Right time. Right place. Right concentration.

Research profile


Profile


Updated on March 22, 2018

Professional Profile

Dr Elizabeth de Lange has been trained as a chemist, with specialization in Biophysical Chemistry (Groningen University, Groningen, The Netherlands). She obtained her PhD in Pharmacology (Leiden- Academic Center for Drug Research (LACDR), Leiden University, The Netherlands). She got tenure at the LACDR. She currently is Professor on Predictive Pharmacology and the Principal Investigator of the Predictive Pharmacology Group in the Research Division of Systems Biomedicine & Pharmacology of the LACDR.

Research profile

Dr 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.

Dr 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, Dr 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 Alzheimer’s disease, 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.

The final emphasis is on translation of models to the human situation, and to validate the model predictions by actually observed human (clinical) data.

Key research aspects

To increase the efficiency of the drug development process and general health by contributing to the unraveling of mechanisms which determine (CNS) target site pharmacokinetics (PK) and related (CNS) pharmacodynamics (PD). This includes experience with and focus on:

  • Tissue barrier transport mechanisms
  • Tissue distribution mechanisms
  • Role of transporters in (CNS) drug disposition
  • Neurodegeneration – Parkinson’s disease, Alzheimer’s disease, Epilepsy, etc
  • Evaluation and implementation of biomarkers of drug effects and of disease (metabolomics)
  • Target site (biophase) interaction kinetics
  • Mechanism-based pharmacokinetic (PK) – pharmacodynamic (PD) modeling
  • Physiology based (PB) PK-PD models
  • Theoretical studies, simulations, modeling (mathematics)
  • Intra- and Interspecies translation

Honors /Awards

  • LACDR Nominee for the Faculty Education Award 2017
  • Breakthroughs Faculty of Science- Our Talents & Discoveries in 2016: Liesbeth de Lange (LACDR) – Predicting Drug Behaviour in the brain
  • Fellow Award of the American Association of Pharmaceutical Scientists (2013)- Each year, AAPS elevates a few members to Fellowship in recognition of their professional excellence in fields relevant to AAPS’s mission. Each fellow has demonstrated a sustained level of superior and distinguished professional achievement and contributions in fields related to this mission.
  • Invited honored speaker: Hugh Davson Honorary Memorial Lecture at the British Physiological Society Symposium on “The Blood-Brain Barrier: Mechanisms Regulating Integrity and Transport” on “Application of Intracerebral Microdialysis Studies to Aspects of Blood-Brain Barrier Function”, London, United Kingdom. 1998.
  • Golden Award Royal Dutch Chemical Society for Thesis on: “Measurement of Neurotransmitters and Metabolites in Fish (Carp) Brain by High Pressure Liquid Chromatography and Electrochemical Detection” at the Hospital Laboratory, Department of Neurology, Academic Hospital Groningen, the Netherlands. 1985

Grants / Scholarships

  • TRAIN (Translational Intestinal Models, IWT grant)-. “Systems pharmacology model (QSP) for the prediction of intestinal/colonic drug distribution and efficacy for coxibs targeting colorectal cancer”. IWT O&O project Collaboration Janssen Pharmaceutica, KU Leuven, U Gent. (2017- 2021).
  • CRC Grant. Exosomes as Liquid Biopsy in Alzheimer’s disease- search for early translation of molecular phenotype from rat to human – (2017-2021)
  • Qinghai Yangzong Company, China. Grant ”Elite young researchers study abroad plan”: Exosomes as Liquid Biopsy in Alzheimer’s disease- search for early translation of molecular phenotype from rat to human – (2016-2017)
  • Sophia Children Hospital Grant: “Evidence-based pharmacology in severe pediatric traumatic brain injury (TBI)”. (2016-2018)
  • SHIONOGI Science Program Grant. “Metabolomic multivariate and translational approaches for predicting dopaminergic system functionality in human”. (2014-2015)
  • European Innovative Medicines Initiative (IMI) Grant. K4DD (Kinetics for Drug Development)- (2013-2017) (http://www.k4dd.eu). (2012-2017)
  • Top Institute Pharma Grant. Pharmacokinetic-Pharmacodynamic Platform 2 (2013-2016)- “Development of a generic regional brain distribution model and CNS target interaction/biomarker model”. (2013-2017)
  • “LACDR Scientific Director Grant”- PhD project. “Translational approaches for predicting dopaminergic system functionality in human”. (2013-2017).
  • European Innovative Medicines Initiative (IMI) Grant. “DDMoRe: Drug Disease Model Resources”. (2011-2015). (http://www.ddmore.eu/) (2011-2016
  • STW Project Grant ON TIME: development of commercial and health care applications concerning chronobiology), on “Influence of circadian rhythms on blood-brain barrier transport and intracerebral distribution”. PI: Prof J Meijer LUMC- (2012-2016)
  • Daiichi Sankyo Pharmaceutical Company, Japan Grant– “Impact of P-glycoprotein on intracerebral distribution and (biomarkers of) effects of antispychotic drugs”, (2012-2015)
  • European Seventh Framework Programme (FP7) Grant: “EURIPIDES, the EUropean Research initiative to develop Imaging Probes for early In-vivo Diagnosis and Evaluation of response to therapeutic Substances”. (2008-2012). (www.Euripides-europe.com)
  • Top Institute Pharma Grant. Project No T5- 105: Nanoscience as a tool for improving bioavailability and Blood Brain Barrier penetration of CNS drugs. 10 partners, ~30 participants). (2007-2012). (http://www.tipharma.com/pharmaceutical-research- projects/brain-diseases/nanoscience-and-the-bbb.html)
  • Pfizer UK Grant. PhD project “Translational pharmacology of dopamine receptor agonists and antagonist; prolactin and oxytocin as biomarkers”. (2005-2008)
  • Eli Lilly & Company Grant. PhD project: Systems Pharmacology and Blood-Brain Barrier Functionality in Parkinson’s disease. (2001-2005)
  • Pfizer UK Grant. PhD project: “The free drug hypothesis; fact or fiction”. (2001-2005) (1 PhD student)
  • GlaxoSmithKline Grant. PhD project: “Mechanism-based PK/PD modelling of Opioids; role of biophase distribution and target interaction kinetics. (2000-2003)
  • KWF (Dutch Cancer Society) Grant. Postdoctoral Research Fellowship-“The role of the blood- brain barrier and P-glycoprotein efflux on transport of anticancer agents to a tumor in the brain”. (1995-1999)
  • Sandoz scholarship for attending the International Conference on Cerebral Vascular Biology. Duluth (MN), United States of America, 1992

Research supervision

PhD students:

  • Tin Q- (PhD Student)- Exosomes as Liquid Biopsy in Alzheimer’s disease- search for early translation of molecular phenotype from rat to human. CRC Scholarship, 2016-2020
  • Gebhart A. (PhD Student)- Translational Intestinal Models (TRAIN). “Systems pharmacology model (QSP) for the prediction of intestinal/colonic drug distribution and efficacy for coxibs targeting colorectal cancer”. IWT O&O project Grant. Collaboration Janssen Pharmaceutica, KU Leuven, U Gent (For us 1 PhD student)-2016-2020
  • Vendel E. (PhD Student)- Development of a 3D generic drug brain distribution model by advanced mathematical approaches (collaboration Mathematical Institute Leiden), 2015-2019
  • Van den Brink, W.(PhD student) Internal Grant. “Translational approaches for predicting dopaminergic system functionality in human”. 2013-2017
  • De Witte W. (PhD student). Grant by IMI “Kinetics for Drug Discovery (K4DD)” Consortium. Workpackage: “In vivo translation: development of predictive modelling approaches” Promotion 2017
  • Yamamoto Y. (PhD student) Grant by Top Institute-Pharma PKPD Modeling Platform 2. Workpackage: “Mechanism-based interspecies extrapolation of PK-PD for CNS compounds”, Promotion 2017
  • Kervezee L (PhD student, LUMC Division of Neurophysiology/Neuropharmacology)- (STW Project Grant ON TIME: development of commercial and health care applications concerning chronobiology), on “Influence of circadian rhythms on blood-brain barrier transport and intracerebral distribution”. Promotion 2017
  • Westerhout J (PhD student) – “Prediction of brain target site PK on the basis of CSK concentrations: Impact of mechanisms of blood-to-brain transport and intra-brain distribution” – (Grant by Top Institute Pharma Project No T5- 105 and Title: Nanoscience as a tool for improving bioavailability and Blood Brain Barrier penetration of CNS drugs, 10 partners, ~30 participants), Promotion 2014
  • Stevens J (PhD student) – “Translational pharmacology of dopamine receptor agonists and antagonist; prolactin and oxytocin as biomarkers”– (PhD Grant by Pfizer), Promotion 2011
  • Ravenstijn PGM (PhD student) – Systems Pharmacology and Blood-Brain Barrier Functionality in Parkinson’s Disease – (PhD Grant by Eli Lilly & Company), Promotion 2009
  • Van Steeg TS (PhD student) – “The free drug hypothesis; fact or fiction” – (PhD Grant by Pfizer), Promotion 2008
  • Groenendaal D (PhD student) – “Mechanism-based PK/PD modelling of opioids; role of biophase distribution and target interaction kinetics” – (PhD Grant by GSK), Promotion 2007

External PhD students:

  • Mangas V. (PhD Student, Miguel Hernandez University, Valencia, Spain). “Use of microdialysis in unraveling factors in brain distribution of anti-schizophrenia drugs. 2013..
  • Kwan P (PhD student, University of Glasgow, UK). “P-glycoprotein Mediated Efflux of Anti- Epileptic Drugs; Preliminary Studies in Mdr1a Knockout Mice”. 2001
  • Marchand S (PhD student, University of Poitiers, France). “In Vitro and In Vivo Investigations on Fluoroquinolones; Effects of the P-glycoprotein Efflux Transporter on Brain Distribution of Sparfloxacin”. 2000
  • Xie R. (PhD student, Uppsala University, Sweden, ULLA Grant). “The role of P-glycoprotein in BBB Transport of Morphine: Transcortical Microdialysis Studies in Mdr1a (-/-) and Mdr1a (+/+) mice”. 1997
  • LeQuellec A. (PhD student, Universite Paul Sabatier de Toulouse, France). “Development of a Microdialysis Approach for Measuring in the Pineal Gland in the Rat”. 1992

Post-Docs:

