Science Pool

Investigating Protein-Facilitated Uptake of OATP Substrates: From In Vitro Data to PBPK Modeling

The fourth and final webinar in this series on drug transporters was presented by Christine Bowman from Genentech.

About the Webinar

Christine will discuss the concept of protein-facilitated uptake and the recently proposed hypothesis of a transporter-induced protein binding shift In vitro data generated with hepatocytes and HEK293 cells will be described as well as the results of using the HEK293 data for input in PBPK models. The results suggest that high affinity binding to transporters may change the equilibrium of nonspecific binding between drugs and plasma proteins, leading to greater cellular uptake and clearance than currently predicted.

About the Speaker

Christine Bowman PhD Associate Scientist, DMPK | Genentech Christine Bowman is an Associate Scientist in the Drug Metabolism and Pharmacokinetics Department at Genentech, Inc. Her research interests include improving in vitro to in vivo extrapolation with new in vitro methods and PBPK modeling. Prior to Genentech, Christine received her PhD from the University of California, San Francisco in the laboratory of Dr. Leslie Benet during which time she was the recipient of a National Science Foundation Graduate Research Fellowship and PhRMA Foundation Pre-Doctoral Fellowship in Pharmaceutics. Christine is an author and coauthor of 16 peer-reviewed scientific publications.

Watch the webinar to learn more!

[hs-form id="768e7ce5-f1a6-44f7-b20b-a3042c53e0a4" show="hide on login" url="https://news.evotecsciencepool.com/hubfs/Sciencepool/Videos%20and%20Webinars/Cyprotex%20webinars%20and%20videos/focus-on-drug-transporters-webinar-series-christine-bowman-genentech-sept2020.m4v"]

Impact of Pre-incubation Time on Transporter Inhibition Potency

The third webinar in our series on drug transporters was presented by Felix Huth from Novartis.

About the Webinar

For some inhibitor compounds, pre-incubation with the inhibitor leads to more potent IC₅₀ values in uptake transporter inhibition assays. One contributing factor to the higher inhibition potency is the time required to reach steady state concentrations for the inhibitor. The dependent factors influencing this equilibration time will be described as well as the clinical relevance.

About the Speaker

Felix Huth PhD ADME Scientist | Novartis Felix Huth received his PhD in Natural Product Chemistry from the University of Göttingen, Germany. After starting his career in a Biotech company in 1999, he joined the pharmaceutical company Altana in 2004 as biotransformation specialist. He extended his ADME knowledge, i.e. in enzyme and transporter kinetics, PBPK modeling and DDI. After joining Novartis in 2013, he developed in the role of an ADME/DDI specialist with focus on transporters and PBPK modeling, reflected by more than 20 peer-reviewed publications.

Watch the webinar to learn more!

[hs-form id="5385d516-f2dd-4038-8e90-5eb7b3e85574" show="hide on login" url="https://news.evotecsciencepool.com/hubfs/Sciencepool/Videos%20and%20Webinars/Cyprotex%20webinars%20and%20videos/focus-on-drug-transporters-webinar-series-felix-huth-novartis-sept2020.m4v"]

Date: 8th - 13th April 2022

Location: New Orleans Ernest N. Morial Convention Center, LA, United States

Attending: Francisco Cruzalegui, Michael Esquerre, Pierre Fons, Pascale Lejeune, Itta MacNevin, Jeremiah Treanor, Nathalie Joly

Find out about the science Evotec will show here

Join our scientific experts at booth #1111!

If you wish to meet with us in New Orleans, get in touch via the form below, we will be happy to arrange a meeting.

Learn more about AACR 

P-gp Transport Kinetics - Compound-Specific Selection of In Vitro Assay Design and Kinetic Parameter Estimation

The second webinar in this series on drug transporters was presented by Birk Poller from Novartis.

About the Webinar

Robust and reliable determination of the kinetic parameters for efflux transporters, primarily P-glycoprotein, has remained a challenging task. Different cell types, assay setups and kinetic models together with the physicochemical drug properties affect the outcome of in vitro studies. In this webinar, the results of a systematic study will be presented together with a compound-specific guidance for the assessment of efflux transporter kinetics.

