Predicting Accurately to De-Risk Early Development
An exposure-driven, translational approach, linking early ADME with biomarker discovery, can help teams define the therapeutic window long before lead candidate nomination, according to Hong Wan from BioDuro.
The margin for error within drug development is becoming ever narrower, as R&D costs continue to rise, competition pressures intensify, and regulatory expectations grow. As a result, industry is looking at improvements earlier in the development lifecycle that can help to reduce potential attrition later on and, ultimately, improve the prospects for commercial success.
In this exclusive interview, The Pharma Navigator sits down with Hong Wan, Senior Vice President, DMPK, BioDuro, to discuss the integration of early absorption, distribution, metabolism, and excretion (ADME) data with biomarker discovery, the new parameters to prioritize in light of increasing therapeutic complexity, and the potential predictive power of Organ-on-a-Chip and organoid technologies.
Integrating Early ADME Data
TPN: How are early ADME data being integrated with biomarker discovery to build more accurate 'therapeutic window' models before a lead candidate enters the clinic?
Wan (BioDuro): Early ADME data are integrated with biomarker discovery through an exposure-driven, translational approach that links pharmacokinetics, target engagement, and biological response. In vitro ADME data are used to predict in vivo PK and guide compound selection, while in vivo PK studies confirm exposure–time relationships across species. This PK understanding informs the design of relevant toxicology studies at clinically meaningful exposures and the selection of in vivo efficacy models in which biomarker or PD readouts can be quantitatively correlated with systemic or tissue exposure.
By integrating exposure, biomarker response, and emerging safety signals into early PK/PD models, teams can estimate safety margins and construct more accurate therapeutic window projections prior to lead candidate nomination and clinical entry.
Prioritizing New Parameters
TPN: With the rise of proteolysis targeting chimeras (PROTACs), X-drug conjugates (XDCs), and large-volume biologics, what new parameters must be prioritized in early-stage metabolism studies that traditional assays might miss?
Wan (BioDuro): Traditional ADME models were largely optimized for small molecules and often do not capture the unique structural and mechanistic features of emerging modalities such as PROTACs, XDCs, and large biologics.
For PROTACs, early metabolism studies must prioritize parameters such as linker stability, differential metabolism of each warhead, permeability and intracellular exposure, and non-linear PK driven by target-mediated drug disposition, requiring adapted in vitro ADME and in vivo PK assays. For ADCs and other XDCs, metabolism assessments focus on conjugate stability, linker cleavage rates, payload release, and tissue distribution, using MS/MS-based bioanalysis alongside combined MS and ligand-binding assays to quantify intact conjugate, total antibody, and released free payload in both PK and toxicology studies.
Together, these expanded parameters enable a more accurate understanding of exposure, efficacy, and safety drivers that traditional small-molecule ADME assays may overlook.
Potential of Other Technologies
TPN: How are 'Organ-on-a-Chip' or 3D organoid technologies being integrated into early toxicology screening?
Wan (BioDuro): Organ-on-a-Chip and 3D organoid technologies are being incorporated into early toxicology screening as complementary, translational tools to bridge the gap between traditional in vitro assays and in vivo animal studies. Their integration relies on the generation of robust validation datasets that benchmark chip- or organoid-derived toxicity readouts against well-characterized animal and clinical reference compounds.
Once qualified, these systems are used to evaluate human-relevant endpoints such as tissue-specific toxicity, chronic or low-dose effects, and mechanistic biomarkers that may not be captured in conventional assays. When combined with exposure measurements and traditional toxicology data, Organ-on-a-Chip and organoid models can enhance human safety prediction, support compound prioritization, and help de-risk candidates earlier in development.
Hong Wan, PhD, is Vice President, Drug Metabolism and Pharmacokinetics. Dr. Wan joined BioDuro as Senior Vice President of DMPK. He brings over 25 years of pharmaceutical industry experience from roles at leading organizations including AstraZeneca and Hengrui Pharmaceuticals, with expertise spanning DMPK, bioanalysis, and preclinical safety assessment across small molecules, peptides, ADCs, PROTACs, and other novel modalities.
Dr. Wan has contributed to the evaluation of numerous preclinical candidates and led studies enabling multiple IND filing, with several programs advancing to approved drugs. He has authored and co-authored over 50 publications in peer-reviewed journals. In addition, Dr. Wan is on the Editorial Boards of ADMET/DMPK; Expert Opinion on Drug Metabolism & Toxicology, and was the Co-Chair of the 9th IAPC International Meeting: Emerging Technologies in Drug Discovery and Development, which took place on Sept 23-25, 2024 in Shanghai.
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