This webinar will highlight the utility of mechanistic PBPK modeling to not only predict fetal circulatory THC concentrations but also fetal tissue THC concentrations, including in the brain. The approach outlined will provide a blueprint to develop a PBPK model to predict tissue drug exposure in any population. The audience will gain an understanding of how to identify and quantify key pathways involved in driving fetal drug exposure, determine the impact of each pathway, and incorporate them into a PBPK model to predict fetal drug exposure in both the fetal circulation as well as tissues. They will also learn how transcriptomics and proteomics can inform the effects of a drug on molecular signatures within a target tissue such as the brain.

This symposium/webinar is intended to draw attention to our recent findings (in press at Communications Biology) showing that human liver microsomes and recombinant enzymes may misidentify CYP enzymes responsible for metabolism of new drug entities. Given the potential seriousness of the inaccuracies, we would like to share this with the drug metabolism community and regulatory authorities.

Physiologically based pharmacokinetic (PBPK) modelling is an approach that utilizes the knowledge of the physiological and biological elements of the human or animal body, otherwise known as “systems data”, to predict the PK of drugs when used in conjunction with relevant compound or drug data. This involves model development of both the compound and the population of interest in a suitable PBPK platform.

Drug-drug interactions (DDIs) mediated by renal transporters such as OCT2 and MATE1/2K pose significant challenges in drug development and clinical pharmacology. Traditional approaches to assess DDI risk often rely on in vitro inhibition data and clinical studies using probe drugs. However, recent advances, including the use of endogenous biomarkers, extended clearance concepts, and physiologically based pharmacokinetic (PBPK) modeling, offer promising alternatives for early prediction and mechanistic understanding of transporter-mediated DDIs.

This seminar aligns with addressing the questions and concerns early stages of a research career, emphasizing how early investigators craft a coherent scholarly identity while navigating institutional structures, mentorship, and funding ecosystems.

This webinar aims to introduce novel research on emerging transporters and their potential involvement in disease modulation and treatment. This includes characterizing the activity of OCTN1 and LAT1 in the brain and spinal cord, the role of these transporters in influencing the efficacious exposure of ergothionine and pregabalin and their therapeutic effect in preclinical mice models of Alzheimer's Disease and cold allodynia, respectively.

Pregnane X receptor (PXR) transcriptionally induces drug-metabolizing enzymes such as CYP3A4/5 to control drug metabolism, and might cause drug-drug interactions, toxicities, and resistance. Therefore, inhibitors of PXR and CYP3A4/5 might have therapeutic value. Many drugs bind to and activate PXR, and CYP3A4/5 metabolize 50% of the marketed drugs. The large and dynamic ligand binding pockets of PXR, CYP3A4, and CYP3A5 enable their promiscuous accommodation of structurally diverse ligands, and present challenges to selectively modulate them. We take structural, chemical and pharmacological approaches to selectively modulate PXR and CYP3A4/5. Our efforts provide effective approaches and novel chemical probes (e.g., inhibitors of PXR, CYP3A4 and CYP3A5) to selectively modulate the promiscuous drug metabolism pathway.

Accurately modeling complex drug-drug interactions (DDIs), including those involving non-CYP3A4 pathways, and underestimation of clearance predictions for substrates of aldehyde oxidase (AO) remain as challenges in drug development. In this webinar, Diane Ramsden will present compelling data showcasing quantitative predictions of enzyme and transporter induction including a promising application involving accurate derivation of steady-state AUC changes stemming from complex DDIs including simultaneous induction and inhibition. While , Stephanie Piekos will showcase data demonstrating improved intrinsic clearance predictions for compounds metabolized by AO, highlighting sustained, enhanced enzyme activity over extended culture periods as a new strategy for predicting AO-mediated metabolism. Together, these insights demonstrate how an advanced in vitro hepatic model can address distinct but complementary gaps in translational pharmacokinetics. Moderated by Edward LeCluyse.

The resurgence of covalent inhibitors as a viable therapeutic approach continues to expand and positively impact patients, particularly for targets previously considered undruggable. The application of targeted covalent inhibitor (TCI) strategies is broadening the range of druggable targets. Adopting and implementing appropriate computational and experimental paradigms will facilitate the design and selection of clinical candidates throughout the drug discovery and development process. While well-defined steps for the development of targeted covalent drugs are evolving, this presentation will outline a general strategy for the discovery and development of TCIs. Additionally, pharmacokinetic/pharmacodynamic (PK/PD) and efficacy mechanistic models for covalent drugs will be discussed. These mechanistic PK/PD/efficacy models derived from pre-clinical and clinical experience will enhance our understanding of the pharmacokinetic and pharmacodynamic interplay and assist in designing next-generation covalent drugs.

Join us for an exciting webinar spotlighting emerging research led by African trainees tackling some of the continent’s most pressing health challenges. This session, with attendees drawn from the recently concluded ISSX Africa workshop, will feature four dynamic presentations exploring complex pharmacokinetics drug-drug interactions (DDI) and modelling in African patients.