Abstract

The substitution of hydrogen with deuterium — a stable, non-radioactive isotope — represents a subtle and mechanistically powerful strategy in modern drug discovery. This webinar will introduce DMPK scientists and medicinal chemists to the kinetic isotope effect (KIE), exploring the physicochemical basis by which the stronger C–D bond can attenuate drug metabolism and influence a compound's pharmacokinetic profile. Drawing on both preclinical and clinical examples, attendees will gain an appreciation for how deuterium incorporation can be leveraged in drug design and as a mechanistic probe for identifying the site of metabolism. The presentation will also address the limitations of this approach — including metabolic switching and when to expect scenarios where no isotope effect is observed. Attendees will leave with a practical, foundational framework for evaluating when and how deuterium substitution can be a meaningful tool in their DMPK and medicinal chemistry toolkit. 

Educational Needs Statement

The kinetic isotope effect is well known across the industry; however, it is a nuanced subject that can sometimes be misunderstood, inappropriately utilized in an attempt to solve metabolic liabilities, or simply conjured up as a magic fix-all. For a complex subject such as this, one that can be quite useful when applied at the right time and for the right reason, our industry would benefit from a refresher on this subject. The goal of this webinar is to educate on the kinetic isotope effect as a tool for drug discovery. 

Learning Objectives

Educate DMPK scientists and medicinal chemists about the kinetic isotope effect and using deuterium for Medicinal Chemistry design in Drug Discovery. By the end of this webinar, the audience will have a foundational understanding of what the effect is and in what circumstances it can be employed to improve the DM properties of a drug candidate. 

Abstract:

Biotransformation science is critical to understanding the metabolic fate, pharmacokinetics, safety, and efficacy of new therapeutics. Biotransformation Stories highlights emerging research from doctoral trainees applying both established and evolving approaches to drug and xenobiotic metabolism. Emily Gracey will explore advanced human in vitro models for studying drug metabolism and toxicology, including 3D cultures, organoids, induced pluripotent stem cell-derived models, and microphysiological systems. These technologies offer opportunities to better recapitulate human physiology, improve preclinical translation, and complement conventional 2D cultures and animal models. Ian Levasseur’s presentation will examine the metabolism of BKI-1708, a promising anti-Cryptosporidium agent that forms an unusual, pharmacologically active hemiaminal metabolite. Using human liver microsomes, selective CYP inhibition, recombinant enzymes, and LC-MS/MS, CYP2C8 was identified as the primary enzyme responsible for metabolite formation, illustrating how mechanistic biotransformation studies can inform pharmacokinetics and drug–drug interaction risk. These stories will showcase how emerging scientists are addressing contemporary biotransformation challenges and provide a forum for engagement between academic trainees and industrial DMPK scientists.

Educational Needs Statement: 

A trained biotransformation scientist is becoming increasingly difficult to find for industrial biotransformation bench scientist positions. Intellectual property concerns have long limited access to novel compounds and metabolism studies, and recent decreases in funding available to support basic DMPK science have created additional challenges for doctoral students and postdocs in biotransformation and related fields. We see an urgent need to give exposure to those working on projects in this space both to highlight their exciting work and to inspire them and their peers to continue working on projects with a focus on drug and xenobiotic metabolism. 

Learning Objectives: 

• Give a platform for trainees to highlight their emerging science. 
• Provide an opportunity for industrial scientists to interact with a few of the next generation of biotransformation scientists. 
• Provide the audience with a few examples of how academia is tackling biotransformation questions. 

