An overview of research projects at the Predictive Pharmacology group.
- Prediction of human (CNS) target site concentrations in health and disease
- Drug-target binding kinetics in vivo
- Spatial (3D) CNS drug distribution model
- Prediction of human gut (colon cancer) target site concentrations and PKPD relationships
- Predicting early Alzheimer’s disease stage in human
- Drug delivery formulations to improve drug delivery to tissues protected by barriers
- Cellular bioavailability
Prediction of human (CNS) target site concentrations in health and disease
In the vision of Prof. de Lange we will only be able to predict human (central nervous system, CNS) target site concentrations and effects if we perform systematic, condition-dependent, integrative, and strictly quantitative research, providing smart data, combined with advanced mathematical modelling (“Mastermind Research Approach”).
- De Lange E, Hammarlund-Udenaes M. Translational aspects of blood-brain barrier transport and central nervous system effects of drugs: From discovery to patients. Clin Pharmacol Ther. 2015 Apr;97(4):380-94. doi: 10.1002/cpt.76. Epub 2015 Feb 20
- De Lange ECM, van der Brink W, Yamamoto Y, de Witte W, Wong YC. Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics. Expert Opin Drug Discov. 2017 Dec;12(12):1207-1218. doi: 10.1080/17460441.2017.1380623. Epub 2017 Sep 21.
With this profound and systematic approach, Prof de Lange and her team have been able to unravel the individual contributions and mutual interdependencies of pharmacokinetic (PK) processes that play a role in CNS drug distribution, and has proven be the only portal to the development of the detailed physiologically-based pharmacokinetic (PBPK) CNS drug distribution model (LeiCNS1) that is able to adequately predict rat and human PK profiles in multiple physiological compartments of the CNS.
With this model, as first in the world, it is now possible to predict PK profiles of compounds at different CNS locations in human, solely on the basis of compound properties that can be obtained in vitro/in silico. In other words, the mathematical model can replace the use of many experimental animals. This will have a great impact on the success in CNS drug discovery and development, and the diminishing of the use of experimental animals.
Yamamoto Y, Danhof M, de Lange EC. Microdialysis: the Key to Physiologically Based Model Prediction of Human CNS Target Site Concentrations. AAPS J. 2017 Mar 9. doi: 10.1208/s12248-017-0050-3
Yamamoto Y, Välitalo PA, Huntjens DR, Proost JH, Vermeulen A, Krauwinkel W, Beukers MW, van den Berg DJ, Hartman RH, Wong YC, Danhof M, van Hasselt JG, de Lange EC*. Predicting drug concentration-time profiles in multiple CNS compartments using a comprehensive physiologically-based pharmacokinetic model. CPT Pharmacometrics Syst Pharmacol. 2017 Sep 11. doi: 10.1002/psp4.12250. [Epub ahead of print]
Yamamoto Y, Välitalo PA, van den Berg DJ, Hartman R, van den Brink W, Wong YC, Huntjens DR, Proost JH, Vermeulen A, Krauwinkel W, Bakshi S, Aranzana-Climent V, Marchand S, Dahyot-Fizelier C, Couet W, Danhof M, van Hasselt JG, de Lange EC*. A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Prediction of Human Brain Target Site Concentrations. Pharm Res. 2017 Feb;34(2):333-351. doi: 10.1007/s11095-016-2065-3
Yamamoto Y, Välitalo PA, Wong YC, Huntjens DR, Proost JH, Vermeulen A, Krauwinkel W, Beukers MW, van den Berg DJ, Hartman RH, Wong YC, Danhof M, Kokkif H, Kokkif M, van Hasselt JGC, de Lange ECM*. Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach. Eur J Pharm Sci. 2018 Jan 15;112:168-179.
The CNS PBPK model is currently: further optimized – adding more physiological details (LeiCNS3); being adapted for specific CNS diseases with emphasis on neurodegenerative diseases like Alzheimer’s disease, traumatic brain Injury, and brain tumors; and linked to target interaction for further unravelling of factors in CNS drug effects as described below.
Drug-target binding kinetics in vivo
A next, general pharmacological problem to be tackled is how drug-target binding kinetics in vivo, affects target occupancy as an important indicator of the time-course of drug effects. Drug target binding kinetics (BK) typically has been determined in isolation, while in the living body all PK processes in the body occur in parallel. Therefore, there is a need for integration of these processes. This was part of the IMI K4DD project. A number of generic mathematical models have been developed that provide substantial insights in the condition-dependent contribution of these different processes.
De Witte WE, Wong YC, Nederpelt I, Heitman LH, Danhof M, van der Graaf PH, Gilissen RA, de Lange EC. Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients. Expert Opin Drug Discov. 2015 Oct 20:1-19. [Epub ahead of print]
De Witte WEA, Danhof M, van der Graaf PH, de Lange EC. The implications of target saturation for the use of drug-target residence time. Nat Rev Drug Discov. 2018 Dec 28;18(1):82-84.
