The African continent harbors unparalleled genetic diversity yet remains largely underrepresented in  pharmaceutical  research  and  development.  Pharmacogenomics  is  fundamental  to  precision medicine strategies, and although to date largely absent from implementation, representing the genetic diversity of the African population within the laboratory is critical to the democratization of stratified  and  effective  healthcare  in  Africa.  Afrocentric  preclinical  resources  could  support precision  medicine on  the  continent  and  reshape  the  global  underrepresentation  of  African genetics  in  science. Models  which  could  begin  to  address  this  include  primary  human hepatocytes,  immortalized  hepatic  cell  lines,  and human induced  pluripotent  stem  cell  (hiPSC)derived hepatocyte-like cells – derived from individuals of African genetic ancestry. The feasibility of an African hepatic modeling platform is slowly being realized due to the convergence of several technologies and methodologies which have traditionally been siloed on the continent.

This ISSX webinar will feature three presentations! The webinar will also 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 2023 North American ISSX meeting. The graduate student presenters will be introduced by their mentors, who will also participate in the question and answer portion of the webinar.

PREDICTION AND VERIFICATION OF FETAL EXPOSURE TO DUAL BCRP/P-GP DRUG SUBSTRATES USING THE PROTEOMICS INFORMED EFFLUX RATIO-RELATIVE EXPRESSION FACTOR (ER-REF) APPROACH AND PBPK MODELING AND SIMULATION

To inform fetal drug safety, it is important to determine or predict fetal drug exposure throughout pregnancy. The former is not possible in the first or second trimester. In contrast, at the time of birth, fetal drug exposure, relative to maternal exposure, can be estimated as Kp,uu (unbound fetal umbilical venous (UV) plasma area under the curve (AUC)/unbound maternal plasma (MP) AUC), provided the observed UV/MP values, spanning the dosing interval, are available from multiple maternal-fetal dyads. However, this fetal Kp,uu cannot be extrapolated to other drugs. To overcome the above limitations, we have used an efflux ratio-relative expression factor (ER-REF) approach to successfully predict the fetal Kp,uu of P-gp substrates. Because many drugs taken by pregnant people are also BCRP substrates, here, we extend this approach to drugs that are effluxed by both placental BCRP and P-gp or P-gp alone. To verify our predictions, we chose drugs for which UV/MP data were available at term: glyburide and imatinib (both BCRP and P-gp substrates) and nelfinavir (only P-gp substrate). First, the ER of the drugs was determined using Transwells and MDCKII cells expressing either BCRP or P-gp. Then, the ER was scaled using the proteomics-informed REF value to predict the fetal Kp,uu of the drug at term. The ER-REF predicted fetal Kp,uu of glyburide (0.43), imatinib (0.42), and nelfinavir (0.40) fell within two-fold of the corresponding in vivo fetal Kp,uu (0.44, 0.37, and 0.46, respectively). These data confirm that the ER-REF approach can successfully predict fetal drug exposure to BCRP/ P-gp and P-gp substrates, at term.

METABOLOMICS-BASED BIOMARKER APPROACH FOR IDENTIFICATION AND VALIDATION OF CLINICAL ENDOGENOUS BIOMARKERS OF RENAL ORGANIC ANION TRANSPORTERS

