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New DMPK screening and development strategies for CNS candidate compounds
This webinar will discuss the concept of Kp,uu as a measure of CNS penetration along with the different methodologies available to assess CNS penetration and highlight the complexities of translation of this to human.
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Agenda
- Introduction to the brain and BBB
- Brain physiology, blood flow and fluid compartments;
- Mechanisms of drug passage across BBB
- “Free drug theory”
- Importance of the Kp,uu concept
- Predicting and measuring drug brain exposure
- In vitro methods for assessing BBB permeability;
- In vivo methods to measure brain exposure;
- Methods to measure unbound brain concentration – current findings and challenges;
- Pharmacokinetics of brain exposure and translation to humans
- In vitro to in vivo extrapolation of Kp,uu to human – current findings and challenges
- Existing cell-based models representing BBB
- CNS penetration of drugs across different species
Moderated by: Chris Bode – VP of Scientific Affairs at Pharmaron
Speakers:
Margareta Hammarlund-Udanaes, Ph.D. – Professor of Pharmacokinetics and Pharmacodynamics at Uppsala University
Margareta Hammarlund-Udenaes, PhD, is a Professor of Pharmacokinetics and Pharmacodynamics at Uppsala University, Sweden, since 1999, Professor Emerita since 2020. She has supervised 20 PhD’s and published more than 130 original articles. She is an Editor of the book Drug Delivery to the Brain – Principles, Methodology and Applications (Springer, 2014; 2nd Ed 2022). Her h-index is 53 (Google Scholar). She was the Dean of the Faculty of Pharmacy at Uppsala University 2017-2020.
Dr Hammarlund-Udenaes became a Fellow of the American Association of Pharmaceutical Scientists in 2005, became an International Fellow of the Academy of Pharmaceutical Science and Technology in Japan in 2015, and an Honorary Member of the Swedish Academy of Pharmaceutical Sciences in 2016. She also received the Arïens Award in Pharmacology in the Netherlands in 2021 for her scientific achievements. She is a former Associate Editor of Pharmaceutical Research, former EAB member of the Journal of Pharmaceutical Sciences and presently an EAB member of Fluids and Barrier of the CNS. Among others, she was the Chair of the Gordon Conference on Barriers of the CNS in 2014 and of the 8th International Symposium on Microdialysis in 2016, and is co-organizing the 14th Cerebrovascular Biology meeting to be held in Uppsala 2023.
The main scientific interest of Dr Hammarlund-Udenaes is drug delivery to the brain, based on pharmacokinetic-pharmacodynamic principles with a translational perspective. This is a critical area for pharmaceutical research, because of the severe limitations imposed on the development of drugs for the CNS by the blood-brain barrier (BBB). The work to date has resulted in new innovative methods to measure brain drug delivery in discovery and development settings. It has revealed basic relationships of BBB function and brain physiology regarding the transport of exogenous compounds and has provided a new understanding of how drugs are handled by the BBB and the brain. Disease influence and the role of nanodelivery on BBB transport of drugs and peptides are also investigated.
Danxi Li, Ph.D. – Senior Director, in vitro ADME at Pharmaron
Dr. Li is working as one of the main study directors of in vitro ADME department at Pharmaron and leading an experienced team to support various sponsors from early screening to regulatory submission. As ADME project coordinator, she helps sponsors to establish many specific assay platforms in Pharmaron, provides scientific input to optimize assay systems and ensures high quality data submission in a time efficient way. Before joining Pharmaron in early 2011, Dr. Li has worked at University of Medicine and Dentistry in New Jersey, USA, for 2 years as a visiting researcher. Her research work there focused on functionality investigation of CYP polymorphism using transfected cell models, which was continued work from her Ph.D. thesis work at Zhejiang University in China.
Elnaz Gozalpour, Ph.D. – Associate Director, DMPK at Pharmaron
Elnaz joined Pharmaron in June 2022 as an Associate Director in DMPK team of Drug Discovery. Prior to this, she was an Associate Principal Scientist in ADME/DMPK at AstraZeneca, Cambridge, U.K. In her previous position, she was supporting drug discovery projects at preclinical stages across Oncology, Neuroscience and Cardiovascular therapeutic areas. Elnaz joined AZ after finishing her Ph.D. in Molecular Pharmacology at Radboud university medical centre of Nijmegen (The Netherlands). She completed her undergraduate (BSc and MSc) in Molecular Biology and Human Genetics, respectively at Tehran University, Iran.
Elnaz has experience in ADME and DMPK in vitro sciences, drug transporters, and DDI. She is particularly interested in the application of innovative in vitro models of kidney and BBB to investigate and improve in vitro-in vivo extrapolation (IVIVE), interspecies differences and PB-PK modeling. During her time at AstraZeneca (AZ), she was leading the establishment of renal model using 3D microfluidic systems at AZ and Loughborough university. Being DMPK lead in Neuroscience projects, she has had a strong impact on the implementation of CNS strategy for distinct species. She is also interested to study polymorphisms of drug transporters and their association with ADME in different populations.
Elnaz has been a member of the American Association of Pharmaceutical Scientists (APSS), Drug metabolism and discussion group (DMDG) and Federation of European Biochemical Societies (FEBS). She has given a number of poster and podium presentations at the meetings and conferences of the above-mentioned societies. She has also contributed to the recent white paper of the International Transporters Consortium (ITC) on drug transporters in 2022.
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