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This week discoveries: Prof. dr. Liesbeth de Lange
8th October 2019 @ 13:15 - 13:55
Prediction of drug behavior in the brain: from hocus pocus to a mathematical model
Despite enormous advances in CNS research, CNS disorders remain the world’s leading cause of disability. This accounts for more hospitalizations and prolonged care than almost all other diseases combined, and indicates a high unmet need for good CNS drugs and drug therapies.
Following dosing, not only the chemical properties of the drug and blood–brain barrier (BBB) transport, but also many other processes will ultimately determine brain target site kinetics and consequently the CNS effects. The rate and extent of all these processes are regulated dynamically, and thus condition dependent. Therefore, differences in conditions such as species, gender, genetic background, tissue, age, diet, disease, drug treatment etc., results in considerable inter-individual and intra-individual variation, often encountered in CNS drug therapy.
For effective therapy, drugs should access the CNS “at the right place, at the right time, and at the right concentration”. To improve CNS therapies and drug development, details of inter-species and inter-condition variations are needed to enable target site pharmacokinetics and associated CNS effects to be translated between species and between disease states. Specifically, such studies need to include information about unbound drug concentrations which drive the effects. To date the only technique that can obtain unbound drug concentrations in brain is microdialysis. This (minimally) invasive technique cannot be readily applied to humans, and we need to rely on translational approaches to predict human brain distribution, target site kinetics, and therapeutic effects of CNS drugs.
In this presentation by Prof. dr. Liesbeth de Lange of the Leiden Academic Centre for Drug Research, strategic and systematic CNS drug research using advanced preclinical experimental designs and mathematical modelling, according to the “Mastermind Research Approach” is explained. It has provided knowledge on the contributions and variability of individual processes in animals that can be translated to the human situation. Thus, on the basis of a number advanced preclinical microdialysis based investigations a mathematical model has been developed that is able to predict drug behavior within human CNS. Examples will be provided on the predictive value of this comprehensive mathematical model.
This Week’s Discoveries takes place every Tuesday between 13.15 and 13.55 hours in the Sitterzaal of the Oort building.
In a 15 minute talk two of our scientists gives a presentation aimed at a broad audience followed by 5 minutes discussion.
Before the lectures,12.50- 13.15 hrs a small lunch is available.
Prior to the lecture of Prof. dr. Liesbeth de Lange, Dr Pleuni Pennings (San Francisco State University) will present a Lorentz Center Highlight lecture
Title Challenging conventional wisdom on the evolution of resistance to multi-drug HIV treatment: Lessons from data and modeling.
Speaker Pleuni Pennings (San Francisco State University) Pleuni is an assistant professor and evolutionary biologist it the Biology department at SFSU. Most of her research currently focuses the evolution of drug resistance in HIV. She wants to understand what determines the rate of evolution of drug resistance, so that we can find ways to halt the evolution of drug resistance. She is participating in the Lorentz Center workshop Predicting Evolution that is being held from 7 Oct 2019 through 11 Oct 2019