This webinar will highlight the challenges and limitations for prediction of in vivo clearance for aldehyde oxidase (AO) substrates in human. Further, the consequences of poor prediction of AO clearance when developing physiologically-based pharmacokinetic (PBPK) models for AO and dual AO-CYP substrates will be explained. Attendees will receive the latest research aimed at overcoming these challenges being performed by two academic centres of excellence.Joint webinar between Centre for Applied Pharmacokinetic Research (CAPKR; University of Manchester, UK) and Proteomics-based Research Initiative for Non-Cytochrome P450 Enzymes (PRINCE; Washington State University, US), two academic research consortia sponsored by pharmaceutical industry. Co-chairs: - Dr Daniel Scotcher (University of Manchester, UK) - Dr. Bhagwat Prasad (Washington State University, WA). 

Aldehyde oxidase (AO) is a cytosolic molybdoflavoprotein enzyme, expressed mainly in liver, with wide range of substrates and capable of mediating oxidation and reduction metabolism. Following from progress towards reducing cytochrome P450 (CYP) liabilities of new drugs, AO has emerged as an increasingly common alternative metabolic pathway for drug metabolism. In particular, several drug development programs have failed due to poor prediction of in vivo drug clearance by AO; for example, toxicity and poor bioavailability in first-in-human trials. This webinar will explain the existing challenges of in vitro-in vivo extrapolation (IVIVE) of intrinsic clearance of AO and dual AO CYP substrates from a variety of in vitro systems, and the latest research to resolve these. The development of physiologically-based pharmacokinetic (PBPK) models for AO and dual AO-CYP substrates will be presented. In particular, the value and challenges of proteomics abundance data across tissues and population groups, and reverse translation of clinical data will be discussed. Relevance to clinical pharmacology including drug-drug interactions and dose adjustment in specific populations will be discussed.

Speakers: 

- Dr Sandhya Subash (Washington State University, WA): "Key Factors Affecting Quality and Translatability of in vitro AO Mediated Metabolism Data"

- Dr Nihan Izat (University of Manchester, UK): "Current Perspectives on IVIVE of Aldehyde Oxidase and PBPK Modelling Strategies"

Unique GSH adduct formation was found in this study where the GSH adduct was formed through rearrangement reaction. So, there was no characteristic -129 neutral loss in this rearranged GSH adduct. Additionally it was direct GSH adduct where no CYP mediated Bioactivation was required. The GSH adduct formation was catalyzed by ?-glutamyltranspeptidase and non specific peptidase. The GSH adduct formation was compared between Pyrimidine, Pyridazine and Pyridine series and it was found that GSH adduct formation was maximum in case of Pyrimidine followed by Pyridazine and Pyridine. This trend was in keeping with the diminishing electrophilicity across these series, as demonstrated by in silico modeling. Hence, mechanistic insights gained from this study could be used to assist a medicinal chemistry campaign to design compounds that were less prone to the formation of reactive metabolites.

Certain aromatic nitriles are well-known inhibitors of cysteine proteases.The mode of action of these compounds involves the formation of a reversible or irreversible covalent bond between the nitrile and a thiol group in the active site of the enzyme. However, the reactivity of these aromatic nitrile-substituted heterocycles may lead inadvertently to nonspecific interactions with DNA, protein, glutathione, and other endogenous components, resulting in toxicity and complicating the use of these compounds as therapeutic agents. In the present study, the intrinsic reactivity and associated structure y property relationships of cathepsin K inhibitors featuring substituted pyridazines [6-phenylpyridazine-3-carbonitrile, 6-(4-fluorophenyl)-pyridazine-3-carbonitrile, 6-(4-methoxyphenyl)pyridazine-3-carbonitrile, 6-p tolylpyridazine-3-carbonitrile], pyrimidines [5-ptolylpyrimidine-2-carbonitrile, 5-(4-fluorophenyl)pyrimidine-2-carbonitrile], and pyridines [5-p-tolylpicolinonitrile and 5-(4-fluorophenyl)picolinonitrile] were evaluated using a combination of computational and analytical approaches to establish correlations between electrophilicity and levels of metabolites that were formed in glutathione- and N-acetylcysteine-supplemented human liver microsomes.