  • Wong, E. Grant by IMI “Kinetics for Drug Discovery (K4DD)” Consortium. Workpackage 3: “In vivo translation: development of predictive modeling approaches”. 2014-2017
  • Tajena A. Grant by Top Institute-Pharma: PKPD Modeling Platform 2. Workpackage 1: “Mechanism-based interspecies extrapolation of PK-PD for CNS compounds”. 2013-2016
  • Shimizu S (Post-doc, Daiichi Sankyo Pharmaceutical Company, Japan)- “Impact of P- glycoprotein on intracerebral distribution and (biomarkers of) effects of antispychotic drugs”, 2012-2014
  • Krekels E (Post-doc, transferred to University of Uppsala). Grant by IMI “Drug Disease Model Resources (DDMoRe)”. Workpackage: “Model library Prototypes”, 2012-2016
  • Syvanen S (Post-doc). In project “Biological Evaluation of New Radiotracers for Predicting P-gp Related BBB Transport”. Grant by FP7 “EUropean Research initiative to develop Imaging Probes for early In-vivo Diagnosis and Evaluation of response to therapeutic Substance (EURIPIDES) consortium. 2008-2012
  • Reichel, V (Post-doc, University of Heidelberg, Germany). “Mrp4 transport at the blood-brain barriers in vivo”. 2010
  • Niederlander H, (Post-doc, University of Groningen, The Netherlands). “LCMS Analysis of Remoxipride in Microdialysates and Plasma”. 2007-2008
  • Sills G (Post-doc, University of Glasgow, United Kingdom). “P-glycoprotein Mediated Efflux of Anti-Epileptic Drugs; Preliminary Studies in Mdr1a Knockout Mice”. 2001
  • Desrayaud S (Post-doc, Sandoz Pharma, Switzerland). “Effect of the Mdr1a Gene Disruption on the Tissue Distribution of SDZ PSC 833, a Multidrug Resistance- Reversing Agent, in Mice”. 1998

Staff mobility within Erasmus Programme:

  • Erdo F- Pázmány Péter Catholic University  –  Budapest- Dec, 2015

Positions


Positions:

2017-present Principal Investigator Predictive Pharmacology, Systems Biomedicine and Pharmacology, LACDR, Leiden University, The Netherlands
2013-2017 Acting Head Division of Pharmacology LACDR, Leiden University, the Netherlands
2004-2017 Head of the Target Site Equilibration Group LACDR/Pharmacology, Leiden University, the Netherlands
2013-2016 International Affairs Committee (IAC) member (AAPS)
2013-2014 Chair of the Annual Meeting Programming Committee of the American Association of Pharmaceutical Scientists (AAPS)
2012-2013 Co-Chair of the Annual Meeting Programming Committee of the American Association of Pharmaceutical Scientists (AAPS)
2012-present Secretary/Treasurer DD Breimer Foundation
2012-2013 Past-Chair of the PPDM Section of the American Association of Pharmaceutical Scientists (AAPS)
2011-2012 Chair of the PPDM Section of the American Association of Pharmaceutical Scientists (AAPS)
2010-2011 Chair-Elect of the PPDM Section of the American Association of Pharmaceutical Scientists (AAPS)
2010-present Founder and chair/secretary of the BBBNedwork Foundation (http://www.bbbnedwork.nl)
2009-present Founder and owner of In Focus (CNS drug Courses &Consultancy, http://www.infocus-ecmdelange.nl)
2009-2010 Vice-Chair of Pharmacokinetics, Pharmacodynamics and Drug Metabolism (PPDM) Section of the American Association of Pharmaceutical Scientists (AAPS)
2007-2009 Past-Chair Microdialysis Focus Group American Association of Pharmaceutical Scientists (AAPS)
2006-2008 Director of Pharmacokinetic Studies at BrainsOnLine, Groningen, the Netherlands
2005-2007 Chair Microdialysis Focus Group of the American Association of Pharmaceutical Scientists (AAPS)
2001-2004 Assistant Professor LACDR/Pharmacology, Leiden University, the Netherlands (Tenure track)

Lectures


Invited Lectures:

(only the accepted displayed)