About the Speaker

Birk Poller Senior Principal Scientist | Novartis Birk Poller is an ADME Scientist at Novartis, working in the Pharmacokinetic Sciences department. He is responsible for in vitro permeability and drug transport studies and acts as deputy lead for an in vitro enzyme, transporter and plasma protein binding group. In addition, Birk Poller serves as ADME and DDI expert in cross-functional project teams throughout the translational drug development phases. His recent research on elucidating the interplay between drug transport and metabolism in the context of clearance prediction and drug-drug interactions resulted in several scientific publication. Before joining Novartis in 2010, Birk obtained his PhD from the University of Basel, Switzerland and he conducted postdoctoral research in blood-brain barrier pharmacokinetics at the Netherland Cancer Institute in Amsterdam.

Watch the webinar to learn more!

[hs-form id="abfbeada-8b42-41c2-b2a4-80a3e39c771e" show="hide on login" url="https://news.evotecsciencepool.com/hubfs/Sciencepool/Videos%20and%20Webinars/Cyprotex%20webinars%20and%20videos/focus-on-drug-transporters-webinar-series-birk-poller-novartis-sept2020.m4v"]

Date: 27th - 31st March 2022

Location: San Diego Convention Center, CA, United States

Attending: Christopher Strock, Claire White, David Cerny, Felix von Haniel, Illaria Masotto, Matteo Sartori, Michael Campognone, Monday Ogese, Paul Walker, Ralf Geiben Lynn, Stephen Madden

Cyprotex and Evotec will be exhibiting and showcasing their research at the 61st Annual Society of Toxicology Meeting (SOT) and ToxExpo on March 27-31 in San Diego, CA.

Join our scientific specialists at booth #1226-1127 and don't forget to include our hosted seminar and poster presentations in your SOT itinerary!

If you wish to meet with us in San Diego, get in touch via the form below, we will be happy to arrange a meeting.

Our scientific program

Cyprotex Hosted Seminar
Multi-Organ and Species-Specific Safety Profiling using Transcriptomics
Presented by Paul Walker, PhD
Date: March 29, 2022
Time: 10:30 AM - 11:30 AM PDT
Room: 23C

Poster Presentations
Identifying Seizures with MEA: Complementary Human and Rat Neuronal Models Enhance Predictivity
Presented by Chris Strock, PhD
Date: March 28, 2022
Time: 2:30 PM- 4:15 PM PDT
Abstract Number/Poster number: 3289/P439

Development of In Vitro Assays to Predict Potential Immunotoxicological Liabilities of Candidate Drugs using Human Peripheral Blood Mononuclear Cells
Presented by Monday Ogese, PhD
Date: March 29, 2022
Time: 9 AM- 10:45 AM PDT
Abstract Number/Poster number: 4121/P825

Evaluating Functional and Structural Cardiotoxicants using Calcium Flux, HCI and High Throughput Transcriptomics
Presented by Stephen Madden, PhD
Date: March 30, 2022
Time: 9 AM - 10:45 AM PDT
Abstract Number/Poster number: 4377/P331

High Throughput RNA-Seq Profiling of 3D Liver Organoids to Predict Drug-Induced Liver Injury (DILI)
Presented by Paul Walker, PhD
Date: March 30, 2022
Time: 10:45 AM- 12:30 PM PDT
Abstract Number/Poster number: 4449/P449

Learn more about the 61st SOT Annual Meeting and ToxExpo

Quantitative Prediction of Drug-Drug Interactions with Common Statin Co-meds: A Framework for Decision-making within Drug Discovery/Development

The first webinar in this series on drug transporters was presented by Hayley Atkinson from Cyprotex.

About the Webinar

Due to polypharmacy, drug-drug interactions (DDIs) continue to account for 5% of UK hospital admissions and as such remain a major regulatory concern. This is particularly true for common co-meds such as statins which due to their prescribing prevalence in patients with co-morbidities have high potential for DDI. Within Drug Discovery and Development we are moving away from relatively simple hazard identification of DDI potential using basic static equations detailed in regulatory guidance to actual risk analysis and mitigation using quantitative prediction of DDI. Using mechanistic static equations we can predict the AUC change of each statin due to inhibition of its critical enzyme/transporter pathway(s) so that the clinical team can make a decision on whether any potential DDI is simply a pharmacokinetic DDI or a clinically significant DDI requiring intervention. The statin mechanistic equation model requires very few in vitro input parameters and can be utilised towards aiding preclinical development candidate selection and towards reducing unexpected clinical findings in patients providing a useful tool in Drug Discovery and Early Development.