De Witte WEA, Rottschäfer V, Danhof M, van der Graaf PH, Peletier LA, de Lange ECM. Modelling the delay between pharmacokinetics and EEG effects of morphine in rats: binding kinetic versus effect compartment models. J Pharmacokinet Pharmacodyn. 2018 Aug;45(4):621-635. doi: 10.1007/s10928-018-9593-x. Epub 2018 May 18.
De Witte WEA, Rottschäfer V, Danhof M, van der Graaf PH, Peletier LA, de Lange ECM. Correction to: Modelling the delay between pharmacokinetics and EEG effects of morphine in rats: binding kinetic versus effect compartment models. J Pharmacokinet Pharmacodyn. 2018 Oct;45(5):763. doi: 10.1007/s10928-018-9604-y.
De Witte WEA, Vauquelin G, van der Graaf PH, de Lange EC. The influence of drug distribution and drug-target binding on target occupancy: The rate-limiting step approximation. Eur J Pharm Sci. 2017 May 12. pii: S0928-0987(17)30252-X. doi: 10.1016/j.ejps.2017.05.024
de Witte WEA, Versfelt JW, Kuzikov M, Rolland S, Georgi V, Gribbon P, Gul S, Huntjens D, van der Graaf PH, Danhof M, Fernández-Montalván A, Witt G, de Lange ECM. In vitro and in silico analysis of the effects of D2 receptor antagonist target binding kinetics on the cellular response to fluctuating dopamine concentrations. Br J Pharmacol. 2018 Nov;175(21):4121-4136. doi: 10.1111/bph.14456. Epub 2018 Sep 21
De Witte W, Danhof M, Van der Graaf PH, de Lange EC. In vivo Target Residence Time and Kinetic Selectivity: The Association Rate Constant as Determinant. Trends Pharmacol Sci. 2016 Oct;37(10):831-42
Nederpelt I, Kuzikov M, de Witte WEA, Schnider P, Tuijt B, Gul S, IJzerman AP, de Lange ECM, Heitman LH. From receptor binding kinetics to signal transduction; a missing link in predicting in vivo drug-action. Sci Rep. 2017 Oct 26;7(1):14169. doi: 10.1038/s41598-017-14257-4.
Vlot AHC, Witte WEA, Danhof M, van der Graaf PH, van Westen GJP, de Lange ECM*. Target and tissue selectivity prediction by integrated mechanistic pharmacokinetic-target binding and quantitative structure activity modelling AAPSJ. 2017 Dec 4;20(1):11. doi: 10.1208/s12248-017-0172-7.
Furthermore, with the recently started (01 Jan 2020) a consortium on “Effective combinational treatment of chronic pain in individual patients by an innovative quantitative systems pharmacology (QSP) pain relief approach”(QSPainRelief) consortium we aim to develop a Quantitative Systems Pharmacology (QSP) model platform that integrates the LEICNS3 and drug-target binding kinetic models and the neural circuit QSP models of InSilicoBioSciences to predict combinations of existing drugs to better relief pain in chronic pain patients while reducing side effects. The consortium consists of 10 partners from 6 different countries.
Key objectives are:
- Consolidating cutting-edge treatment models for chronic pain
- Identifying novel combinational therapies of existing drugs and in silico-simulated treatments
- Validating novel combinational therapies preclinically in vitro and in vivo
- Conducting clinical studies to detect functional biomarkers
- Improving the clinical guidelines for pain relief in stratified patient groups
- Personalising pain relief treatment for each patient
- Improving the scientific understanding of chronic pain regarding age, sex, disease and genetic factors
For more information see: https://www.qspainrelief.eu/
Spatial (3-Dimensional) CNS drug distribution model
Spatial (3-Dimensional) CNS drug distribution model
Another research line is the development of a spatial CNS drug distribution model, by ultimately including the 3-dimensional anatomical organization of the CNS. The mathematical level of this research is very challenging, and therefore is performed in collaboration with the Mathematical Institute of our Faculty of Science (Dr. Vivi Rottschäfer).
Vendel E, Rottschäfer V, de Lange EC. Improving the prediction of local drug distribution profiles in the brain with a new 2D mathematical model. Bull Math Biol. 2018 Aug 8. doi: 10.1007/s11538-018-0469-4. [Epub ahead of print]
Vendel E, Rottschäfer V, de Lange ECM. The need for mathematical modelling of spatial drug distribution within the brain. Fluids Barriers CNS. 2019 May 16;16(1):12. doi: 10.1186/s12987-019-0133-x. Review
Prediction of human gut (colon cancer) target site concentrations and PKPD relationships
The advanced insights obtained for the CNS PBPK model development are currently used to develop advanced mathematical models for drug distribution prediction in other body tissues protected by barriers, such as the gut. The gut PBPK model will be linked to drug effects for treatment, in particular, of colon cancer. This research is part of the IWT TRAIN project.