 Metabolites that were characterized in this study featured substituted thiazolines that were formed following rearrangements of transient glutathione and N-acetylcysteine conjugates. Peptidases including ?-glutamyltranspeptidase were shown to catalyze the formation of these products, which were formed to lesser extents in the presence of the selective ?-glutamyltranspeptidase inhibitor acivicin and the nonspecific peptidase inhibitors phenylmethylsulfonyl fluoride and aprotinin. Of the chemical series mentioned above, the pyrimidine series was the most susceptible to metabolism to thiazoline-containing products, followed, in order, by the pyridazine and pyridine series. This trend was in keeping with the diminishing electrophilicity across these series, as demonstrated by in silico modeling. Hence, mechanistic insights gained from this study could be used to assist a medicinal chemistry campaign to design cysteine protease inhibitors that were less prone to the formation of covalent adducts.

Attendees will be educated on the need to understand effect of disease state on transport activity and PK of drugs. Emerging modeling approach to predict PK in NASH/Hepatic impairment population will be discussed. Enable model-informed drug development - understanding disease effects.

The liver and kidney play central role in the pharmacokinetics (PK) of drugs and new molecular entities (NMEs). Several solute carriers (SLCs) including OATP1B1/1B3/2B1, NTCP, OAT2 and OCT1 and efflux pumps including MRPs, Pgp, BCRP are highly expressed on the sinusoidal/canalicular membranes and have the potential to dictate hepatic clearance. Similarly, renal transporters (OCT2/OATs/MATEs) are important in the renal elimination of drugs and metabolites. Disease-states such as renal- and hepatic-impairment is associated with multiple pathophysiological and biological changes including variable and non-uniform reduction in metabolic/transporter activity, altered plasma protein binding, hepatic blood flow and portal-systemic shunting, etc. and may lead to altered blood or plasma clearance of drugs eliminated by liver. This presentation will discuss the disease-induced changes in expression and function of OATP1B and other drug transporters along with drug metabolizing enzymes, and the implications on the clinical pharmacokinetics in patient populations. Emphasis will be placed on the proteomics- and/or PBPK-informed translation to predict PK changes in organ impairment.

This talk is meant to inform the global drug metabolism and pharmacokinetics research and applications community of DMPK work being done in Africa. It is hoped to highlight opportunities for research collaboration. This webinar intends to focus on the following objectives:

1. Present progress in DMPK research and applications in Africa;

2. To demonstrate how preclinical and clinical DMPK has improved the use of drugs in the treatment of infectious diseases;

3. To make the Global scientific community aware of the liver tissue biobank from people of African ancestry as a DMPK research resource they can access.

This webinar aims to introduce various tools/platforms, the use of primary human hepatocyte spheroids, cryo-electron microscopy, and bioengineered microRNA, in drug transporter research and drug discovery. The webinar also aims to recognize graduate students and postdoctoral fellows from academia who carried out transporter-related research and presented their work in the form of a poster at the 2022 ISSX/MDO International Meeting.

This webinar will feature three presentations and help scientists better understand:
1) the utility of using 3D primary human hepatocyte spheroids to study hepatic transporters
2) application of bioengineered microRNA in regulation of solute carrier (SLC) transporters
3) the structures of organic cation transporters revealed by electronic microscopy which help understand substrate or inhibitor binding with transporters.

This presentation provides an overview of mechanistic PK models developed to characterize ADME properties of therapeutic proteins (TPs), which can be used to support model-informed discovery and development of TPs. As the next-generation of TPs with diverse physicochemical properties and mechanism-of-action is being developed rapidly, there is an urgent need to better understand the determinants for the ADME of TPs and evolve existing platform PK models to facilitate successful bench-to-bedside translation of these promising drug molecules.

This webinar aims to highlight current knowledge about albumin-mediated uptake by organic anion transporters expressed in liver and kidney. Special emphasis will be placed on in vitro evidence to support the hypothesis and the complexity confounded by the non-specific binding of the drug-albumin complex. Possible implications to improve the prediction of transporter-mediated hepatic and renal clearance for highly protein bound drugs will be discussed.

