Division of Systems Biomedicine and Pharmacology
Prof. Elizabeth de Lange is concerned with the allocation of resources for the conduct of science towards the goal of best serving the public interest. Also, while she underscores that there is still the need for using animals in drug research, she is concerned about this use, and advocates the use of the Mastermind Research Approach by which knowledge obtained from animals can be condensed and stored in mathematical models.
Prof. de Lange has a clearly visible and original personal line of research, initially mostly focused on the CNS, but more and more expanding to other tissues and generic pharmacological research questions, which are specified below. She is one of the few in the world that is able to perform and bridge advanced experiments and analytical techniques with mathematical modelling, as a unique approach to build robust mathematictical models for the prediction of drug effects in human, which is the ultimate aim of her research. Specifically, Prof. de Lange started groundbreaking work of applying intracerebral microdialysis to the study of drug transport across the blood-brain barrier (BBB), developing new insights in the role of transporters at the BBB and within the CNS, as well as the impact of (disease) conditions on CNS drug distribution. Within the last years, her initial research focus on the CNS has expanded to other body tissues (gut) and fluids (blood clotting), as well as to generic pharmacological problems.
Her program focuses on the development of general translational Pharmacokinetic (PK)-Pharmacodynamic (PD) models using advanced in vivo animal experimentation, analytical techniques and mathematical modeling approaches. It involves identification and characterization of the rate and extent of key factors in PK and PKPD relationships and their condition dependency. These key factors involve the kinetics of the drug in plasma; passive and active drug transport into and out of the target tissue; drug distribution within the target tissue; drug equilibration to the target site; and the ability of the drug to interact with the target, in conjunction with biomarkers of the effect. Particular emphasis lies on but is not restricted to the Central Nervous System (CNS), and the role of drug-target interactions in the relationship between dose and effect profiles.
This research has a comparative and integrative design to elucidate conditional influences on individual mechanisms. It includes the cycle of simulations - predictions - experimental testing - data modeling - simulations, etc. Experiments typically involve monitoring techniques in (freely moving) chronically instrumented animals, including microdialysis. The microdialysis technique enables to monitor free drug concentrations in a selected tissue, which is an indispensable tool in characterizing rate and extent of passive and active drug dsitribution parameters, and is most valuable to reveal active concentrations at the target site. Moreover, the microdialysis technique can be used to monitor biomarker kinetics.
Such techniques are applied in healthy animals, as well as in models of Parkinson’s disease and Epilepsy in which disease progression plays a role. The final emphasis is on translation of models to the human situation, and to validate the model predictions by actually observed human (clinical) data.
- Yamamoto Y., Välitalo P.A., Wong Y.C., Huntjens D.R., Proost J.H., Vermeulen A., Krauwinkel W., Beukers M.W., Kokki H., Kokki M., Danhof M., van Hasselt J.G.C., de Lange E.C.M., Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach. Eur J Pharm Sci. 2018; 112: 168-179.
- Vlot A.H.C., Witte W.E.A., Danhof M., van der Graaf P.H., van Westen G.J.P., de Lange E.C.M., Target and tissue selectivity prediction by integrated mechanistic pharmacokinetic-target binding and quantitative structure activity modelling AAPSJ. 2017; 20(1): 11.
- De Lange E.C.M., van der Brink W., Yamamoto Y., de Witte W., Wong Y.C., Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics. Expert Opin Drug Discov. 2017;12(12): 1207-1218.
- van den Brink W.J., Elassais-Schaap J., Gonzalez B., Harms A., van der Graaf P.H., Hankemeier T., de Lange E.C.M., Remoxipride causes multiple pharmacokinetic/pharmacodynamic response patterns in pharmacometabolomics in rats. Eur J Pharm Sci. 2017;109: 431-440.
- De Witte W., Danhof M., van der Graaf P.H., de Lange E.C., In vivo Target Residence Time and Kinetic Selectivity: The Association Rate Constant as Determinant. Trends Pharmacol Sci. 2016; 37(10): 831-42.
- Stevens J., Ploeger B., Hammarlund-Udenaes M., Osswald G., van der Graaf P.H., Danhof M., de Lange E.C.M., Mechanism-based PK-PD model for the prolactin biological system response following an acute dopamine inhibition challenge: quantitative extrapolation to humans. J Pharmacokinet Pharmacodyn 2012 39(5): 463-77.