Pharmacometabolomic; prediction of system-wide multi-biomarker drug response
The lack of success of new CNS drugs in clinical development is in part due to the complexity of the CNS, unexpected side effects, difficulties for drugs to penetrate the brain, but also by the lack of biomarkers. This research line, called pharmaco-metabolomics integrates PKPD modeling and metabolomics, and used the Mastermind Research Approach to obtain time-course data on drug distribution, and in parallel to metabolomics PD in different body fluids (CNS extracellular fluid, cerebrospinal fluid, plasma). Combining PKPD modeling of the drug and metabolite kinetics with statistical techniques such as Principle Component Analysis, reveal also unexpected drug effects. (Collaboration with Prof. Thomas Hankemeier and Prof. Piet Hein van der Graaf).
Van den Brink WJ, van den Berg DJ, Bonsel F, Hartman R, Wong YC, van der Graaf PH, De Lange ECM. Blood-based biomarkers of quinpirole pharmacology: multivariate PK/PD and metabolomics to unravel the underlying dynamics in plasma and brain. CPT Pharmacometrics Syst Pharmacol. 2019 Feb;8(2):107-117. doi: 10.1002/psp4.12370. Epub 2019 Jan 24.
Van den Brink WJ, Elassais-Schaap J, Gonzalez B, Harms A, van der Graaf PH, Hankemeier T, de Lange ECM. Remoxipride causes multiple pharmacokinetic/pharmacodynamic response patterns in pharmacometabolomics in rats. Eur J Pharm Sci. 2017 Nov 15;109:431-440. doi: 10.1016/j.ejps.2017.08.031. Epub 2017 Sep 4
Van den Brink WJ, Palic S, Kohler I, de Lange ECM. Correction to: Access to the CNS: Biomarker Strategies for DopaminergicTreatments.Pharm Res. 2018 Mar 19;35(5):102. doi: 10.1007/s11095-018-2388-3.
Van den Brink WJ, van den Berg DJ, Bonsel FEM, Hartman R, Wong YC, van der Graaf PH, de Lange ECM. Fingerprints of CNS drug effects: a plasma neuroendocrine reflection of D2 receptor activation using multi-biomarker pharmacokinetic/pharmacodynamic modelling. Br J Pharmacol. 2018 Oct;175(19):3832-3843. doi: 10.1111/bph.14452. Epub 2018 Aug 31.
Van den Brink WJ, Wong YC, Gülave B, van der Graaf PH, de Lange EC*. Revealing the Neuroendocrine Response After Remoxipride Treatment Using Multi-Biomarker Discovery and Quantifying It by PK/PD Modeling. AAPS J. 2017 Jan;19(1):274-285. doi: 10.1208/s12248-016-0002-3
Van den Brink WJ, Hankemeier Th, Van der Graaf PH, de Lange ECM. Bundling arrows: improving translational CNS drug development by integrated PK/PD-metabolomics. Expert Opin Drug Discov. 2018 Jun;13(6):539-550. doi: 10.1080/17460441.2018.1446935. Epub 2018 Mar 8.
Predicting early Alzheimer's disease stage in human
A new research line is the development of liquid biopsy fingerprints to predict early Alzheimer’s disease (AD) stage in human in readily accessible body fluids in human (in collaboration with: Dr. Geert-Jan Groeneveld, CHDR; Prof. Elga de Vries, Free University Medical Center; and others).
A literature search on current state-of-the-art-knowledge on fluid based biomarkers of AD, especially at the earlier stages, indicated gaps in useful (longitudinal and multilevel) data. Currently, such smart data are being obtained from animal experimentation and from humans. The final goal is to develop a systems model on Alzheimer’s disease progression, on the basis of multiple body fluid biomarker fingerprints, which would allow assessment of AD stage, and effects of drugs.
Hurtado MO, Kohler I, de Lange EC. Next-generation biomarker discovery in Alzheimer's disease using metabolomics - from animal to human studies. Bioanalysis. 2018 Sep 1;10(18):1525-1546. doi: 10.4155/bio-2018-0135. Epub 2018 Sep 10.
Another research line is focused on the influence of drug delivery formulations such as liposomes for increased drug delivery to the CNS (Prof. Margareta Hammarlund-Udenaes, Uppsala University; Dr. Pieter Gaillard, to-BBB)
- Hu Y, Gaillard PJ, de Lange ECM, Hammarlund-Udenaes M. Targeted Brain Delivery of Methotrexate by Glutathione PEGylated Liposomes: How can the Formulation Make a Difference? Eur J Pharm Biopharm. 2019 Apr 2. pii: S0939-6411(18)31441-3. doi: 10.1016/j.ejpb.2019.04.004.
- Hu Y, Gaillard PJ, Rip J, de Lange EC, Hammarlund-Udenaes M. In Vivo Quantitative Understanding of PEGylated Liposome's Influence on Brain Delivery of Diphenhydramine.Mol Pharm. 2018 Dec 3;15(12):5493-5500. doi: 10.1021/acs.molpharmaceut.8b00611.
- Hu Y, Rip J, Gaillard PJ, de Lange EC, and Hammarlund-Udenaes M. The Impacts of Liposomal Formulations Based on Different Phospholipids on the In Vivo Release and Brain Delivery of Methotrexate: A Microdialysis Study- J Pharm Sci. 2017 Mar 18. pii: S0022-3549(17)30166-1. doi: 10.1016/j.xphs.2017.03.009.