Universiteit Leiden

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Research project

Pharmacometabolomics; 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.

Elizabeth (Liesbeth) de Lange



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, G├╝lave 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.
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