In Focus

Updated on May 22nd, 2020

Research 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. Recently, she received an Honorary Doctorate from Uppsala University.
Elizabeth de Lange has a strong expertise in Physiology-Based Pharmacokinetic-Pharmacokinetic (PBPK) and mechanism-based Pharmacokinetic-Pharmacodynamic (PKPD) modeling, mostly focused on the Central Nervous System (CNS). Her other international recognition is on generating strategic data by preclinical experiments, using a combination of state-of-the art multi-level animal experimental designs (including microdialysis sampling), and bio-analytical techniques (Mastermind research approach; De Lange, 2013: https://fluidsbarrierscns.biomedcentral.com/articles/10.1186/2045-8118-10-12).

This extensive, highly structured and systematic approach has proven to be the road to translate between species for 1) successful prediction of human CNS effects (Stevens et al, 2012; https://link.springer.com/article/10.1007/s10928-012-9262-4) and 2) successful prediction of the pharmacokinetics of drugs in multiple locations in human CNS, solely on the basis of plasma pharmacokinetics and compound’s physico-chemical properties, by the rat and human CNS PBPK drug distribution model (Yamamoto et al, 2018; https://openaccess.leidenuniv.nl/bitstream/handle/1887/69843/Yamamoto_2018_T.pdf?sequence=1)

Moreover, good academic research practices (GARP), use of standard operations procedures (SOP), and good data management (DM) are key. In the research group of Prof Elizabeth de Lange, it is a prerequisite to work according to those lines.

Elizabeth de Lange has published more than 130 papers (h-index=38) and has provided more than 130 invited lectures. She has organized more than 85 conferences/ symposia / courses / workshops. Also, she has had multiple leadership positions in large organizations, such as the American Association of Pharmaceutical Scientists (AAPS). In 2013, she received the prestigious AAPS Fellow Award as recognition of her professional excellence, for the demonstrated sustained level of superior and distinguished professional achievement and contributions in fields related to the mission of the AAPS.

The current research is on further improvement of treatment of CNS diseases, with focus on Alzheimer’s disease, ultimately for the individual patient (‘tailor-made’). As treatment effects can very between people due to variations in genetic background, development, lifestyle, and health status (disease stage), the mathematical models should consider these personal variations. To that end, first, these models should be able to adequately diagnose different stages of Alzheimer’s disease, and then be able to provide a proper disease stage specific prediction of drug effects. Also, the biology of Alzheimer’s disease needs to be really understood. To that end we focus mainly on processes that play a role in Alzheimer’s disease progression, first generating a data base of multiple endogenous compounds, obtained from samples of multiple locations in the body of experimental animals during the life span.

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

For more information please see: https://www.universiteitleiden.nl/en/staffmembers/elizabeth-liesbeth-de-lange#tab-1

Updated on May 20th, 2020

Positions:

Leiden University, Leiden, The Netherlands

Secundary positions

Updated on May 20th, 2020

Invited Lectures:

(only the accepted displayed)