Abstract: In patients with renal impairment, tubular secretion of drugs via drug transporters is reduced. As a possible mechanism, the chronic inflammatory state associated with renal injury may affect the expression and activity of drug transporters. However, the relationship between inflammatory status and drug transporter expression have not been clarified using patient samples. In this study, we analyzed the expression levels of drug transporters in human kidney specimens and examined the effects of inflammatory cytokines on the expression and activity of renal drug transporters, organic anion transporter (OAT) 1 and 3, using three-dimensionally cultured human proximal tubular epithelial cells (3D-RPTEC) [1,2]. Proteomic analysis of non-tumor portion specimens of kidneys removed from patients with renal tumors revealed 93 transporters including OAT1. Enrichment analysis of proteins negatively correlated with OAT1 and OAT3 expression in human kidney using Metascape revealed GO terms related to inflammation. To characterize the direct effects of inflammatory cytokines on RPTECs, IL-1β and TNFα were exposed to 3D-RPTECs. As a result, mRNA expression of OAT1 and OAT3 was decreased and the uptake activity of the OAT1 substrate [3H] PAH was reduced. The decrease in mRNA expression due to inflammatory cytokine exposure was suppressed by the addition of the NF-κB inhibitor benzoxathiole. In conclusion, our studies revealed that inflammatory cytokines negatively regulate the expression of renal drug transporters OAT1 and OAT3.

Learning Objectives:

- What is the role of renal drug transporters?
- How does renal impairment and/or inflammation affect renal function (especially transporter function)
- Familiarization with methods and tools that can be used to study renal drug handling

Target Audience: DMPK scientists with particular interest in renal drug transport and the effect of disease / inflammation on kidney function.

Educational Needs Statement: Knowledge gaps continue to exist regarding the impact of renal disease on drug transport in proximal tubular cells

This webinar is designed to provide an overview of emerging strategies transforming pharmacokinetic (PK) prediction in modern drug discovery. It will explore how high-throughput physiologically based pharmacokinetic (HT-PBPK) modelling, combined with machine learning, enables rapid, structure-driven prediction of PK properties, reducing reliance on experimental data in early discovery.
This session will highlight the application of HT-PBPK workflows for large-scale compound prioritisation, alongside advances in modelling beyond Rule-of-Five (bRo5) compounds such as PROTACs and cyclic peptides. Through case studies, speakers will demonstrate how novel physicochemical descriptors improve the prediction of key ADME and in vivo PK endpoints, including permeability, solubility, and systemic exposure. Together, these approaches offer new opportunities to enhance decision-making and accelerate the design of developable drug candidates.

By the end of this webinar, participants will be able to:

1. Describe how in silico inputs can replace in vitro data to enable scalable pharmacokinetics prediction. 2. Assess the value of novel physicochemical descriptors in improving ADME and pharmacokinetics predictions
3. Interpret prediction accuracy (e.g., fold-error ranges) and identify key success factors (e.g., clearance pathway classification, ML confidence).
4. Understand the drug development challenges posed by PROTACs and cyclic peptides
5. Describe emerging strategies for modelling beyond Rule-of-Five (bRo5) compounds

Placental ATP binding cassette (ABC) and solute carrier (SLC) transporters regulate the transfer of nutrients, endogenous compounds, drugs and metabolites between mother and fetus, impacting fetal development and pregnancy outcomes. Identification and accurate quantification of these transporters is critical for predicting nutrient and drug disposition and assessing drug safety throughout pregnancy. Proteomics and transcriptomics offer complementary strategies for identifying and quantifying transporter abundance in placental tissue of varying gestational age. 

The key focus of the NIH‑funded Transporter Elucidation Network (TEN) aims to identify, quantify, and characterize SLC and ABC transporters in the human placenta, the lactating mammary gland, developing gut, and blood-brain barrier.  This webinar will focus on the placenta and feature investigators from the University of Washington Transporter Elucidation Center (UWTEC) and the Integrated Transporter Elucidation Center (InTEC), two of the four Centers that comprise the NIH TEN.

The webinar will begin with proteomic approaches, both targeted and untargeted, and how they offer complementary strategies for identifying and quantifying transporter abundance in placental tissue.  The webinar will then describe newly identified gestational age associated changes in nutrient transporter expression, novel associations between maternal and infant factors, including environmental chemical exposures, and ABC and SLC transporter enrichment in over 250 placentas from the US-based Understanding Pregnancy Signals and Infant Development (UPSIDE) cohort.  Finally, transcriptomic analyses defining the spatial and temporal landscapes of SLC and ABC mRNA expression in human placentas will be presented and discussed. 

