拉利汀与 DPP-4 的结合亲和力（Kd）在血浆中（0.0740 nM）高于组织中（1.29 nM）。在扩大到人类时，该模型捕捉到了利拉利汀在人类成年人中明显而复杂的非线性药代动力学行为，其特征是血浆暴露量呈非比例增加、剂量依赖性清除率和分布容积，以及半衰期长，多次给药后几乎没有蓄积。我们的建模工作不仅新颖，而且具有重要意义，因为使用利拉利汀作为模型化合物开发的全身 PBPK-TMDD 模型平台可应用于其他表现出 TMDD 的小分子化合物，以促进其最佳剂量选择。