  • Physico-chemical drug properties and human CNS system characteristics: determinants of CNS pharmacokinetics at different locations in human brain. AGAH-Summit.  Muenchen. Apr 2018
  • Prediction of human CSF and ISF concentrations based on rodent model exposure. Cerebral Vascular Biology Conference, Parkville, Australia, Dec, 2017
  • Replacement of the use of animals by mathematical models: Translational approaches to predict human CNS PKPD Caleidoscoop van het Honours College Beta & Life Science. Oct, 2017
  • Keynote: Quantitative approaches to unravel PKPD relationships of CNS active drugs. PhD-Course on Basic Neuropsychopharmacology and Cognitive Enhancement VU Amsterdam. ONWAR (onderzoeksschool neurowetenschappen Amsterdam-Rotterdam), Sept, Amsterdam, NL, Sept 2017
  • Prediction of small molecule CNS distribution- a Physiology-based pharmacokinetic modelling approach. TNO, Rijswijk, NL, Sept 2017
  • Drug-Receptor binding kinetics and residence time in relation to other body processes. Fall American Chemical Society (ACS). Symposium on Kinetics/Residence Time, Washington, Aug, 2017
  • Systems Pharmacology Workshop- Dutch Federation of Pharmacological Sciences (NFW)- Utrecht University, Jun 2017
  • Excellence in Science. 6th FIP Pharmaceutical Sciences World Congress (PSWC), Stockholm, Sweden, 2017
  • On binding kinetics in vivo; integration of multiple processes that govern local target site pharmacokinetics. European Federation of Medicinal Chemistry (EFMC) Short Course “Target binding kinetics”- Oegstgeest. NL, Apr 2017
  • Influence of Parkinson’s disease condition in the rat on blood-brain barrier transport and effects of L-DOPA. Symposion “alpha-Synuclein at the Blood-Brain Barrier in Parkinson`s Disease”. International Academic Forum in the old town of Heidelberg, DE, Apr 2017
  • Targeting the CNS: translational research approaches. Meindert Danhof Honorary Symposium- Four decades of research in PK, PD and beyond. Leiden University, Leiden, NL, Mar 2017
  • Prediction of drug effects in human. LACDR PhD introduction Course- Mar 2017
  • Keynote Binding kinetics and protein binding. Actelion Science day 1, Basel, CH.  Jan 2017
  • Keynote BBB CNS distribution. Actelion Science day 2, Basel, CH.  Jan 2017
  • Predicting human brain pharmacokinetics and effects using translational modelling of rat microdialysis data. Chinese University of Hong Kong University, Hong Kong, China, Jan 2017
  • Bloedsuikerregulatie- simuleren van biologische processen.  Interactieve lezing- De 31ste NIBI Onderwijsconferentie. Lunteren- Jan 2017- LAYMEN
  • Lotgevallen van farmaca in het lichaam.  LACDR Preclass University – Jan 2017- LAYMEN
  • Evaluation of blood-brain barrier transport and CNS drug metabolism in diseased and control brain after intravenous L-DOPA in a unilateral rat model of Parkinson’s disease. World Digital Pathology Congress, Madrid, SP, Dec 2016
  • Women in Science- an academics perspective- AAPS Annual meeting. Denver, USA, Nov 2016.
  • Prediction of BBB transport and CNS drug distribution; considerations for anticancer drugs. 2nd CNS Anticancer Drug Discovery & Development Conference. Phoenix, USA, Nov 2016
  • Drug-induced changes in metabolomics of plasma, brain extracellular fluid and cerebrospinal fluid. Symposium session “Brain and Body Metabolomics: Probing into the System, Solving the Matrix”. AAPS Annual meeting. Denver, USA, Nov 2016.
  • Support For CNS Drug In First In Human Studies By Translational Modelling- Exploratory Clinical Development World Europe- Berlin, DE, 26-27 oct 2016
  • Indispensable Role of Microdialysis in translational CNS PKPD. Galapagos, Paris, Oct, 2016”.
  • Keynote: Preclinical-based prediction of human CNS target site concentrations: towards informing early phase of clinical trials. Clinical Trials excellence Forum., Munich, DE, 12-14 Oct 2016
  • Development of a generic 3d drug distribution brain model. Conference on Complex systems (session Mathematical Pharmacology), Amsterdam. Sept 2016.
  • The MasterMind Research Approach towards predicting human target site concentrations and effects. GSK, Webinar. Aug, 2016
  • Considerations in CNS drug development. Heptares. London, UK, Jul 2016
  • BBB, BCSFB, models and modeling -. Tools for translational transporter science. Meet the Experts: The Transporter Conference. Budapest, Hungary, May, 2016,
  • Keynote: Indispensable Role of Microdialysis in translational CNS PKPD. 8th International Symposium on Microdialysis in Drug Research and Development. Uppsala, SE, May, 2016
  • Medicijntransport over de bloedhersen-barriere. Symposium der SvBMT Protagoras: “The Ageing Brain – Slowing it down”. Technical University Eindhoven, Faculty of Biomedical Engineering, May 2016
  • Featured speaker: Translational CNS pharmacology- A perspective on current and future scientific approaches. Annual Research Day in Pharmaceutical Sciences (including discussion with 25 PhD students), University of Wisconsin- Madison, WI, USA , Feb 2016
  • Keynote: Translational pharmacology: what do we need? K4DD Fellow Symposium. Frankfurt, DE, Jan 2016
  • About the Division of Pharmacology (Cluster Systems Pharmacology) at the LACDR- PhD Introductory Course on Drug Research -– Noordwijkerhout, NL, Nov 2015
  • Systems Approach to Biomarker Inquiries in Drug Discovery and Development: Can We, Should We, Integrate Microdialysis with Imaging Modalities? AAPS Annual Meeting, Orlando Florida, USA, Nov 2015
  • Interspecies scaling and CNS PBPK – Round table on translational approaches and issues in the development of CNS drugs. 11th International Conference on Cerebrovascular Biology, Paris, Jun 2015
  • Lack of relation between BBB P-gp expression and BBB P-gp efflux in a rat model of pharmacoresistant epilepsy. 11th International Conference on Cerebrovascular Biology, Paris, Jun 2015
  • CNS drug distribution and effects – a systems pharmacology fingerprint approach on antipsychotics. 6th Transporter Meeting on Clinically Relevant Transporters. Berlin, Germany, 2015
  • Pharmacometrics in psychiatry, de Lange, E. In Topical Talks: Talks of interest in the biomedical and life sciences, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://hstalks.com/?t=BL1003696-deLange), May 2015.
  • The Mastermind research Approach for Prediction of Human CNS drug effects: Right place, Right time, Right concentration in Health and Disease. 2nd International Summit on Clinical Pharmacy, San Francisco, USA, Dec 2014
  • Prediction of methotrexate CNS distribution in different species – influence of disease conditions, II Congress of the Brazilian Pharmaceutical Sciences Association. Búzios, Brazil, Sept 2014.
  • PKPD relationships of CNS active drugs. PhD-Course on Basic Neuropsychopharmacology and Cognitive Enhancement VU Amsterdam. ONWAR (onderzoeksschool neurowetenschappen Amsterdam-Rotterdam), Sept, Amsterdam, NL, Sept 2014
  • Pharmacometric approaches to predict human antipsychotic drug effects. Gordon Conference, Barriers of the CNS, Colby-Sawyer College, New London, NH, USA, Jun, 2014
  • Development of a translational generic brain distribution model using microdialysis; what about methotrexate? University of Bonn, Bonn, May, 2014
  • CNS active compounds and the importance of quantitative assessment on the role of target site distribution in PKPD relationships. Prosensa, Leiden, The Netherlands, Nov, 2013
  • Towards improved prediction of CNS drug distribution and effects- The Mastermind Research Approach –. UCB Pharma, Braine-l’Alleud, Belgium, Oct, 2013
  • Towards prediction of human PKPD relationships of CNS drugs: The use of Physiologically- based PK(-PD) modeling. 7th International Symposium on Microdialysis in drug Research and Development. Poitiers. France. May 2013
  • BBB: Future perspectives in CNS drug Research. Zing Conferences “Barriers of the CNS”. Lanzarote, Canary Islands, Spain, Feb 2013
  • For human brains sake; Develop and use predictive models. This weeks Discoveries, Faculteit Wiskunde en natuurwetenschappen, Leiden, NL, Feb 2013
  • The role of blood-brain barriers in PK-PD relationships of CNS drugs. Workshop “Beating the Blood-Brain and other blood barriers”, Lisbon, Portugal, Feb 2013
  • Prediction of brain distribution and effects of CNS active drugs”. Leids Natuurkundig Gezelschap, Leiden, NL, Nov 2012- LAYMEN
  • Farmacokinetiek- De verdieping van de Greep. Bioscoop Waddinxveen, NL, Nov 2012- LAYMEN
  • The Perspective of the Free Drug to PK and Further to PD. Roundtable Session “Small Molecule Plasma and Tissue Protein Binding: Set it Free“. 2012 AAPS Annual Meeting Chicago, IL, USA. Oct 2012
  • Mechanism-based PK-PD Model for the Prolactin Biological System Response Following a Dopamine Inhibition Challenge -Quantitative Extrapolation to Humans. Symposium “Biomarkers of CNS Function: From Mice to Man“. 2012 AAPS Annual Meeting Chicago, IL, USA. Oct 2012
  • On the role of blood-brain barrier transport in health and disease. Short Course “Optimizing Drug Delivery across the Blood-Brain Barrier: New Approaches to an Old Problem”. 2012 AAPS Annual Meeting Chicago, IL, USA. Oct 2012
  • The brain black box; mechanisms of getting in, moving within, and getting out. Sigma Lustrum Symposium “Inside and Outside the Box”. Nijmegen, The Netherlands, Apr 2012- LAYMEN
  • Mechanism-Based PK-PD Model for the Prolactin Biological System Response Following a Dopamine Inhibition Challenge – Quantitative Prediction to Humans. 7th Annual International Conference on “Predictive Human Toxicity and ADME/Tox Studies” Mondial Research Group Conference, Zaventem, Belgium, Jan, 2012
  • Success in Prediction from Rat to Human: Translational Approach for Action of Dopaminergic Agents, Dutch Center for Timing Research (CTR) meeting. LUMC, Leiden, NL. Nov 2011
  • Modeling & Simulation of brain ECF versus CSF pharmacokinetics for drugs with different PhysChem properties. In Mini‐symposium “Human CSF Concentrations; How Predictive Can We Get?”. 2011 AAPS Annual Meeting and Exposition. Washington DC, USA, Oct 2011.
  • The Role of Blood-Brain Barrier Transport in PKPD relationships of CNS drugs in Health and Disease. 9th International Conference on cerebral Vascular Biology. Leiden, The Netherlands, Jun 2011
  • Microdialysis in PKPD Research Clinical Perspective from Preclinical Studies. Trinity College, Dublin, IR. June 2011
  • Prediction of human brain target site concentrations: the preclinical approach using microdialysis. J Westerhout & ECM de Lange. Top Institute Pharma Spring Meeting, Utrecht, The Netherlands, Apr 2011
  • PK/PD modelling of CNS active drugs; the use of microdialysis to unravel factors in CNS target site distribution. PK/PD Review Day. Abbott GmbH & Co. KG, Ludwigshafen, DE, Mar 2011
  • Microdialysis in Preclinical Drug Development. American College of Clinical Pharmacology, 2010 Frontiers Symposium, New Orleans, LA, United States of America, Nov 2010
  • Mechanism-based PK/PD modelling of CNS active drugs. Post-Graduate Course Neuro- and Psychopharmacology by Medical Pharmacology, VUMc, Amsterdam, The Netherlands, Oct 2010
  • Translational PK-PD modeling for Remoxipride using Prolactine as PD marker. 2nd Annual Marcus Evans- POP PK/PD meeting on Integrating advanced PK/PD Models with Systems Biology to make Early Impacts in the Decision Making Process. Amsterdam, The Netherlands, Sept 2010
  • Assessment of the impact of BBB transport on concentration-effect relationships of CNS active drugs. Monitoring Molecules in Neuroscience, Brussels, Belgium, Sept 2010
  • Impact of transporters at BBB and BSCFB on predictive value of CSF for target site PK: P- glycoprotein”. Third Annual Symposium of SFB35 on Transmembrane Transporters in Health and Disease, Vienna, Austria, Sept 2010
  • PK/PD relationships of CNS Active Drugs. The Role of BBB Transport. Abbott DMPK Symposium: “Challenges of the Blood Brain Barrier”. Abbott GmbH & Co. KG, Ludwigshafen, Germany, Jun 2010.
  • Collaborative project management: Areas for development. NextLevelPharma Meeting on Enhancing Performance of early Phase Development Projects, Prague, Czech Republic, Apr 2010
  • Mechanism-based PKPD modelling of CNS-active drugs. COST Exploratory Workshop on Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU. Brussels, Feb 2010.
  • Integration of BBB transport and intra-brain conversion of L-DOPA in rotenone treated responder and control brain side in rat: A population PK model. Uppsala University, Sweden, Nov 2009
  • Assessing Novel Applications of Mechanism-and Physiologically-Based Modelling in Drug Development – Techniques and Technological Advancements. Conference on Population PK- PD: Fulfilling its Promise as a Tool to Optimise Clinical Drug Development. London, UK, Sept 2009.
  • Considerations of factors between dose and target site concentrations of CNS active drugs, Ludwig-Maximilians-University Munich, Germany. Jun 2009.
  • Considerations for CSF concentrations to predict target site concentrations of CNS active drugs”. 8th International Conference on Cerebral Vascular Biology Sendai, Japan, Jun 2009
  • Translation approaches for ultimate Pgp functionality assessment in epilepsy patients. Stichting Epilepsie Instellingen Nederland (SEIN). Heemstede, The Netherlands, Feb 2009
  • Microdialysis to study the pharmacokinetics of drugs in the CNS. UCB symposium “Delivery of Drugs to the CNS”. Château du Lac, Genval, Belgium. Nov 2008
  • Towards Visualisation of the Role of P-glycoprotein in Brain Distribution of Antiepileptic Drugs in Relation to Pharmacoresistance; the Preclinical Approach. VUMc, Division of Nuclear Medicine & PET Research. Amsterdam, the Netherlands, Apr 2008
  • Modulation of Blood-Brain Barrier function and GABAA receptor properties in pharmacoresistant epilepsy. Translational Workshop “Basic Scienstists meet Clinicians” at the 10th Annual International Clinical Symposium Kempenhaeghe: “Epilepsy & Sleep Update”. Heerze, the Netherlands. Apr 2008.
  • ABC transporters of Choroid Plexus Epithelial Cells in the Homeostasis of the Cerebrospinal Fluid. The VIIIth European Meeting on Glial Cells in Health and Disease. London, United Kingdom, Sep 2007.
  • ABC transporters. ISN/ASN Meeting. Workshop on the Functional Neurochemistry of CSF Handling Cells Cancun, Mexico, Aug 2007
  • Microdialysis in Mechanism-Based PK-PD Modelling; Characterisation of Complex Biophase Distribution Kinetics”. 5th International Symposium on Microdialysis in Drug Research and Development, Leiden, the Netherlands, Apr 2007
  • Microdialysis in Pharmacokinetic/Pharmacodynamic Research – the Clinical Perspective from Preclinical Studies. Biomade, Groningen, the Netherlands, Feb 2007
  • Considerations in Assessment and Prediction of CNS Target Concentrations: the Value of Microdialysis. GlaxoSmithKline, Harlow, United Kingdom, Jan 2007
  • The Use of Microdialysis in Mechanism-Based PK/PD Modelling; A Tool in Preclinical to Clinical Extrapolation. AAPS, Workshop “Microdialysis Principles, Application, and Regulatory Perspectives”. Nashville, TX, USA. Nov 2005
  • Considerations in the Assessment and Prediction of CNS Target Concentrations: Approaches to Assess CNS Penetration. DMDG & GMP meeting. Pfizer, Sandwich, United Kingdom, Dec 2005
  • Biomarkers and Mechanism-Based Pharmacokinetic-Pharmacodynamic Modelling; a Perfect Symbiosis. PharmSci Faire, EUPHEPS, Nice, France. Jun 2005
  • The Value of Microdialysis in Assessment of Blood-Brain Barrier Transport Characteristics; Applications on Animal Models of Epilepsy. Stichting Epilepsie Instellingen Nederland (SEIN). Heemstede, the Netherlands, Jun 2005
  • The Role of Blood-Brain Barriers and Active Transporters in CNS Drug Effects; Studies in Physiological and Pathological Conditions using Intracerebral Microdialysis. Department of Biomonitoring & Sensoring. Institute of Pharmacy, University of Groningen, Groningen, the Netherlands, Dec 2005
  • The Use of Intracerebral Microdialysis to Explore the Extracellular Space of the Brain. LACDR Division of Analytical Biosciences LACDR, Leiden, the Netherlands, Apr 2005
  • Microdialysis and Biomarkers – a Perfect Symbiosis. Cerebrospinal Fluid Forum. Leiden University medical Center (LUMC), Leiden, the Netherlands, May 2005
  • Factors between Drug Dosing and CNS Effects; Plasma Pharmacokinetics, Protein Binding, BBB Functionality and CNS Disorders. 7th International Symposium on Signal Transduction in the Blood-Brain Barriers. Potsdam-Sanssouci, Berlin, Germany, Sep 2004.
  • The Role of Blood-Brain Barriers and Active Transporters in CNS Drug Effects: Studies in Physiological and Pathological Conditions Using Intracerebral Microdialysis. 4th International Symposium on Microdialysis in Drug Research and Development. Vienna, Austria, Jun 2004
  • Blood-Brain Barrier Functionality and Effects of Neuroprotective Drugs in Neurodegenerative Diseases; Study Goals in the Rat Rotenone Model of Parkinson’s disease. Medical Faculty, Division of Pharmacology Amsterdam Free University Amsterdam, the Netherlands, Feb 2004
  • Blood-Brain Barrier Functionality in Neurodegenerative Diseases- Experimental Approaches. Division of Pharmacokinetics and Drug Therapy. Department of Pharmaceutical Biosciences Uppsala University, Sweden, Mar 2004.
  • Therapeutic Considerations in BBB functionality Changes in Brain Diseases. 2nd Endoneuropsychology meeting. Doorwerth, the Netherlands, Jun 2004.
  • The Relevance of CSF as a Measure of Brain Target Concentrations. Pfizer Ltd. Sandwich, United Kingdom, Apr 2003
  • Biophase Equilibration in the Central Nervous System the Role of the Blood-Brain Barrier in Concentration-Effect Relationships of Drugs during Neurodegenerative Disease Progression, Monitoring Molecules in Neuroscience, Stockholm, Sweden, Jun 2003
  • Considerations in the Prediction of Brain Target Concentrations, Eli Lilly, Indianapolis, IN, United States of America, Sep 2002
  • Drug Transport through Blood-Brain Barrier and Blood-Cerebrospinal Fluid-Barrier at the 5th International Symposium on Signal Transduction in Blood-Brain Barriers “. Potsdam- Sanssouci, Germany, Aug 2002
  • Interpretation of Microdialysis Data, 3rd International Symposium on Microdialysis in Drug Research and Development. Minneapolis, United States of America, Jun 2002
  • Blood-Brain Barrier (BBB), Neurodegeneration and Polyamines: Perspective of Epilepsy and Parkinson’s disease, EURON Winterschool Maastricht, the Netherlands. Feb 2002
  • Potential Influences of Epilepsy on Drug Transport of Antiepileptic Drugs Across the Blood- Brain Barrier, Stichting Epilepsie Instellingen Nederland (SEIN). Heemstede, the Netherlands, Jun 2001
  • Blood-Brain Barrier and P-glycoprotein; Drug Transport and Interactions, PET Center Amsterdam –Amsterdam, the Netherlands, Feb 2001
  • Recovery Issues Related to P-glycoprotein Transport at the Level of the Blood-brain barrier”. 2nd International Symposium on Microdialysis in Drug Research and Development, Stockholm, Sweden, Jun 2000
  • Impact of the Blood-brain barrier on Distribution of Drugs into the CNS. Nederlands- Belgische Vereniging voor Experimentele en Klinische Neurowetenschappen (EKN; Dutch- Belgium Society for Experimental and Clinical Neurosciences). Janssen Pharmaceutica, Beerse, Belgium, Jun 2000
  • BBB Transport and Brain Distribution with Special Emphasis on P-glycoprotein. Lilly Development Centre, Mon-Saint-Guibert, Belgium, May 2000
  • Effects of P-glycoprotein on BBB Transport Studied with Intracerebral Microdialysis: Concomitant Changes in In Vivo Recovery. 8th International Conference on In Vivo Methods “Monitoring Molecules in the Neurosciences”. Stoney Brooke, NY, United States of America, Sept 1999
  • Important aspects of the microdialysis technique in studying BBB transport. Glaxo Wellcome, Verona, Italy, Jun 1999
  • Microdialysis in mdr1a (-/-) mice. The role of P-glycoprotein in BBB transport. 1st International Symposium on Microdialysis in Drug Research and Development, Noordwijkerhout, the Netherlands, Apr 1998
  • Davson Honory Memorial Lecture: Application of Intracerebral Microdialysis Studies to Aspects of Blood-Brain Barrier Function. British Physiological Society Symposium on the Blood-Brain Barrier: Mechanisms Regulating Integrity and Transport. London, United Kingdom, Nov 1998
  • Blood-brain barrier (BBB) Transport of Drugs: Factors of Influence and In Vivo Methodologies, Lilly Development Centre, Mon-Saint-Guibert, Belgium, 1998
  • Application of Microdialysis in Blood-Brain Barrier Transport of Drugs, Department of Biopharmaceutics and Pharmacokinetics, University of Uppsala, Uppsala, Sweden, 1998
  • Effects of SDZ PSC 833 on Brain Distribution of Rhodamine-123. Sandoz Pharma LTD, Biopharmaceutical Department, Basle, Switzerland, 1996
  • The Pharmacokinetics of Drug Uptake into the Brain Including the Importance of Protein Binding. Henry Steward Conference Studies on Understanding the Blood-Brain Barrier and its Implications in Targeting Strategies. London, United Kingdom, 1996
  • The Application of Intracerebral Microdialysis in the Study of Blood-Brain Barrier Transport of Drugs, Department of Pathology, Academic Hospital of Leiden, Leiden University, Leiden, the Netherlands, 1995
  • The Use of Intracerebral Microdialysis to Study BBB Transport Characteristics of Drugs, Servier Research Group Londen, United Kingdom, 1994
  • Het Transport van Antikankermiddelen over de Bloedhersen-Barriere en Bloed- hersentumor-Barriere, gemeten met Behulp van Intracerebrale Microdialyse in de Rat. Department of Medicine, University of Antwerp, Wilrijk, Belgium, 1994
  • Pharmacokinetics of the P-Glycoprotein Substrate Rhodamine-123 in Brain, Determined by Intracerebral Microdialysis in mdr1a (-/-) and (+/+) Mice”. International Conference on “Cerebral Vascular Biology; Biology and Physiology of the Blood-Brain Barrier”. Paris, France, 1994
  • The Transport of Methotrexate into an Experimental Brain Tumor Measured by Intracerebral Microdialysis. International Workshop on Molecular Mechanisms regulating the Permeability of the Blood-Brain Barrier. Szeged, Hungary, 1993
  • The Use of Intracerebral Microdialysis to Study BBB Transport Characteristics of Drugs. Sandoz Pharma LTD, Biopharmaceutical Department, Basle, Switzerland, 1993
  • The Use of Intracerebral Microdialysis to Study Blood-Brain Barrier Transport in Health, after Modification and in Disease. International Conference on Cerebral Vascular Biology. Duluth (MN), United States of America, 1992
  • Application of Intracerebral Microdialysis to Determine Drug Transport Characteristics across the Blood-Brain Barrier. International Symposium on Drug Transport into the Brain: Concepts and Strategies Noordwijkerhout, the Netherlands, 1992
  • The Use of Intracerebral Microdialysis for the Characterization of Drug Transport into the Brain. 5th International Conference on In Vivo Methods: Monitoring Molecules in the Neurosciences. Noordwijkerhout, the Netherlands, 1991