Plasma proteins or human serum albumin have been reported to increase the in vitro uptake clearance of highly albumin-bound anionic drugs. Various hypothesis and mechanistic models have been proposed to explain such phenomenon. However, some controversial observations have suggested that possible artifact of the non-specific binding may complicate the data interpretation. This special webinar will be started with two presentations given by the graduate students (their works were presented at the 2022 International ISSX meeting as poster presentations), followed by a panel discussion with all speakers, their scientific mentors, and international renowned experts in transporter field. The knowledge gained from this presentation will help scientists at all levels to learn the concept of albumin-mediated uptake effects by transporters; understand their complexity and current knowledge gaps. The discussion will also provide some insights and practical considerations on designing in vitro transport kinetic studies for highly protein bound drugs to improve their in vitro to in vivo extrapolation. 

Speakers:                                                                                                                                                                                               Mengyue (Melody) Yin, University of Washington, USA                                                                                                                                   Shawn Pei Feng Tan, University of Manchester, UK

Panelists:                                                                                                                                                                                                    Aleksandra Galetin, University of Manchester, UK                                                                                                                                        Jash Unadkat , University of Washington, USA                                                                                                                                              Yuichi Sugiyama, Josai International University, Japan

This workshop is organized through the efforts of the ISSX Biotransformation Mechanisms and Pathways Focus Group and is chaired by Carley Heck of Pfizer and Valerie Kramlinger of Vanderbilt University.

This virtual workshop will focus on the impact of small organic molecule metabolism science on both drug discovery and drug development. This three day workshop will dissect the types of in vitro and in vivo drug metabolism studies conducted to support the drug discovery-development pipeline, including the experimental and analytical techniques used and the impact of the data generated. Some of the exciting topics to be covered are: the importance of drug metabolites, analytical techniques of metabolite ID, prediction of human circulating metabolite profiles, metabolite biosynthesis, human ADME study strategies and impact, and both the pharmaceutical industry and regulatory perspectives on the value of human ADME studies and drug metabolism science. Each session of this workshop will feature 4-5 expert speakers, a daily panel discussion, and poster sessions; the latter will be selected from the pool of abstracts from the students and industry attendees.

The workshop includes access to all presentation slides and recordings.

For many years I worked within Big Pharma at Pfizer. For the last decade plus I have worked with many smaller drug discovery and development groups, some of them under the umbrella of Medicines for Malaria Venture (MMV, https://www.mmv.org/). Within the research programs I see there are many common areas of understanding and still some areas which cause enormous confusion. The biggest area of misunderstanding is what total and free drug concentrations mean in terms of drug dynamics, in vitro and in vivo and what actually governs, in vivo, the total and free concentrations of drugs in tissues and the circulation. The first part of the seminar will examine these aspects and describe the author’s interpretation. The role and importance of drug binding with in vitro assays will be stressed. The central role of intrinsic clearance in determining free drug concentration will be explained and the misunderstandings of what drug distribution and Distribution Volume explored. The author will advance that once free drug is correctly interpreted it can move “projected clinical dose” to a holistic central role in the objectives of drug discovery programs, rather than a checklist of arbitrary multiple objectives.

Webinar Abstract Title: Drug Metabolism and Jordan; Focus on the Circassians and the Chechens Subpopulations 

This webinar is going to extend the discussion initiated in the award lecture that was presented in Seattle in September 2022 in recognition of my sustained contributions to the field of drug metabolism research. I was the recipient of the 2022 ISSX Award for Outstanding Achievement in Xenobiotic Research by a Scientist from an Underrepresented Nation.

The Jordanian population is composed of different ethnicities, the overwhelming majority are Arab (98%) and the remaining non-Arabs are Circassians, Chechens, Armenian, and Kurds. Circassians and Chechens in Jordan are two minority populations with Caucasian ancestry, each is genetically isolated due to endogamous marriage. Our group has studied these subpopulations and compared the similarities and differences between these genetically distinct populations and the Jordanian Arabs. We investigated the variability in the prevalence of certain conditions like diabetes, hypertension, and cancer which could inform our understanding of the cause and etiology of the disease

The webinar is going to discuss some of the pharmacogenetic studies performed in Jordan and highlight their findings. Moreover, pharmacogenetic studies of Circassians and Chechens have also been conducted and could similarly utilize an understanding of medication response leading to personalized therapy.

Our findings emphasize the importance of the inclusion of different populations and diverse ethnic subpopulations in genetic and pharmacogenetic studies to better understand health, aging, and how a disease develops and emphasize the importance of personalized medicine.