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Dissertation
Impact of target-mediated drug disposition (TMDD) for small molecules in drug discovery and drug development
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2025
Abstract
Target-mediated drug disposition (TMDD) is generally described as a pharmacokinetic (PK) phenomenon in which drug disposition is significantly influenced by a substantial fraction of drug molecules (relative to the administered dose) binding to a high-affinity and low-capacity pharmacological target. TMDD can occur in both large and small molecules but is more widely recognized in biologics such as monoclonal antibodies (mAbs), likely due to their target-specific design. Despite being originally defined by Gerhard Levy in 1994 through observations in small-molecule drugs, TMDD in small molecules has received limited attention over the past two decades. In the recent 10 years, however, the development of more potent compounds and advances in bioanalytical methods have brought increasing attention to TMDD in small molecules during drug development. TMDD introduces complexity into the dose-exposure-response relationship, undermining standard assumptions of linearity and making it more difficult to determine optimal clinical dosing strategies. Compared to its role in drug development, the impact of TMDD during the drug discovery stage remains largely unrecognized, despite its potential to influence lead compound selection, preclinical dose optimization, and downstream development. To address these challenges, this dissertation combines pharmacometrics modeling and mass spectrometry (MS)-based proteomics to improve the understanding and characterization of TMDD in small molecules across both discovery and development stages. TMDD behaviors were evaluated using quantitative models developed from preclinical and clinical datasets, while proteomic analysis was applied to measure the abundance of key pharmacological targets in animal species and humans.
A dual TMDD-pharmacodynamic (PD) model was developed for clofutriben, a potent 11β- hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitor, to describe the nonlinear PK and PD observed at hepatic and adipose target sites in obese patients with type 2 diabetes. The model effectively captured the complex dose-response relationship and offered a valuable tool for optimizing dose regimens in future clinical trials. In a separate case, PF-07059013, a modulator of sickle hemoglobin polymerization, was evaluated using a semi-mechanistic model that characterized a novel form of TMDD, in which nonlinear PK arises from positive cooperative binding to the high-capacity target, hemoglobin. This modeling approach provided mechanistic insight into the compound’s disposition and supported dose selection for both preclinical and clinical investigations.
In parallel, absolute protein abundance of key TMDD-related targets—HSD-1, monoamine oxidase B (MAO-B), and soluble epoxide hydrolase (sEH)—was quantified in humans, rats, and mice using a global MS-based proteomics platform. These targets have consistently shown TMDD-associated nonlinear PK across various small-molecule inhibitors, indicating TMDD class effects. The study identified species-specific variability in target levels and proposed a human target capacity range of approximately 1,000 to 10,000 nmol as being most predictive of TMDD- driven nonlinear PK. These findings provide a quantitative framework for assessing TMDD risk early in the discovery process.
Lastly, the concept of target-mediated low plasma exposure was explored through the development of a minimal physiologically based pharmacokinetic (mPBPK) model. Model fitting and simulation results highlighted that target-mediated low plasma exposure should be carefully considered during lead compound optimization.
Together, these studies advanced the understanding of TMDD across both discovery and development stages, contributing to more informed lead candidate optimization and more precise clinical dose selection.
Details
- Title: Subtitle
- Impact of target-mediated drug disposition (TMDD) for small molecules in drug discovery and drug development
- Creators
- Min Xu
- Contributors
- Guohua An (Advisor)Maureen Donovan (Committee Member)Jonathan Doorn (Committee Member)Sandeep Dutta (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacy (Pharmaceutics)
- Date degree season
- Autumn 2025
- Publisher
- University of Iowa
- Number of pages
- xvi, 223 pages
- Copyright
- Copyright 2025 Min Xu
- Language
- English
- Date submitted
- 10/18/2025
- Description illustrations
- illustrations, graphs, tables
- Description bibliographic
- Includes bibliographic references (pages 213-223).
- Public Abstract (ETD)
- Some drugs show unusual behavior in the body when a large portion of the drug binds tightly to specific targets, a process known as target-mediated drug disposition (TMDD). While TMDD can occur in both large and small molecules, it was overlooked in small molecules until the past decade. Renewed interest in small-molecule TMDD has emerged with the development of more potent compounds and advances in bioanalytical techniques. In drug development, small-molecule TMDD often leads to nonlinear pharmacokinetics (PK), making it difficult to predict the relationship between dose, drug concentration, and response. In drug discovery, TMDD remains underrecognized, even though it can influence lead compound selection, dose selection, and later stages of development. To better understand TMDD across the drug development pipeline, this thesis integrated pharmacometrics modeling and mass spectrometry (MS)-based proteomics to investigate TMDD in drug (1) development and (2) discovery. A dual TMDD-pharmacodynamic (PD) model was developed for clofutriben, an HSD-1 inhibitor, capturing nonlinear PK/PD in hepatic and adipose. PF-07059013, a sickle hemoglobin modulator, was evaluated using a semi-mechanistic model to describe a novel form of TMDD, where nonlinear PK resulted from positive cooperative binding to hemoglobin. Both models supported rational dose selection. Additionally, proteomics quantified HSD-1, MAO-B, and sEH levels across species and proposed a human target capacity range (1000 10000 nmol) predictive of TMDD-driven nonlinearity. A minimal PBPK model demonstrated how target-mediated low plasma exposure can complicate lead candidate evaluation. Collectively, this work improves the mechanistic understanding of small-molecule TMDD and guides dose selection and compound optimization.
- Academic Unit
- Pharmacy
- Record Identifier
- 9985135148002771
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