Publications


Updated on March 22, 2018

Publications

Published * = corresponding author

1. Van der Brink W, Hankemeier Th, Van der Graaf PH, de Lange ECM*. Bundling arrows: improving translational CNS drug development by integrated PK/PD-metabolomics. Exp Opin Drug Disc,2018,  accepted

2. van den Brink WJ, Palic S, Köhler I, de Lange ECM*. Access to the CNS: Biomarker Strategies for Dopaminergic Treatments. Pharm Res. 2018 Feb 15;35(3):64. doi: 10.1007/s11095-017-2333-x.

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, Meindert Danhof 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. doi: 10.1016/j.ejps.2017.11.011. Epub 2017 Nov 11.

4. Wong YC, Ilkova T, van Wijk RC, Robin Hartman R, de Lange ECM*. Development of a population pharmacokinetic model to predict brain distribution and dopamine D2 receptor occupancy of raclopride in non-anesthetized rat.  Eur J Pharm Sci. 2018 Jan 1;111:514-525. doi: 10.1016/j.ejps.2017.10.031. Epub 2017 Nov 5.

5. 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.

6. Ketharanathan N, Yamamoto Y, Rohlwink U, Wildschut E, Hunfeld M, de Lange EC, Tibboel D. Analgosedation in paediatric severe traumatic brain injury (TBI): practice, pitfalls and possibilities. Childs Nerv Syst. 2017 Oct;33(10):1703-1710. doi: 10.1007/s00381-017-3520-0. Epub 2017 Sep 6

7. Taneja A, Vermeulen A, Huntjens D, Danhof M, De Lange ECM, Proost JH. Translational Modeling Of Prolactin Response: Can It Inform Clinical Dosing? Pharmacol Res Perspect. 2017 Dec;5(6). doi: 10.1002/prp2.364

8. Xiaomei Chen, Tim Slättengren, Elizabeth C.M. de Lange, David E. Smith, Margareta Hammarlund-Udenaes. Revisiting Atenolol as a Low Passive Permeability Marker Fluids Barriers CNS. 2017 Oct 31;14(1):30. doi: 10.1186/s12987-017-0078-x.

9. 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.

10. 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

11. 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.

12. van den Brink WJ, Elassaiss-Schaap J, Gonzalez-Amoros B, Harms AC, van der Graaf PH, Hankemeier T, de Lange ECM*. Multivariate pharmacokinetic/pharmacodynamic (PKPD) analysis with metabolomics shows multiple effects of remoxipride in rats . Eur J Pharm Sci 109C (2017) pp. 431-440  DOI: 10.1016/j.ejps.2017.08.031

13. 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]

14. Van Dijkman S, Voskuyl RA, de Lange EC. The Danhof biomarker classification system on epilepsy. Eur J Pharm Sci. 2017 May 17. pii: S0928-0987(17)30263-4. doi: 10.1016/j.ejps.2017.05.035

15. 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

16. Kervezee L, van der Berg DJ, Hartman RH, Meijer J, de Lange EC*. Diurnal variation in the pharmacokinetics and brain distribution of morphine. Eur J Pharm Sci. 2017 May 27. pii: S0928-0987(17)30277-4. doi: 10.1016/j.ejps.2017.05.048

17. Hu Y, Rip J, Galliard 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. [Epub ahead of print]

18. 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

19. Schuetz DA, de Witte WEA, Wong YC, Knasmueller B, Richter L, Kokh DB, Sadiq SK, Bosma R, Nederpelt I, Heitman LH, Segala E, Amaral M, Guo D, Andres D, Georgi V, Stoddart LA, Hill S, Cooke RM, De Graaf C, Leurs R, Frech M, Wade RC, de Lange ECM, IJzerman AP, Müller-Fahrnow A, Ecker GF. Kinetics for Drug Discovery – An industry driven effort to target drug residence time. Drug Discov Today. 2017 Jun;22(6):896-911. doi: 10.1016/j.drudis.2017.02.002. Epub 2017 Apr 13.

20. Bot I, Ortiz Zacarías NV, de Witte WE, de Vries H, van Santbrink PJ, van der Velden D, Kröner MJ, van der Berg DJ, Stamos D, de Lange EC, Kuiper J, IJzerman AP, Heitman LH.  A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice. Sci Rep. 2017 Dec;7(1):52. doi: 10.1038/s41598-017-00104-z

21. Erdo-Pázmány F, Denes L, de Lange EC. Age-associated physiological and pathological changes at the blood- brain barrier – A review.  J Cereb Blood Flow Metab. 2017 Jan;37(1):4-24

22. 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

23. Shimizu S, Hoedt SM, Sanjuan VM, Cristea S, Geuer JK, den Berg DV, Hartman R, Bellanti F, de Lange EC*. Target Site Investigation for the Plasma Prolactin Response: Mechanism-Based Pharmacokinetic-Pharmacodynamic Analysis of Risperidone and Paliperidone in the Rat. Drug Metab Dispos. 2017 Feb;45(2):152-159. doi: 10.1124/dmd.116.072306

24. 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

25. Taneja A, Vermeulen A, Huntjens DR, Danhof M, De Lange EC, Proost JH. Summary data of potency and parameter information from semi-mechanistic PKPD modeling of prolactin release following administration of the dopamine D2 receptor antagonists risperidone, paliperidone and remoxipride in rats. Data Brief. 2016 Aug 6;8:1433-7. doi: 10.1016/j.dib.2016.07.060.

