2025 ISSX International Meeting

Lijuan Hou , Sr. Director | WuXi AppTec DMPK Department

Xin Gu, Ph.D.,  Associate Director, Drug Metabolism | WuXi AppTec, Laboratory Testing Division, Cranbury, New Jersey, USA

The rise of novel therapeutic modalities—such as challenging small molecules, peptides, oligonucleotides, and ADCs—offers exciting opportunities but also brings complex ADME-PK and biotransformation challenges. In this ISSX Breakfast Symposium, WuXi AppTec's DMPK scientists, contributors to the new Wiley book Drug Metabolism and Pharmacokinetics: Frontiers, Strategies, and Applications, will share practical, modality-specific strategies and real-world case studies, including:

Challenging Small Molecules: Overcoming solubility, recovery, and bioavailability barriers.ADCs: Optimizing in vitro system selection, payload release assessment, and ADME-PK evaluation.TIDES: Applying advanced LCHRMS and proprietary workflows to resolve metabolism complexities.

Learning Objectives:

Identify key ADME-PK and biotransformation challenges across diverse modalities.Apply targeted strategies and analytical methods to improve preclinical study design.Integrate ADME and metabolism insights to enhance development efficiency and clinical translation.

Yajuan Bi, Ph.D. | Senior Scientist II, WuXi AppTec DMPK

In vitro metabolic stability and protein binding studies are crucial for optimizing oligonucleotide drugs, as they significantly impact drug delivery, distribution, retention, and safety. However, reported studies have shown inconsistent results in siRNA drug binding due to varying plasma protein binding (PPB) assay methods. This presentation will briefly introduce various systems used for studying the metabolic stability of oligonucleotide drugs and their applicability, as well as different techniques used for protein binding studies and their characteristics. We will highlight the challenges and discrepancies between different PPB assay methods and provide reasons behind the inconsistent PPB findings regarding siRNAs. This presentation aims to improve the reliability of PPB assessments in oligonucleotide drug development and potentially influence future research methodologies.

Lingling Zhang , Ph.D. | Director, WuXi AppTec DMPK Department

GLP-1 receptor agonists, including mono-, dual-, and triple-receptor analogs engineered through sequence and fatty acid chain modifications, have gained significant momentum in treating type 2 diabetes and obesity. Understanding the absorption, distribution, metabolism, and excretion (ADME) of these large peptides (3,000~6,000 Da) necessitates radiolabeling techniques.

14C is the preferred isotope for GLP-1 analogs, consistent with clinical requirements. However, their low administered doses (0.15~3 mg/kg) demand high specific activity (~200 mCi/mmol). Prolonged half-lives further complicate ADME studies: excretion profiling and quantitative whole-body autoradiography (QWBA) often require >30 days of urine, feces, and carcass collection. Metabolite identification in excreta, bile, and plasma is particularly challenging due to catabolic pathways (e.g., β-oxidation of fatty acid moieties) beyond amide hydrolysis.

This presentation will detail:

Radiolabeling synthesis strategies for linear and cyclic GLP-1 peptides.Complete excretion recovery methodologies in rodents and non-human primates.Key metabolite profiling/identification of modified amino acids and fatty acid chains, supported by case studies.