Endogenous substrates of drug transporters can be used as phenotypic biomarkers to predict transporter-mediated drug-drug interactions (DDIs), drug toxicity, and inter-individual variability in transport function. Inhibition of renal organic anion transporter (OAT) 1 and 3-mediated uptake and multidrug resistance-associated protein (MRP) 2 and 4-mediated efflux can increase plasma concentration and decrease urine amount of endogenous substrates, respectively, which can be used as clinical biomarkers. We identified and validated clinically relevant biomarkers of OAT1/3 and MRP2/4 using a state-of-the-art metabolomics-based DMET biomarker discovery (MDBD) approach. Untargeted metabolomics of the plasma and urine samples collected from a clinical furosemide/probenecid pharmacokinetic DDI study (n=16) yielded >10,000 features (m/z values) that were either increased or decreased in plasma and urine samples in the presence of probenecid (dual OAT/MRP inhibitor). Features that were significantly increased in plasma (1.5 to 10-fold) and were either decreased or non-significantly increased in urine samples were characterized as putative OAT1/3 biomarkers. Similarly, identification of putative MRP2/4 biomarkers included features that were significantly decreased in urine (by >45%) with non-significant change in plasma. Putative OAT1/3 biomarkers (m/z range, 130-384) belonged to the following pathways: tryptophan metabolites, steroids, peptides, glucuronide conjugates, and fatty acids. MRP2/4 biomarkers (m/z range, 110-510) were majorly bile acids, fatty acids, steroids, glycosides, and peptides. In vitro validation of the identified OAT1/3 biomarkers confirmed 12 putative OAT1 substrates as OAT1 biomarkers (>1.4-fold uptake in transporter over-expressing cells, p-value <0.05), 17 as OAT3 biomarkers and 21 as dual OAT1/3 biomarkers. This high-throughput and robust MDBD approach to identify and validate biomarkers is applicable beyond transporters.          

HOW MUCH IS ENOUGH? BI-907828: A MDM2-P53 ANTAGONIST WITH LIMITED BBB PENETRATION BUT POTENT EFFICACY IN GLIOBLASTOMA MDM2–p53 inhibition may be effective in glioblastoma (GBM). This study evaluates the pharmacokinetics/pharmacodynamics of BI-907828, a potent antagonist of MDM2, in GBM, and demonstrates a translational paradigm with a focus on a unified “Delivery – Potency – Efficacy” relationship in drug development for central nervous system(CNS) tumors. BI-907828 was tested for cytotoxicity and MDM2–p53 pathway inhibition. Systemic pharmacokinetics and transport mechanisms controlling CNS distribution were evaluated in mice. BI-907828 free fractions in cell media, mouse and human specimens were measured to determine “active” unbound concentrations. Efficacy measures, including overall survival and target expression were assessed in mouse orthotopic GBM xenografts. BI-907828 exhibited potent inhibition of MDM2–p53 pathway and promoted cell death in GBM TP53 wild-type cells. MDM2-amplified cells are highly sensitive to BI-907828, with an effective unbound concentration of 0.1 nmol/L. The CNS distribution of BI-907828 is limited by blood–brain barrier (BBB) efflux mediated by P-gp, resulting in a Kp,uu_brain of 0.002. Despite this seemingly “poor” BBB penetration, weekly administration of 10 mg/kg BI-907828 extended median survival of orthotopic GBM108 xenografts from 28 to 218 days (P < 0.0001). This excellent efficacy can be attributed to high potency, resulting in a limited, yet effective, exposure in the CNS. These studies show that efficacy of BI-907828 in orthotopic models is related to high potency even though its CNS distribution is limited by BBB efflux. Therefore, a comprehensive understanding of all aspects of the “Delivery – Potency – Efficacy” relationship is warranted in drug discovery and development, especially for treatment of CNS tumors.

Selective chemical inhibitors are critical for reaction phenotyping to identify drug-metabolizing enzymes that are involved in the elimination of drug candidates. Although relatively selective inhibitors are available for the major cytochrome P450 enzymes (CYP), they are quite limited for the less common CYPs and non-CYPs. To address this gap, we developed a multiplexed high throughput screening (HTS) assay using 20 substrate reactions of multiple enzymes to simultaneously monitor the inhibition of enzymes in a 384-well format. Four 384-well assay plates can be run at the same time to maximize throughput. This is the first multiplexed HTS assay for drug-metabolizing enzymes reported. The HTS assay is technologically enabled with state-of-the-art robotic systems and highly sensitive modern LC-MS/MS instrumentation. Virtual screening is utilized to identify inhibitors for HTS based on known inhibitors and enzyme structures. Screening of ~4000 compounds generated many hits for many drug-metabolizing enzymes. This webinar will highlight the characterization of selective inhibitors of CYP3A5 (loteprednol etabonate) and AO (erlotinib and dibenzothiophene). We encourage colleagues from other organizations to explore their proprietary libraries using a similar approach to identify better inhibitors that can be used across the industry.