26. 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

27. Taneja A, Vermeulen A, Huntjens D, Danhof M, De Lange EC, Proost JH. A comparison of two semi-mechanistic models for prolactin release and prediction of receptor occupancy following administration of dopamine D2 antagonists in rats. Eur J Pharmacol. 2016 Oct 15;789:202-14. doi: 10.1016/j.ejphar.2016.07.005.

28. Bakshi S, De Lange EC, vd Graaf PH, Danhof M, Pelletier B. Mathematical Pharmacology: Tutorial Phase plane analysis in Pharmacological experiments. CPT Pharmacometrics Syst Pharmacol. 2016 Jul;5(7):339-51. doi: 10.1002/psp4.12098

29. 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]

30. 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

31. Ruigrok M, De Lange ECM*. Emerging Insights for Translational PK and PK-PD studies: Towards Prediction of Nose-to-Brain Transport in Humans. AAPS J. 2015 May;17(3):493-505. doi: 10.1208/s12248-015-9724-x. Epub 2015 Feb 19. Review

32. Vendel E, de Lange EC* Functions of the CB1 and CB 2 receptors in neuroprotection at the level of the blood-brain barrier. Neuromolecular Med. 2014 Sep;16(3):620-42. doi: 10.1007/s12017-014-8314-x. Epub 2014 Jun 15.

33. Kervezee L, Hartman R, van den Berg DJ, Shimizu S, Emoto-Yamamoto Y, Meijer JH*, de Lange EC*. Diurnal variation in P-glycoprotein-mediated transport and cerebrospinal fluid turnover in the brain. AAPS J. 2014 Sep;16(5):1029-37. doi: 10.1208/s12248-014-9625-4. Epub 2014 Jun 11.

34. Bogdanović RM, Syvänen S, Michler C, Russmann V, Eriksson J, Windhorst AD, Lammertsma AA, de Lange EC, Voskuyl RA, Potschka H. (R)-[11C]PK11195 brain uptake as a biomarker of inflammation and antiepileptic drug resistance: evaluation in a rat epilepsy model.Neuropharmacology. 2014 Oct;85:104-12.

35. Westerhout J, van den Berg DJ, Hartman R, Danhof M, de Lange EC*. Prediction of methotrexate CNS distribution in different species – influence of disease conditions. Eur J Pharm Sci. 2014 Jun 16;57:11-24.

36. Rip J; Chen L; Hartman R; van den Heuvel A, Reijerkerk A; van Kregten J; van der Boom B; Appeldoorn CCM; de Boer M; Maussang D; de Lange ECM; Gaillard PJ. Glutathione PEGylated liposomes; pharmacokinetics and delivery of cargo across the blood-brain barrier in rats. J Drug Target. 2014 Jun;22(5):460-7.

37. Syvänen S, Russmann V, Verbeek J, Eriksson J, Labots M, Zellinger C, Seeger N, Schuit R, Rongen M, van Kooij R, Windhorst AD, Lammertsma AA, de Lange EC, Voskuyl RA, Koepp M, Potschka H. [11C]quinidine and [11C]laniquidar PET imaging in a chronic rodent epilepsy model: Impact of epilepsy and drug-responsiveness. Nucl Med Biol. 2013 Aug;40(6):764-75.

38. Vlasakakis G, Comets E, Keunecke A, Gueorguieva I, Magni P, Terranova N, Della Pasqua O, de Lange EC and Kloft C. White Paper: Landscape on Technical and Conceptual Requirements and Competence Framework in Drug/Disease Modeling and Simulation. CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e40; doi:10.1038/psp.2013.16

39. Westerhout J, Smeets J, Danhof M, de Lange EC*. The impact of P-gp functionality on non- steady state relationships between CSF and brain extracellular fluid. J Pharmacokinet Pharmacodyn. (2013) 40:327-342

40. De Lange ECM*. Utility of cerebrospinal fluid in translational neuroscience. In: Special Issue “Translational Modeling In Neuroscience”. Editor P Bonate. J Pharmacokinet Pharmacodyn. 2013 June; 40(3): 315-326.

41. Vlasakakis G, Comets E, Georguieva I, Magni P, Terranova N, della Pasqua O, De Lange EC, Kloft C. Landscape on technical and conceptual requirements in Drug / Disease Modelling & Simulation. CPT Pharmacometrics Syst Pharmacol. May; 2(5): e40, 2013

42. De Lange ECM*. The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects. Fluids and Barriers of the CNS 2013, 10:12.

43. Taneja A, Nyberg J, de Lange EC, Danhof M, Della Pasqua O. Application of ED-optimality to screening experiments for analgesic compounds in an experimental model of neuropathic pain. J Pharmacokinet Pharmacodyn. 2012 Dec; 39(6): 673-81.

44. Verbeek J, Eriksson J, Syvänen S, Labots M, de Lange EC, Voskuyl RA, Mooijer MPJ, Rongen M, Lammertsma AA, and Windhorst AD. [11C]-phenytoin revisited: synthesis by [11C]-CO carbonylation and first evaluation as a P-gp tracer in the rat. EJNMMI Res. 2012 Jul 2; 2(1): 36

45. Syvänen S, M Labots, Y Tagawa, J Eriksson, AD Windhorst, AA Lammertsma, EC de Lange, RA Voskuyl. Altered GABAA receptor density and unaltered blood-brain barrier transport in a kainate model of epilepsy: an in vivo study using [11C]-flumazenil and PET. J Nucl Med. 2012 53(12): 1974-83

46. Voskuyl RA, Syvanen S, Russman V, Verbeek J, Eriksson J, Schuit R, Windhorst AD, Labots M, Rongen M, Lammerstma AA, De Lange EC, Potschka H. Brain P-Glycoprotein function studied in rats with two novel PET radiotarcers: [11C]-Quinidine and [11C]-laniquidar. Differences between controls and epileptic respondesr and non-responders. Epilepsia, 53: Special Issue S5, 131-132, 2012

47. Stevens J, Ploeger B, Hammarlund-UdenaesM, Osswald G, vd Graaf PH, Danhof M and De Lange ECM*. 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

48. Westerhout J, Ploeger B, Smeets J, Danhof M, De Lange ECM*. Physiologically-based pharmacokinetic modeling to investigate regional brain distribution kinetics in rats. AAPS J. 2012 Sep;14(3):543-53

49. Froklage, FE, Syvänen S, Hendrikse NH, Huisman MC, Molthoff CFM, Tagawa Y, Reijneveld JC, Heimans JJ, Lammertsma AA, Eriksson J, de Lange ECM and Voskuyl RA: [11C]-Flumazenil brain uptake is influenced by the blood-brain barrier efflux transporter P-glycoprotein. European Journal of Nuclear Medicine and Molecular Imaging Research 2:12. 2012

50. Verbeek J, Syvänen S, Schuit RC, Eriksson J, de Lange EC, Windhorst AD, Luurtsema G, Lammertsma AA. Synthesis and preclinical evaluation of [(11)C]-D617, a metabolite of (R)- [(11)C]verapamil. Nucl Med Biol. Nucl Med Biol. 39(4): 530-9. 2012

51. Ravenstijn PGM, Drenth H, Baatje MS, O’Neill MJ, Danhof M and de Lange ECM*. Evaluation of BBB transport and CNS drug metabolism in diseased and control brain after intravenous L- DOPA in a unilateral rat model of Parkinson’s disease. Fluids and Barriers of the CNS, 9:4, 2012 (doi:10.1186/2045-8118-9-4 )

52. Syvänen S, M Schenke, DJ van den Berg, RA Voskuyl and ECM de Lange*. Alteration in P- glycoprotein functionality affects intrabrain distribution of drugs more than brain entry – A study in rats subjected to status epilepticus by kainate. AAPS J; 14(1): 87-96, 2012

53. ECM de Lange*. The physiological characteristics and transcytosis mechanisms of the blood- brain barrier (BBB). Special issue “Brain Drug Delivery Systems”, in: Current Pharmaceutical Biotechnology; 13(12) 2319-2327, 2012

54. Stevens J, Ploeger B, van der Graaf PH, Danhof M, de Lange ECM*. Systemic- and direct nose- to-brain transport in the rat; a mechanistic pharmacokinetic model for remoxipride after intravenous and intranasal administration. Drug Metab Disp, 39(12): 12 2275-2282, 2011

55. Syvänen S, de Lange ECM, Tagawa Y, Schenke M, Molthoff CFM, Windhorst AD, Lammertsma AA and Voskuyl RA: Simultaneous in vivo measurements of receptor density and affinity using [11C]-Flumazenil and positron emission tomography: comparison of full saturation and steady state methods. Neuroimage, 57, 928-37. 2011

56. Westerhout, J, M Danhof, De Lange ECM*. Preclinical prediction of human brain target site concentrations: Considerations in extrapolating to the clinical setting. J Pharm Sci.; 100(9): 3577-3593, 2011

57. Syvänen S, G Luurtsema, CFM Molthoff, AD Windhorst, MC Huisman, AA Lammertsma, RA Voskuyl, De Lange EC. (R)-[11C]-Verapamil PET studies to assess changes in P-glycoprotein expression and functionality in rat blood-brain barrier after exposure to kainate-induced status epilepticus. BMC Medical Imaging 2011, 11:1 doi:10.1186/1471-2342-11-1

58. Stevens J, DJ van den Berg, S de Ridder, HAG Niederländer, PH van der Graaf, M Danhof, de Lange ECM*. Online solid phase extraction with liquid chromatography-tandem mass spectrometry to analyze remoxipride in small plasma-, brain homogenate-, and brain microdialysate samples. J Chromatogr B Analyt Technol Biomed Life Sci 878(13-14):969-75 (2010)

59. Van Steeg TJ, Krekels EHJ, Freijer J, Danhof M, and De Lange EC*. Effect of altered AGP plasma binding on heart rate changes by S(-)-propranolol in rats using mechanism-based estimations of in vivo receptor affinity (KB,vivo). J Pharm Sci. 2010 May ;99 (5):2511-20

60. Kooij G, van Horssen J, de Lange EC, Reijerkerk A, van der Pol SM, van Het Hof B, Drexhage J, Vennegoor A, Killestein J, Scheffer G, Oerlemans R, Scheper R, van der Valk P, Dijkstra CD, de Vries HE.T lymphocytes impair P-glycoprotein function during neuroinflammation. J Autoimmun. 2010 Jun;34(4):416-25.