About the Speaker

Hayley Atkinson PhD Associate Principal Scientist | Cyprotex Hayley Atkinson is an Associate Principal Scientist in the permeability and drug transporter team at Cyprotex, UK where she acts as deputy scientific lead for drug transporter studies.  Her research interests include prediction of transporter mediated drug-drug interactions with improved in vitro assays.  Prior to joining Cyprotex in 2013, Hayley received her PhD from the University of Liverpool under Prof. Munir Pirmohamed where she conducted research on anti-epileptic drug transporters at the blood-brain barrier in the context of drug resistance.

Watch the webinar to learn more!

[hs-form id="e52f470e-0e88-41ac-99f1-349b2316ef8a" show="hide on login" url="https://news.evotecsciencepool.com/hubfs/Sciencepool/Videos%20and%20Webinars/Cyprotex%20webinars%20and%20videos/focus-on-drug-transporters-webinar-series-hayley-atkinson-cyprotex-sept2020.m4v"]

SARM1 is a NADase whose action triggers the destruction of axons and development of novel SARM1 inhibitors which enables the prevention or delay of neurodegenerative disorders. This paper identifies the binding site for the SARM1 agonist NMN and reveals the structure of full-length SARM1 as elucidated by cryo-electron microscopy (cryo-EM). The structure of apo SARM1 was revealed as an octameric ring, held in an autoinhibitory state by the separation of the active TIR domain at the rim of the ring. The elucidation of autoinhibition release and the identification of the NMN binding site within the autoinhibitory ARM domain opens a path to inhibition of SARM1 via stabilisation of its inactive form. These studies were possible through the close co-ordination of the new cryo-EM team at Evotec, Abingdon with Disarm and academic collaborators in Australia and the USA.

Proposed SARM1 activation mechanism:

LEARN MORE

Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, kills 1.5 to 1.7 million people every year. Macrophages are Mtb’s main host cells and their inflammatory response is an essential component of the host defense against Mtb. However, Mtb is able to circumvent the macrophages’ defenses by triggering an inappropriate inflammatory response. Understanding macrophage interactions with Mtb is crucial to develop strategies to control tuberculosis. The present study aims to determine the inflammatory response transcriptome and miRNome of human macrophages infected with the virulent H37Rv Mtb strain, to identify macrophage genetic networks specifically modulated by Mtb virulence.

LEARN MORE

Cyclohexyl-griselimycin is a preclinical candidate for tuberculosis (TB). In this recent article, we show that this oral cyclodepsipeptide is also active against the intrinsically drug resistant non-tuberculous mycobacterium Mycobacterium abscessus in vitro and in a mouse model of infection. This adds a novel advanced lead compound to the M. abscessus drug pipeline and supports a strategy of screening chemical matter generated in TB drug discovery efforts to fast track the discovery of novel antibiotics against M. abscessus

LEARN MORE

Over recent years, interest in the multi-attribute method (MAM) has grown and the technique has become an important mass spectrometry-based tool for identifying and quantifying the site-specific product attributes and purity information for biotherapeutics such as monoclonal antibodies (mAbs) and fusion molecules. Improving the throughput of sample preparation without introducing chemical modifications and variability will further increase the utility of MAM in drug development.

In this publication, we focus on:

• the development of a fully automated MAM sample preparation protocol incorporating rapid desalting (< 15 min) using miniaturized size-exclusion chromatography columns in pipette tips on an automated liquid handling system which leads to complete rapid digestion of mAbs in approximately 3 hours with excellent reproducibility
• analysis of samples using electrospray ionization mass spectrometry coupled to a U-HPLC system with dual column switching 
• comparison of the new sample preparation method versus manual low artefact sample preparation including analysis of reproducibility, recovery, efficiency and flexibility

LEARN MORE