This workshop is organized through the efforts of the ISSX Transporters Focus Group and is organized by Drs. Aleksandra Galetin, Xinning Yang, Bhagwat Prasad, Xiaoyan Chu, Hong Shen, Pei Feng Shawn Tan (student member), Mitesh Patel, Eva Gil Berglund, and Chitra Saran.

This virtual workshop will bring together scientists from academia, industry, and regulatory agencies to share their research findings, experience, and expert views on endogenous biomarkers for drug transporters, an active research area with rapid advances in recent years. 

The three-day workshop will cover several important topics in these areas: 

-application of transporter biomarker in drug development,
-understanding transporter function changes in specific populations facilitated by biomarker assessment, 
-methods to identify transporter biomarkers, and 
-emerging biomarkers of efflux transporters.  

Each session of the workshop consists of presentations from several expert speakers followed by roundtable discussions, with case study presentations incorporated into one session to showcase the experience and advances in using transporter endogenous biomarkers during drug development. In addition, there will be an interactive virtual poster session, which will be selected from the pool of abstracts from trainees and industry attendees.

Your workshop registration includes access to all presentation slides and recordings.

Drug discovery and development can be described as the sum of multiple steps taken by biotech and pharmaceutical companies to identify and study new chemical or biological entities and convert these into approved marketed medical products. The entire process takes, on average, more than 10 years and over $1-2B, to bring a product to market.

During this process the attrition rate at all stages of drug discovery and early development are high; hence, sponsors are seeking ways to conduct early-stage drug development studies in the most cost-effective manner. The other consideration is the timeline needed to reach first in human (FIH) studies– the faster we can conduct these studies, the better it is for companies seeking to advance these leads further into development or sell the promising assets to potential buyers who are prepared to conduct additional clinical trials beyond Phase 1 studies. 

The elements of drug development leading to IND submission and the conduct of FIH studies include: Drug Metabolism & Pharmacokinetics (DMPK), Safety/Tox, Bioanalytical (GLP/non-GLP) and CMC. With limited and dwindling resources in biotech/pharmaceutical companies, a significant portion of the task of advancing lead compounds to clinical are now conducted by Contract Research organizations (CROs) who are very well equipped to conduct these early development studies. Very often study sponsors struggle to outsource studies, often in small pieces, to reliable CROs. 

Managing the costs and tracking timelines/samples/reports at multiple CROs often become a very inefficient and costly task. It is important to seek CROs that can provide a one stop shop option to drive cost-savings and efficiency, including accelerated timelines to reach FIH studies. Furthermore, proper project management, resolving issues with the best available science, and ability to provide proper/relevant regulatory guidance, are essential components of this one stop shop facilities. To keep the prices manageable (especially with the high attrition rate), many sponsors are also seeking more cost-effective alternatives overseas, including conducting studies in countries such as China (second largest economy in the world).

Frontage Labs has been engaged in R & D activities over the last 20+ years, with substantial investments in facilities in both USA and China. Over the years, it has built a full-service science-driven organization that has participated in bringing products to the market for numerous clients. With its dual presence in USA and China, and being a strong science and issue driven organization, Frontage is now offering end to end services to advance clients’ lead candidates to FIH at very reasonable cost (estimated to be 50% less than what it costs to conduct these studies internally or outsource to multiple vendors) and with constricted timelines. 

In this presentation we will describe the complete package that Frontage offers to clients seeking to advance their lead candidates to FIH and beyond.

This webinar is sponsored by Frontage.

In June 2022, the ICH released the first draft of its harmonized Drug Interaction Studies Guideline (M12). The guideline is the result of several meetings of the Expert Working Group since 2018 with the goal of harmonizing member regulatory agencies' guidelines to create a single guideline that will be used across all member countries. After a review period, the guideline will be adopted in early 2024. This presentation will offer perspectives on the differences between current in vitro drug-drug interaction guidance from the relevant US FDA, EMA and PMDA guidance documents, and how to plan drug development strategies to meet the ICH M12 guideline.