61. Stevens J, E Suidgeest, PH van der Graaf, M Danhof, de Lange ECM*. A new minimal-stress freely-moving rat model for preclinical studies on intranasal administration of CNS drugs, Pharm Res. 2009 Aug; 26(8):1911-7. Epub 2009 May 19

62. Van Steeg TJ, B BoralliV, Krekels EHJSlijkerman, P, Freijer J, Danhof M, and De Lange ECM*. Influence of Plasma Protein Binding on Pharmacodynamics: Estimation of In Vivo Receptor Affinities of b Blockers Using a New Mechanism-Based PK-PD Modelling Approach. J Pharm Sci. 2009 Oct;98(10):3816-28

63. Cremers TI, de Vries MG, Huinink KD, Loon JP, Hart MV, Ebert B, Westerink BH, De Lange EC. Quantitative Microdialysis using Modified Ultraslow Microdialysis: Direct Rapid and Reliable Determination of Free Brain Concentrations with the MetaQuant Technique. J Neurosci Methods. 2009 Apr 15;178(2):249-54. Epub 2008 Dec 14

64. Groenendaal D, Freijer J, Rosier A, de Mik D, Nicholls G, Hersey A, Ayrton A, Danhof M and De Lange EC*. Pharmacokinetic-Pharmacodynamic Modeling of the EEG effects of Opioids: Role of Complex Biophase Distribution Kinetics.  Eur J Pharm Sci, 34; 149-163, 2008.

65. Van Steeg TJ, Freijer J, Danhof M, De Lange EC*. Mechanism-based pharmacodynamic modeling of S(-)-atenolol: estimation of in vivo affinity for the beta1-adrenoceptor with an agonist-antagonist interaction model. J Pharmacol Exp Ther,. Mar;324(3):1234-42, 2008

66. Danhof, M, de Lange EC, Della Pasqua OE, Ploeger BA, Voskuyl RA. Mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) modeling in translational drug research, Trends Pharmacol Sci, vol. 29, no. 4, pp. 186-91, 2008

67. Van Steeg TJ, Freijer J, Danhof M and De Lange EC*. Pharmacokinetic-Pharmacodynamic Modelling of S(-)-Atenolol in rats: Reduction of Isoprenaline-Induced Tachycardia as a Continuous Pharmacodynamic Endpoint”. Br J Pharmacol, 151(3):356-66, 2007

68. Ravenstijn PG, Merlini M, Hameetman M, Murray TK, Ward MA, Lewis H, Ball G, Mottart C, de Ville de Goyet C, Lemarchand T, van Belle K, O’Neill MJ, Danhof M, De Lange EC*. The Exploration of Rotenone as a Toxin for Inducing Parkinson’s disease in Rats, for Application in BBB Transport and PK-PD Experiments. J Pharmacol Toxicol Meth, Vol 57/2 pp 114-130, 2007

69. Van Steeg TJ, Krekels EHJ, Danhof M, and De Lange EC*. Experimental Alteration of Serum AGP and Albumin Concentrations in the Rat; an Approach to Assess the Impact of Changes in Serum Protein Binding on Pharmacodynamics. J Pharmacol Toxicol Meth, 56; 72-78, 2007

70. Groenendaal D, Freijer J, de Mik D, Bouw MR, Danhof M and De Lange EC. Pharmacokinetic- Pharmacodynamic Modelling of the Electroencephalogram Effects of Morphine: the Influence of Biophase Equilibration and P-glycoprotein Interaction. Br J Pharmacol, 151(5):713-20. Epub 2007 Apr 30. 2007

71. Groenendaal D, Freijer J, de Mik D, Bouw MR, Danhof M and De Lange EC*. Population Pharmacokinetic Modelling of Non-linear Brain Distribution of Morphine: Influence of Active Saturable Influx and P-Glycoprotein Mediated Efflux. Br J Pharmacol., 151(5):701-12. Epub 2007 Apr 30, 2007

72. Danhof M, de Jongh J, De Lange EC, Della Pasqua O, Ploeger BA, Voskuyl RA. Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling: Biophase Distribution, Receptor Theory, and Dynamical Systems Analysis. Annu Rev Pharmacol Toxicol, Feb 10;47:357-400, 2007

73. CS Chaurasia, M Müller, E Benfeldt, RJ Sawchuck,, WF Elmquist, BWY Cheung, PM Bungay, H Derendorf, De Lange ECM, CE Lunte, M Hammarlund-Udenaes, I Bolinder, R Bullock, Ch Joukhadar, CH Nordstrom, H Rollema, DF Welty, H Yeo, L Stahle, ED Barshaw, VP Shah, U. AAPS-FDA Workshop White paper: Microdialysis Principles, Application and Regulatory Perspectives – Report from the joint AAPS-FDA Workshop, November 4-5, 2005, Nashville, Tennessee. AAPSJ, JCLINP, Pharm Res, 2007

74. De Lange ECM*, Ravenstijn PGM, Groenendaal D, and van Steeg TS. “Toward the Prediction of CNS Drug Effect Profiles in Physiological and Pathological Conditions Using Microdialysis and Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling”. AAPS Journal, 7(3) article 54, 2005

75. Groenendaal D, Blom-Roosemalen M, Danhof M and De Lange ECM*. High-Performance Liquid Chromatography of Nalbuphine, Butorphanol and Morphine in Blood and Brain Microdialysate Samples: Application to a Pharmacokinetic / Pharmacodynamic Study in Rats. J Chromatogr B Analyt Technol Biomed Life Sic, 822(1-2):230-7, 2005

76. De Lange ECM*. Potential Role of ABC transporters as a Detoxification System at the Blood- Cerebrospinal Fluid-Barrier. Adv Drug Del Rev 56(12); 1793-1809, 2004

77. Luurtsema G, De Lange ECM, Lammertsma AA, Franssen EJF. Transport Across the Blood-Brain Barrier: Stereoselectivity and PET-tracers. Mol Imaging & Biol, 6(5); 306-318, 2004

78. De Lange ECM*, Danhof M. Considerations in the Use of Cerebrospinal Fluid Pharmacokinetics to Predict Brain Target Concentrations in the Clinical Setting: Implications of the Barriers between Blood and Brain. Clin. Pharmacokin, 41, 691-703, 2002

79. Sills GJ, Kwan P, Butler E, De Lange ECM, van den Berg DJ, Brodie MJ. P-glycoprotein Mediated Efflux of Anti-Epileptic Drugs; Preliminary Studies in Mdr1a Knockout Mice. Epilepsy Behav, 3:427-432, 2002

80. Karssen AM, Meijer OC, van der Sandt ICJ, De Boer AG, De Lange ECM and de Kloet ER. The Role of the Efflux Transporter P-glycoprotein in Brain Penetration of Prednisolone. J Endocrinol, 175:251-60, 2002

81. AM Karssen, OC Meijer, ICJ van der Sandt, P J Lucassen, ECM de Lange, AG de Boer and ER de Kloet. Multidrug Resistance P-Glycoprotein Hampers the Access of Cortisol But Not of Corticosterone to Mouse and Human Brain. Endocrinology 2001 142: 2686-2694, doi: 10.1210/en.142.6.2686

82. De Lange ECM*, Marchand S, van den Berg DJ, van der Sandt ICJ, De Boer AG, Delon A, Bouquet S and Couet W. In Vitro and In Vivo Investigations on Fluoroquinolones; Effects of the P-glycoprotein Efflux Transporter on Brain Distribution of Sparfloxacin. Eur J Pharmacol Sci,12: 85-93, 2001

83. De Lange ECM*, De Boer AG, and Breimer DD. Methodological Issues in Microdialysis Sampling for Pharmacokinetic studies. Eds. R. Sawchuk and W.F. Elmquist. Adv Drug Del Rev, 45, 125- 148, 2001

84. Mulder M, Blokland A, van den Berg DJ, Schulten H, Bakker AHF, Terwel D, Honig W, de Kloet ER, Havekes LM, Steinbusch HWM, and De Lange ECM. Apolipoprotein E Protects Against Neuropathology Induced by a High-Fat Diet and Maintains the Integrity of the Blood-Brain Barrier during Aging. Lab. Invest, 81: 953-960, 2001

85. Wijnholds J & De Lange ECM* (shared first author), van den Berg DJ, Scheffer GL, van der Valk M, Schinkel AH, Scheper RJ, Breimer DD and Borst P. Multidrug-Resistance Protein 1 Protects the Choroid Plexus Epithelium and Contributes to the Blood-Cerebrospinal Fluid Barrier. J Clin Invest, 105: 279-285, 2000

86. De Lange ECM*, De Boer AG, and Breimer DD. Microdialysis for Pharmacokinetic Analysis of Drug Transport to the Brain. In: Blood-Brain Barrier as a Dynamic Interface of Drug Delivery to the Brain. Ed. A. Tsuij. Adv Drug Del Revs, 36; 211-217, 1999

87. Xie R, Hammarlund-Udenaes M, De Boer AG and De Lange ECM*. The Role of P-glycoprotein in Blood-Brain-Barrier Transport of Morphine: Transcortical Microdialysis Studies in Mdr1a (-/-) and Mdr1a (+/+) Mice. Br J Pharmacol, 128: 563-568, 1999

88. De Boer AG, De Lange ECM, van der Sandt ICJ and Breimer DD. Transporters and the Blood- Brain Barrier (BBB). Int J of Clin Pharmacol Ther, 36:14-16, 1998

89. De Lange ECM*, de Bock G, Schinkel AH, De Boer AG, and Breimer DD: BBB transport and P- glycoprotein Functionality Using mdr1a (-/-) and Wild-type mice. Total Brain Versus Microdialysis Concentration Profiles of Rhodamine-123. Pharm Res, 15: 1657-1665, 1998

90. Meyer OC, De Lange ECM, Breimer DD, De Boer AG, Workel JO, and De Kloet ER. Penetration of Dexamethasone into Brain Glucocorticoid Targets is enhanced in mdr1a P-glycoprotein Knockout Mice. Endocrinol, 139: 1789-1793, 1998

91. Desrayaud S, De Lange ECM, Lemaire M, Bruelisauer A, De Boer AG and Breimer DD. Effect of the mdr1a Gene Disruption on the Tissue Distribution of SDZ PSC 833, a Multidrug Resistance- Reversing Agent, in Mice. J Pharmacol Exp Ther, 285: 438-443, 1998

92. De Lange ECM*, Danhof M, De Boer AG and Breimer DD: Methodological Considerations of Intracerebral Microdialysis in Pharmacokinetic Studies on Blood-Brain Barrier Transport of Drugs. Brain Res Revs, 25; 27-49, 1997.