Together, this webinar aims to advance understanding of SLC and ABC transporters in fetal nutrient and xenobiotic exposure and highlight emerging technologies that are transforming our ability to characterize placental transporters and their implications for fetal exposure to nutrients and medications.

The International Society for the Study of Xenobiotics (ISSX) is proud to announce that Dr. Donglu Zhang has been named the 2025 recipient of The 2025 ISSX Distinguished Accomplishments in Drug Discovery and Development Award, one of the most prestigious recognitions within the Society. Donglu Zhang's career exemplifies innovation, impact, and leadership in drug metabolism and pharmacokinetics. 

As part of this distinguished recognition, Dr. Zhang delivered his award lecture at the 2025 ISSX International Meeting in Chicago. This webinar offers the broader ISSX community the opportunity to hear his presentation, highlighting the scientific achievements and insights that have shaped his career and contributed meaningfully to the advancement of xenobiotic research worldwide.

The International Society for the Study of Xenobiotics (ISSX) is proud to announce that Dr. Scott Obach has been named the 2025 recipient of the R.T. Williams Distinguished Scientific Achievement Award, one of the most prestigious recognitions within the Society. This award, generously sponsored by Charles Crespi and his family, honors ISSX members who have made substantial and lasting contributions to the field of xenobiotic research.

As part of this distinguished recognition, Dr. Obach delivered his award lecture at the 2025 ISSX International Meeting in Chicago. This webinar offers the broader ISSX community the opportunity to hear his presentation, highlighting the scientific achievements and insights that have shaped his career and contributed meaningfully to the advancement of xenobiotic research worldwide.

About the R.T. Williams Distinguished Scientific Achievement Award Named in honor of R.T. Williams, this award recognizes an ISSX member who has made seminal and sustained scientific contributions to the field. It represents the pinnacle of scientific recognition within ISSX and celebrates vision, dedication, and achievement at the highest international level.

Co-chairs: Daniel Scotcher, University of Manchester, UK and Jaydeep Yadav, Merck, USA

• FiH dose predictions for protein degraders with PKPD modelling
  Jaydeep Yadav, Merck & Co, USA
• Translational strategies for multi-specific antibodies (t-cell engagers) in oncology/ immunology
  Fei Hua, Certara, USA
• Modelling of oligonucleotides and RNAi therapeutics
  Vivaswath Ayyar, GSK, USA
• Applications and considerations of mechanistic modeling in regulatory decision process
  Yuching Yang, Cary, NC, USA

Co chairs: Kevin Johnson, Inotiv, USA and Shuai Wang, Genentech, USA

• Missing metabolites: what’s the big deal?
  Shuai Wang, Genentech, USA

• Metabolic Outliers: When Drug Metabolism Goes Off Script
  Valerie Kramlinger, Amgen, USA

• From Inception to Detection: Tracking Thiol Drug Metabolites
  Simone Schadt, Roche, Switzerland

• Avoiding Missed Metabolites for Confidence at IND Submission
  Matthew Hutzler, Inotiv, USA
• Mass Balance Study Design and Strategies For Addressing Unexpected Metabolites
  Raman Sharma, Pfizer, USA

Co-Chairs: Bhagwat Prasad, Cincinnati Children’s Hospital, USA and Eva Berglund, Certara, USA

• Strengths and weaknesses of biomarker PBPK models to assess transporter-mediated DDIs
  Hiroyuki Kusuhara, The University of Tokyo, Japan

• Endogenous Probes in Practice: Why, When, and How?
  Ryota Kikuchi, AbbVie, USA

• Clinical transporter probes: Selectivity and sensitivity
  Xiaoyan Chu, Merck, USA
• Endogenous transporter probes from a regulatory perspective
  Xinning Yang, Ellicott City, MD, USA