Target-mediated drug disposition (TMDD) in pharmacokinetics and pharmacodynamics (PK/PD) of large-molecule and small-molecule compounds
Creators: name: Wu, Nan
Publisher: name: University of Iowa
Year: 2023

description: Target-mediated drug disposition (TMDD) represents a pivotal phenomenon in pharmacology, where the interaction between a potent drug and its pharmacological target yields significant implications for pharmacokinetics (PK). Large-molecule compounds like erythropoietin are well-recognized to exhibit TMDD, due to the specific binding to high-affinity receptors and minimal non-specific binding. However, the TMDD of small-molecule compounds is often obscured by non-specific bindings with plasma protein such as albumin, which have greater binding capacity. The emergence of more potent small-molecule drugs and sensitive bioanalytical methods has unveiled strong TMDD in various small-molecule compounds, including 11β-hydroxysteroid dehydrogenase type I inhibitor (HSD-1) inhibitors (e.g., SPI-62, ABT-384), soluble epoxide hydrolase inhibitors (sEH) (e.g., TPPU and TCPU), and dipeptidyl petptide 4 (DPP-4) inhibitors (e.g., linagliptin) etc. Both large and small molecule compounds that exhibit TMDD often display nonlinear PK, adding complexity to the task of elucidating the connections between dose, drug exposure, and response. Interestingly, the localization of pharmacological targets contributes to the distinctive non-linear PK patterns observed in small molecules with TMDD, further complicating our comprehension of the dose-exposure-response relationship in this context. To tackle this challenge, the application of advanced pharmacometrics models, drawn from both preclinical and clinical data, becomes essential. These models facilitate more efficient and well-informed decision-making, ultimately enhancing the selection of appropriate dosages for both large and small-molecule compounds exhibiting TMDD throughout the drug development process.
description: My thesis objectives were utilizing pharmacometrics modeling approaches to investigate TMDD's role in the PK of (1) small molecules with pharmacological targets in tissues, and (2) small molecules with pharmacological targets located in plasma, and (3) a large molecule, recombinant human erythropoietin (rhEpo).
description: For the first objective, my initial research (Chapter 2) focused on SPI-62, a potent HSD-1 inhibitor undergoing Phase II clinical trials. A TMDD model was developed to elucidate the nonlinear PK/pharmacodynamics (PD) relationship observed in Phase I clinical trials with healthy adults, providing a foundation for dose selection in current and future clinical studies. The second project (Chapter 3) delved into the preclinical stage, where two sEH inhibitors with pharmacological targets located in tissues exhibited pronounced TMDD characteristics. An interactive TMDD model was established to concurrently characterize TPPU and TCPU PK and the model was applied to predict the target occupancy.
description: Shifting to the second objective, the third project (Chapter 4) highlighted Linagliptin, an FDA-approved DPP-4 inhibitor with pronounced TMDD affecting both tissue and plasma PK. To facilitate dose selection for linagliptin, a comprehensive Whole-Body Physiologically-Based Pharmacokinetic (WB-PBPK) model was built in rats and then was scaled up to human. In the fourth project (Chapter 5), a Quantitative Systems Pharmacology (QSP) model was built to quantify Linagliptin's impact on two incretins, GLP-1 and GIP, alongside influential factors (e.g., glucose, glucagon and insulin) in glycemic control.
description: For the third objective (Chapter 6), our focus is on recombinant human erythropoietin (rhEpo), a crucial therapy for anemia. Extensive investigation was conducted on rhEpo, and it has been reported to exhibit target-mediated drug disposition (TMDD) in both animals and humans. However, a significant knowledge gap exists in comprehending erythropoietin's PK in patients with varying bone marrow conditions, posing a substantial obstacle in dose selection for this unique population. This project developed a comprehensive TMDD model to quantitatively characterize rhEpo PK data in patients undergoing varying stages of bone marrow ablation following hematopoietic transplantation.
description: My work in pharmacometrics models encompasses both large-molecule and smallmolecule compounds, highlighting key distinctions as they exhibit TMDD. These models provide a quantitative framework for characterizing the nonlinear PK and PD of several small molecules, including SPI-62, Linagliptin, TPPU/TCPU, and the large molecule erythropoietin. This quantitative understanding serves as a guiding compass throughout the drug development journey, from preclinical phases through clinical trials to post-clinical stages, embodying the essence of Model-informed Drug Development (MIDD).