93. Hammarlund-Udenaes M, Paalzow LN and De Lange ECM. Drug Equilibration Across the Blood- Brain-Barrier – Pharmacokinetic Considerations Based on the Microdialysis Method. Pharm Res, 14: 128-134, 1997

94. De Lange ECM*, De Boer AG and Breimer DD: Monitoring In Vivo Blood-Brain Barrier Drug Transport: Cerebrospinal Fluid Sampling, the Unit Impulse Response Method and, with Special Reference, Intracerebral Microdialysis. STP Pharm Sci, 7; 17-27, 1997

95. De Lange ECM*, Hesselink MB, Danhof M, De Boer AG and Breimer DD: The Use of Intracerebral Microdialysis to Determine Changes in Blood-Brain Barrier Transport Characteristics. Pharm Res, 12: 129-133, 1995

96. De Lange ECM*, Bouw MR, Danhof M, De Boer AG and Breimer DD: Application of Intracerebral Microdialysis to Study Regional Distribution Kinetics of Drugs in Rat Brain. Br J Pharmacol, 116: 2538-2544, 1995

97. De Lange ECM*, de Vries JD, Zurcher C, Danhof M, De Boer AG and Breimer DD: The Use of Intracerebral Microdialysis to Study Blood-Brain Barrier Transport of Anticancer Drugs in Tumor-Bearing Rat Brain. Pharm Res, 12: 1924-1931, 1995

98. De Lange ECM*, Zurcher C, Danhof M, De Boer AG and Breimer DD: Repeated Microdialysis Perfusions: Periprobe Tissue Reactions and BBB Permeability. Brain Res, 702: 261-265, 1995

99. De Lange ECM*, Danhof M, De Boer AG and Breimer DD: Critical Factors of Intracerebral Microdialysis as a Technique to Determine the Pharmacokinetics of Drugs in Rat Brain. Brain Res, 666, 1-8, 1994

100. De Lange ECM*, Danhof M, De Boer AG and Breimer DD: The Use of Intracerebral Microdialysis to Study Blood-Brain Barrier Transport in Health, after Modification and in Disease. In: Frontiers in Cerebral Vascular Biology: Transport and its Regulation. Eds L.R. Drewes and A.L. Betz. Plenum Press, NY. pp 257-262, 1993

Book Chapters

1. De Lange EC* and Bonate P.  Modeling and Simulation in the Translational Pharmacology of CNS Drugs. Chapter in “Translational Medicine in CNS Drug Development Handbook”- Editor Nomikos. 2017

2. De Lange EC*, Bajza A, Imre P, Csorba A, Dénes L,  and Erdő F. Age-associated changes at the blood-brain barrier. In: AGING: EXPLORING A COMPLEX PHENOMENON. Editor: Shamim Ahmad. Taylor & Francis/CRC Press- 2017

3. De Lange ECM*. Toward a generic PBPK models for brain distribution of CNS drugs. In: Blood- Brain Barrier in Drug Discovery: Optimizing Brain Exposure of CNS Drugs and Minimizing Brain Side Effects. Li Di (Editor), Edward H. Kerns (Editor). Wiley. 2015

4. De Lange ECM*. “Pharmacometrics in Psychiatry”. In ‘Applied Pharmacometrics’. Editors S Schmidt & H Derendorf. Published by Springer and AAPS, 2014

5. De Lange ECM*- PKPD aspects of brain drug delivery in a translational perspective. In Drug Delivery to the Brain- Physiological Concepts, Methodologies, and Approaches. Editors: M. Hammarlund-Udenaes, EC de Lange, and R Thorne. Springer Science + Business Media, 2014

6. De Lange ECM*- Disease influence on BBB transport in neurodegenerative disorders. In Drug Delivery to the Brain- Physiological Concepts, Methodologies, and Approaches. Editors: M. Hammarlund-Udenaes, EC de Lange, and R Thorne. Springer Science + Business Media, 2014

7. De Lange ECM* – Recovery and Calibration Techniques: toward Quantitative Microdialysis- In: Microdialysis in Drug Development- General Aspects. Editor M. Mueller. Springer. 2012

8. De Lange ECM* – Translational approaches for predicting CNS drug effects using microdialysis. In: Microdialysis in Drug Development- General Aspects. Editor M. Mueller. Springer. 2012

9. De Lange EC*. Microdialysis as a Method to Study the Blood-Brain Barrier. In: Handbook of Microdialysis: Methods, Applications and Perspectives. Eds THIF Cremers & BHC Westerink, Academic Press, Elsevier, The Netherlands, p545-572, 2007

10. De Lange EC*. Multidrug Resistance P-glycoprotein and Other Transporters. In: Encyclopedia of Stress. IInd  edition. Chief Editor G. Fink. pp 774 -783, 2007

11. De Boer AG, De Lange ECM, Van der Sandt ICJ, Breimer DD. The Application of Microdialysis Techniques to the Study of Drug Transport across the Blood-Brain Barrier. In: The Blood-Brain Barrier and Drug Delivery to the CNS”. Eds: Begley DJ, Bradbury MW, Kreuter J, 2000.

12. De Lange ECM*, De Boer AG, and Breimer DD. Chapter 11: Intracerebral Microdialysis. In: An Introduction to the Blood-Brain-Barrier. Ed: WM Pardridge. Cambridge University Press, p 94- 112, 1998

13. De Lange ECM*, Danhof M, De Boer AG and Breimer DD: Effects of Perfusate Tonicity and Temperature on Microdialysate AUC values of Acetaminophen and Atenolol obtained from Rat Cortical Brain. In: Drug Transport across the Blood-Brain Barrier. Part B: In Vivo: Microdialysis. Eds: De Boer AG and W. Sutanto. Harwood Academic Publishers, Amsterdam, the Netherlands, p 157-163, 1996

Editor/ Guest Editor

1. Guest Editor of Dedicated Issue To Prof M Danhof- ” Quantitative Pharmacology”. European Journal of Pharmaceutical Sciences. Koos Burggraaf, Elizabeth de Lange, Douwe Breimer, Piet Hein vd Graaf, 2017

2. Guest Editor on Theme issue “Brain Barriers and their Microenvironment: Emerging Models and echniques”. Edited by: Dr Elizabeth de Lange, Prof Britta Engelhardt, Dr Danica Stanimirovic. Fluid and Barriers of the CNS, 2013

3. Editor on the Book: “Drug Delivery to the Brain- Physiological Concepts, Methodologies, and Approaches”. Editors: M. Hammarlund-Udenaes, EC de Lange, and R Thorne. AAPS/ Springer Science and Business Media. 2014; ISBN 978-1-4614-9104-0

 