This webinar is sponsored by BioIVT.

Join us Tuesday, December 5, for a ISSX educational webinar presented by Dr. Chris Mathes, Chief Commercial Officer at AnaBios, and Dr. Shiny Rajan, Director of Tissue Development at Javelin. Together, they will explore the transformative potential of utilizing human primary hepatocytes and liver sinus endothelial cells (LSEC) for in revolutionizing drug development processes. They will discuss how liver tissue chips address the limitations of conventional microfluidic-based tissue chips, offering a physiologically relevant platform for better predict pharmacokinetic endpoints and improve the drug optimization process. Users will learn how Liver Tissue Chips enhance safety assessment and the implications for predicting drug-drug interactions (DDI) and drug-induced liver injury (DILI).

This webinar is sponsored by AnaBios and Javelin Biotech.

Many cancers change their energy metabolic requirements and become "glutamine addicted" for their growth and survival. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) has shown robust efficacy in both preclinical animal models and exploratory clinical studies. Although promising, clinical studies with DON were halted due to its marked dose-limiting toxicities, which were mainly gastrointestinal (GI)-related, as the GI system is highly dependent on glutamine utilization. To overcome these toxicity issues, we sought to develop a DON prodrug that could selectively deliver DON to tumor tissues while sparing normal glutamine-dependent tissues like the GI tract. We designed over 100 prodrugs by installing dual promoeities on DON that can be dislodged by the enriched milieu of esterase and protease enzymes in tumor. Using iterative chemistry and pharmacokinetic efforts, we identified various promising DON prodrugs that showed preferential tumor bioactivation and delivery. Of these, our best DON prodrug, DRP-104 is bio-activated in the tumor while bio-inactivated in gastrointestinal (GI) tissues resulting in 11-fold higher glutamine antagonist delivery to the tumor (target site) versus GI (toxicity site) resulting in robust anti-cancer activity with minimal GI-toxicities. DRP-104, is now being evaluated in Ph1/2a clinical trials in cancer patients (ClinicalTrials.gov Identifier: NCT04471415).

References:
Leone et al., Science 366, 1013-1021 (2019)
Rais et al., Sci. Adv. 8, eabq5925 (2022)

The 2023 ISSX Member Meeting was online on Wednesday, November 29, 2023. You can now access the meeting recording to hear important updates from ISSX President, Scott Obach, ISSX President-Elect, Aleksandra Galetin, ISSX Treasurer, Sandy Pang, ISSX Membership Affairs Committee Chair, Marcel Hop, ISSX Transporters Focus Group Chair, Xinning Yang, and the Co-Chairs of the ISSX/JSSX 2024 Meeting, Natalie Hosea and Kiyomi Ito.

This course was developed by the ISSX Modeling and Simulation Focus Group and was moderated by Maria Posada, Ph.D., Eli Lilly and Company, USA, Oliver Hatley, Ph.D., Certara UK, United Kingdom, and Jaydeep Yadav, Ph.D. Merck, USA.

This short course focuses on the fundamentals of modeling and simulation, spanning several modeling disciplines, including PBPK, QSP, PopPK and Biopharmaceutics, (small molecules, peptides, proteins, or new modalities). The course includes the fundamentals for beginners, advancement, and application, as well as case examples.

SC 1.1 Principles of Population PKPD Modeling
Stacey Tannenbaum, Ph.D., Metrum Research Group, USA

SC 1.2 Informing Drug Discovery and Development using Quantitative Systems Pharmacology Approaches
Jason Chan, Ph.D., Eli Lilly and Company, USA

SC 1.3 PBPK Modelling of Drug-Drug Interactions – Challenges and Opportunities
Aleksandra Galetin, Ph.D., University of Manchester, United Kingdom

SC 1.4 Physiologically Based Mechanistic Oral Absorption Modeling
Kazuko Sagawa, Ph.D., Pfizer, USA