Organized Events


Conferences/ Symposia / Courses / Workshop

  • Barriers of the CNS’ Gordon Research Conference: Discussion Leader on CNS Barrier Function in Disease States. New Londen, New Hampshire, Jun 2018, USA, Discussion Leader
  • Dutch Pharmacological Society (NVF) 40th anniversary meeting. “Energize Pharmacology”. Utrecht, 2018. Organizer
  • 11th International Conference on Cerebral Vascular Biology. Scientific Advisory committee member + Organizer of Symposium Session “Pharmacokinetic-pharmacodynamics for correlating brain fluid concentration to activity”, Australia- Dec 2017- Scientific Committee member
  • Binding kinetics: Time is of the essence. IMI K4DD Scientific meeting. Berlin, 2017, Session Organizer
  • Dutch Pharmacological Society (NVF) 40th anniversary meeting. “Gender differences”. Utrecht, Jun 2017. Organizer
  • Workshop “Excellence in Science”. 6th FIP Pharmaceutical Sciences World Congress (PSWC), Stockholm, Sweden, May 2017- Invited Organizer and Teacher
  • PSWC Young Scientist Satellite Congress in Uppsala, Sweden, May 2017, Advisor.
  • European Federation of Medicinal Chemistry (EFMC) Short Course “Target binding kinetics”- Invited Workshop organizer- Oegstgeest. NL, Apr 2017
  • Honorary Symposium to M Danhof  “Four Decades of Research in Pharmacokinetics and Pharmacodynamics, and beyond”. Leiden, May 2017, Organizer.
  • LACDR Fall Symposium – the four dimensions; in space and time, Leiden, NL, Nov 2016- Organizer
  • Spring Meeting “Nederlandse Vereniging voor Farmacologie”, Groningen, NL, 2016,  Organizing Committee member
  • 11th International Course on Microdialysis. Uppsala, Sweden, 2016, Organizer and teacher
  • 11th International Symposium on Microdialysis in Drug Research and Development. Uppsala, Sweden, 2016, Scientific Committee Member
  • ‘Barriers of the CNS’ Gordon Research Conference: Discussion Leader on CNS Barrier Function in Disease States. New Londen, New Hampshire, Jun 2016, USA, Discussion Leader
  • ‘Barriers of the CNS’ Gordon Research Seminar: PhD mentor. CNS Barrier Function in Disease States. New Londen, New Hampshire, Jun 2016, USA, Mentor
  • “DDMORE Model-Informed drug development in CNS diseases”. 27-31 Jul, 2015. Organizer and Course Leader
  • 10th International Conference on Cerebral Vascular Biology, June 2015, Paris, France. Scientific Committee member.
  • Chair on the AAPS Annual Meeting Programming Committee (AMPC) 2014
  • 7th Noordwijkerhout Symposium on Pharmacokinetics, Pharmacodynamics and Systems Pharmacology- Noordwijkerhout, NL, May 2014, Scientific Committee member.
  • 7th Symposium on Microdialysis in Drug Research and Development. Poitiers. FR, 2013. Scientific Committee Member
  • Co-Chair on the AAPS Annual Meeting Programming Committee (AMPC) 2013
  • Open Forum AAPS PPDM 2012: “Systems Therapeutics: Attaining Intimate Understanding by Unraveling Complexity”. 2012 AAPS Annual Meeting and Exposition. Oct 2012, Chicago, USA. Co-Organizer
  • Symposium “Biomarkers of CNS Function: From Mice to Man“. 2012 AAPS Annual Meeting Chicago, IL, USA. Oct 2012- Organizer
  • Co-Chair on the AAPS Annual Meeting Programming Committee 2012
  • Open Forum AAPS PPDM 2011: “PPDM Lost in Translation: Utility of preclinical models to human ADMET”. 2011 AAPS Annual Meeting and Exposition. Oct 2011, Washington DC, USA. Co-Organizer
  • Mini‐symposium “Human CSF Concentrations; How Predictive Can We Get?”, 2011 AAPS Annual Meeting and Exposition. Oct 2011, Washington DC, USA. Organizer and Moderator
  • 9 th International Conference on Cerebral Vascular Biology, June 2011, Leiden, the Netherlands-  Chair of the organizing Committee.
  • Course on Pharmacokinetics. “Pharmacokinetic Models and Parameters”. 2 times yearly: Oss, the Netherlands, Jan + Dec, 2011. Lecturer
  • PPDM Section Representative on the AAPS Annual Meeting Programming Committee (AMPC) 2011
  • Course on Pharmacokinetics. “Pharmacokinetic Models and Parameters”. 2 times yearly: Oss, the Netherlands, Jan + Dec, 2010. Lecturer
  • Open Forum AAPS PPDM 2010: “Ethnic Sensitivity in PK/PD; Leveraging Clinical Development in Emerging Countries –Using Knowledge of Ethnic Differences to Facilitate Drug Development”. PSWC 2010 / AAPS Annual Meeting in New Orleans, Louisiana, United States, Nov 2010. Co-Organizer
  • 19th LACDR School on Medicinal Chemistry. Lecture on “Pharmacokinetic and Pharmacodynamic Principles”. Oegstgeest, The Netherlands, Oct, 2010. Lecturer
  • LACDR Course on Pharmacokinetics. Oegstgeest, The Netherlands, Sept, 2010. Lecturer
  • Session “Modelling relations between concentrations and effect” at the 13th International Conference on In Vivo Methods. Brussels, Belgium, Sept 2010. Co-organizer and Chair
  • Barriers of The CNS. Gordon-Kenan Research Seminar. New London, NH, USA, Jun 2010- Discussion Leader
  • LACDR Course on Pharmacokinetics. Oegstgeest, The Netherlands, Dec 2009. Lecturer
  • Course on Pharmacokinetics. “Pharmacokinetic Models and Parameters”. 2 times yearly: Oss, the Netherlands, Jan + Dec, 2009. Lecturer
  • AAPS PPDM OPEN FORUM “An Evolution or Revolution in Drug Metabolism: When, Where, Why, What, How?” AAPS Annual Meeting. Los Angeles, USA, Nov 2009. Committee member
  • 18th LACDR School on Medicinal Chemistry. Lecture on “Pharmacokinetic and Pharmacodynamic Principles”. Oegstgeest, The Netherlands, Oct 2009. Lecturer
  • Course on “Blood-Brain Barrier Transport – Principles and Methods”. Uppsala University, Oct 2009. Co-Organizer and Lecturer
  • 8th International Conference on Cerebral Vascular Biology. Scientific Advisory committee member + Organizer of Symposium Session “Importance of kinetic approaches for the understanding of the CNS drug distribution”, Sendai, Japan, Jun 2009
  • Workshop on “Introduction into Pharmacokinetic-Pharmacodynamic Modelling, with Special Emphasis on the Modelling of Cortisol Effects”. Trier-Leiden International Research Training Group on ‘Psychoneuroendocrinology of Stress: From Molecules and Genes to Affect and Cognition’: “Basic Pharmacokinetics”. Eitorf, Germany. Dec 2008. Lecturer, Discussor
  • Course on Pharmacokinetics. “Pharmacokinetic Models and Parameters”. 2 times yearly: Oss, the Netherlands, Jan + Dec, 2008. Lecturer
  • Translational Workshop “Basic Scienstists meet Clinicians” at the 10 th Annual International Clinical Symposium Kempenhaeghe: “Epilepsy & Sleep Update”. Heerze, the Netherlands. Apr 2008. Discussion leader.
  • 11th International Symposium on Signal transduction in the Blood-Brain Barriers, Amsterdam, the Netherlands, Sep 2008. Organizing Committee Member.
  • Course on “Theoretical and Practical Aspects of Quantitative Microdialysis; the MetaQuant Probe II”. Brains On-Line, Groningen, the Netherlands, Jan 2008. Organizer and Lecturer.
  • PK-PD Course. Solvay Pharmaceuticals, Weesp, The Netherlands, Dec 2008. Organizer and Lecturer.
  • Course on Pharmacokinetics. “Pharmacokinetic Models and Parameters”. 2 times yearly: Oss, the Netherlands, Jan + Dec, 2007. Lecturer
  • Workshop on “Quantitative Microdialysis in CNS drug development”. Solvay Pharmaceuticals, Weesp, the Netherlands, Dec 2007. Organizer and Speaker
  • Course on “Theoretical and Practical Aspects of Quantitative Microdialysis; the MetaQuant Probe I”. Brains On-Line, Groningen, the Netherlands. Sep 2007. Organizer and Speaker.
  • Round-table on “Translational Research in Neurological Sciences”. Organizer and Moderator: Elizabeth de Lange. AAPS Annual meeting, San Diego, CA, United States of America. Nov 2007. Organizer and moderator
  • Symposium on “Biomarkers and Metabolic Profiles; Microdialysis Sampling and Analytical Frontiers in Tissue Targeted Metabonomics”. Moderator: Craig Lunte. AAPS Annual meeting, San Diego, CA, United Stated of America. Nov 2007 Organizer
  • 5th International Symposium on Microdialysis in Drug Research and Development, “The Target Site in Focus”. Leiden, the Netherlands, Apr 2007. Organizer, Chair and Speaker
  • Course “Methods in Studies of Drug Delivery to the Brain” ULLA Summerschool, Leiden, the Netherlands, Jul 2007. Co-organizer and Lecturer.
  • Workshop “AAPS Microdialysis Workshop; Application and Regulatory Perspectives”, Nashville, TN, United States of America. Nov 2005. Scientific Committee Member and Speaker.
  • Course “Methods in Studies of Drug Delivery to the Brain”. ULLA Summerschool, Uppsala, Sweden, Jun 2005. Co- Director and Lecturer.
  • Course “Drug Transport into the Brain, Basic Aspects and Therapeutic Implications”, ULLA Summerschool Uppsala, Sweden, Jun 2005. Lecturer.
  • Symposium Session on “Biomarkers in Drug Development”, and presentation on “Biomarkers and Mechanism-Based Pharmacokinetic-Pharmacodynamic Modelling; a Perfect Symbiosis”. EUFEPS PharmSciFaire, Nice, France, Jun 2005. Co-Chair and Speaker.
  • Course on “Basic and Advanced Aspects of Microdialysis” preceding the 4th International Symposium on Microdialysis in Drug Research and Development. Vienna, Austria, Jun, 2004. Presentation: “Troubleshooting in Microdialysis”. Lecturer.
  • 4th International Symposium on Microdialysis in Drug Research and Development. Vienna, Austria, Jun 2004. Scientific Committee Member and Speaker.
  • 3th Dutch Endoneuromeeting Session “The Blood-Brain Barrier in Neurological Diseases”. Doorwerth, the Netherlands, Jun 2004. Co-organizer and Speaker.
  • 2nd Dutch Endoneuromeeting: session “The Blood-Brain Barrier”. Doorwerth, the Netherlands, Jun 2003. Co-Organizer.
  • 5th International Conference on Cerebral Vascular Biology. Amarillo, Texas, United States of America, May-Jun 2003. Scientific Committee Member
  • Course on “Microdialysis in Pharmaceutical Research”, ULLA Summerschool, Paris, France, Jul 2003. Director and Lecturer
  • Course on “Drug Transport into the Brain, Basic Aspects and Therapeutic Implications”, ULLA Summerschool, Paris, France, Jul 2003. Lecturer
  • Research Course on “Microdialysis in Drug Development”. Uppsala, Sweden, Mar 2003. Co- course Director and Lecturer.
  • Course on “Basic and Advanced Aspects of Microdialysis” preceding the 3rd International Symposium on Microdialysis in Drug Research and Development. Minneapolis, United States of America, Jun 2002. “Troubleshooting in Microdialysis” Lecturer.
  • 3rd International Symposium on Microdialysis in Drug Research and Development. Minneapolis, United States of America, Jun 2002. Scientific Committee Member.
  • Course on “Microdialysis in Pharmaceutical Research”, ULLA Summerschool, London, UK, Jul 2001. Co-Director and Lecturer.
  • Course on “Drug Transport into the Brain, Basic Aspects and Therapeutic Implications”, ULLA Summerschool, London, UK, Jul 2001. Lecturer
  • Course on “Microdialysis and Sensoring”. Lecture on “Application of quantitative microdialysis in preclinical studies”, Academic Hospital, Groningen, the Netherlands, Dec 2001. Lecturer.
  • 2n International Symposium on Microdialysis in Drug Research and Development. Stockholm, Sweden, Jun 2000. Co-Chair and Speaker
  • Course on “Basic and Advanced Aspects of Microdialysis” preceding the 2nd International Symposium on Microdialysis in Drug Research and Development. Lecture on “The Need for Quantification of Microdialysis Data”.  Stockholm, Sweden, Jun 2000. Speaker
  • AAPS Microdialysis Focus Group Steering Committee Member. 1999-2001
  • Course on “Microdialysis in Pharmaceutical Research”, ULLA Summerschool, Copenhagen, Denmark, Jul 1999. Co-Director and Lecturer
  • Course on “Drug Transport into the Brain, Basic Aspects and Therapeutic Implications”, ULLA Summerschool, Copenhagen, Denmark, Jul 1999. Lecturer
  • 1st International Symposium on Microdialysis in Drug Research and Development. Noordwijkerhout, the Netherlands, Apr 1998. Co-Chair and Speaker
  • Course on “Basic and Advanced Aspects of Microdialysis” Preceding the 1st International Symposium on microdialysis in drug research and development. Noordwijkerhout, the Netherlands, Apr 1998. Co-organizer and Speaker.
  • Course on “Drug Transport into the Brain, Basic Aspects and Therapeutic Implications”. Lecture on: “In Vivo Systems to Study Drug Transport to the Brain”. ULLA Summerschool, Leiden, the Netherlands. Jul 1997. Lecturer.
  • Course on “Microdialysis in Pharmaceutical Research”. ULLA Summerschool, Leiden, the Netherlands. Jul 1997. Co-director and Lecturer.

In Focus Courses: 

  1. 1st Course on Blood-Brain Barrier in CNS Drug Development: Principles, Transport Kinetics, Diseases & Methods, Uppsala, Sweden – An “In Focus” & “Udenaes Consulting” Co- production]. Oct 2017. Organizer and Lecturer
  2. 2nd Course on Blood-Brain Barrier in CNS Drug Development: Principles, Transport Kinetics, Diseases & Methods, Leiden, The Netherlands – An “In Focus” & “Udenaes Consulting” Co- production]. Oct 2016. Organizer and Lecturer
  3. 3rd Course on Blood-Brain Barrier in CNS Drug Development: Principles, Transport Kinetics, Diseases & Methods, Uppsala, Sweden – An “In Focus” & “Udenaes Consulting” Co- production]. Oct 2015. Organizer and Lecturer
  4. 4th Course on Blood-Brain Barrier in CNS Drug Development: Principles, Transport Kinetics, Diseases & Methods, Uppsala, Sweden – An “In Focus” & “Udenaes Consulting” Co- production]. Oct 2014. Organizer and Lecturer
  5. 5th Course on Blood-Brain Barrier in CNS Drug Development: Principles, Transport Kinetics, Diseases & Methods, Leiden, The Netherlands – An “In Focus” & “Udenaes Consulting” Co- production]. Oct 2013. Organizer and Lecturer
  6. 6th Course on Blood-Brain Barrier in CNS Drug Development: Principles, Transport Kinetics, Diseases & Methods, Uppsala, Sweden – An “In Focus” & “Udenaes Consulting” Co- production]. Oct 2012. Organizer and Lecturer
  7. 7th Course on Blood-Brain Barrier in CNS Drug Development: Principles, Transport Kinetics, Diseases & Methods, Leiden, The Netherlands – An “In Focus” & “Udenaes Consulting” Co- production]. Oct 2011. Organizer and Lecturer
  8. 8th Course on Blood-Brain Barrier in CNS Drug Development: Principles, Transport Kinetics, Diseases & Methods, Leiden, The Netherlands – An “In Focus” & “Udenaes Consulting” Co- production]. Oct 2010. Organizer and Lecturer