• Multi-dimensional research and mathematical approaches for improved and shorter CNS drug development. PKUK Canterbury, Nov 2020
• Medicijngedrag in de hersenen. Marie-Jose Blankwater Lezing.Koninklijke Maatschappij voor natuurkunde- Diligentia, Den Haag, NL, Okt 2020
• Keynote: Modelling and simulation of microdialysis data. 9th International Microdialysis Symposium 2020, Berlin- postponed to 2021
• Mathematical models to predict human drug concentration-time profiles in multiple locations of the CNS.Master Symposium Biomedical Sciences LUMC. Thema ‘Neurology’”, Jun 2020- Online
• A novel approach to integrate PK/PD and pharmacometabolomics in translational CNS drug development” – Symposium – Metabolomics in precision medicine- EPHAR congress, Prague, Jul 2020 – postponed to 2021
• Predictive Model approaches for Pharmacokinetics and Pharmacodynamics in CNS Discovery. Webinar. For 2nd Annual Neuroscience in Discovery & Development Congress. Berlin, Germany, May 2020
• Plenary: A novel CNS drug discovery and development approach: model-based prediction of neuro-pharmacokinetics and pharmacodynamics”. Control Release Society. NL. Apr 2020- postponed to 2021
• Drug properties + CNS PBPK model = Prediction of drug PK profiles in multiple CNS compartments. AAPS 2019 PHARMSCI 360, San Antonio, Texas, Nov 2019
• Prediction of CNS Drug Distribution. AVP workshop. Heidelberg, Germany, Feb 2020.
• PK/PD modeling to inform the identification of blood-based biomarkers of target engagement in the CNS. In: Clinical and Translational Drug Development in Neuroscience: A design, biomarker, imaging, and mathematical modeling opportunity. ASCPT Annual Meeting 2020 symposium. Houston, USA, Mar 2020
• HOVO cursus- Van Mastermind naar Hersenweefsels. Leiden, Nov 2019
• Nose-to-brain transport and its quantification. International Conference on Neurological Disorders. Ahmedabad, India. Oct 2019
• Target engagement in vivo- The role of drug-target binding kinetics in the in vivo context. 20th Annual Drug Discovery Summit and 7th Annual Discovery Chemistry & Drug Design Congress Berlijn, Jun 2019
• Prediction of human CSF and ISF drug concentrations-Application of microdialysis technique. AAPS-IBBS Workshop, Washington, Apr 2019
• Prediction of human CNS drug distribution in health and disease. 2019 Keystone Symposia on Delivering Therapeutics across Biological Barriers. Royal Dublin Society, Dublin, Ireland, May, 2019
• Target occupancy and the importance of on rate. American Chemical Society MEDI symposium on the use of binding kinetics in drug optimization. Session; on the importance of on rate and rebinding, Orlando, FL, Apr, 2019.
• Preclass University- BioFarmaceutical Sciences. LACDR, Leiden, NL. Jan, 2019
• Development of a comprehensive mathematical model to predict CNS drug distribution, target engagement and effects. American Collge on Neuropsycopharmacology (ANCP) Annual Meeting – Hollywood, Florida, USA, Dec, 2018
• Van glazen bol Voorspellen van medicijngedrag in de hersenen: van glazen bol naar wiskundig model. NGL lezing. Huygens laboratorium, Leiden, NL. Nov 2018
• PKPD and CNS safety applications. Safety Pharmacology Society (SPS) Annual Meeting, Washington DC,USA, Oct, 2018
• Towards Model-based Prediction of Human CNS PK and PD. 4th Congress of the Brazilian Association of Pharmaceutical Sciences-ABCF, event that will be held at São Paulo, Brazil, Sep 2018
• Binding kinetics in the in vivo context. European Federation of Medicinal Chemistry in de sessie “Time is of the Essence”. Lubjana, Kroatia. Sep 2018
• Mastermind Research Appoaches to predict PKPD- general considerations. Genentech, San Francisco, USA, Jul, 2018
• Mathematical approaches to develop a spatial brain distribution and binding model, based on units. Quantitative Systems Pharmacology UK 2nd Exchange Workshop, Reading UK, Jul, 2018
• Multi-dimensional research and mathematical approaches for improved and shorter CNS drug development. PKUK Canterbury, Nov 2020
• Medicijngedrag in de hersenen. Marie-Jose Blankwater Lezing.Koninklijke Maatschappij voor natuurkunde- Diligentia, Den Haag, NL, Okt 2020
• Keynote: Modelling and simulation of microdialysis data. 9th International Microdialysis Symposium 2020, Berlin- postponed to 2021
• Mathematical models to predict human drug concentration-time profiles in multiple locations of the CNS.Master Symposium Biomedical Sciences LUMC. Thema ‘Neurology’”, Jun 2020- Online
• A novel approach to integrate PK/PD and pharmacometabolomics in translational CNS drug development” – Symposium – Metabolomics in precision medicine- EPHAR congress, Prague, Jul 2020 – postponed to 2021
• Predictive Model approaches for Pharmacokinetics and Pharmacodynamics in CNS Discovery. Webinar. For 2nd Annual Neuroscience in Discovery & Development Congress. Berlin, Germany, May 2020
• Plenary: A novel CNS drug discovery and development approach: model-based prediction of neuro-pharmacokinetics and pharmacodynamics”. Control Release Society. NL. Apr 2020- postponed to 2021
• Drug properties + CNS PBPK model = Prediction of drug PK profiles in multiple CNS compartments. AAPS 2019 PHARMSCI 360, San Antonio, Texas, Nov 2019
• Prediction of CNS Drug Distribution. AVP workshop. Heidelberg, Germany, Feb 2020.
• PK/PD modeling to inform the identification of blood-based biomarkers of target engagement in the CNS. In: Clinical and Translational Drug Development in Neuroscience: A design, biomarker, imaging, and mathematical modeling opportunity. ASCPT Annual Meeting 2020 symposium. Houston, USA, Mar 2020
• HOVO cursus- Van Mastermind naar Hersenweefsels. Leiden, Nov 2019
• Nose-to-brain transport and its quantification. International Conference on Neurological Disorders. Ahmedabad, India. Oct 2019
• Target engagement in vivo- The role of drug-target binding kinetics in the in vivo context. 20th Annual Drug Discovery Summit and 7th Annual Discovery Chemistry & Drug Design Congress Berlijn, Jun 2019
• Prediction of human CSF and ISF drug concentrations-Application of microdialysis technique. AAPS-IBBS Workshop, Washington, Apr 2019
• Prediction of human CNS drug distribution in health and disease. 2019 Keystone Symposia on Delivering Therapeutics across Biological Barriers. Royal Dublin Society, Dublin, Ireland, May, 2019
• Target occupancy and the importance of on rate. American Chemical Society MEDI symposium on the use of binding kinetics in drug optimization. Session; on the importance of on rate and rebinding, Orlando, FL, Apr, 2019.
• Preclass University- BioFarmaceutical Sciences. LACDR, Leiden, NL. Jan, 2019
• Development of a comprehensive mathematical model to predict CNS drug distribution, target engagement and effects. American Collge on Neuropsycopharmacology (ANCP) Annual Meeting – Hollywood, Florida, USA, Dec, 2018
• Van glazen bol Voorspellen van medicijngedrag in de hersenen: van glazen bol naar wiskundig model. NGL lezing. Huygens laboratorium, Leiden, NL. Nov 2018
• PKPD and CNS safety applications. Safety Pharmacology Society (SPS) Annual Meeting, Washington DC,USA, Oct, 2018
• Towards Model-based Prediction of Human CNS PK and PD. 4th Congress of the Brazilian Association of Pharmaceutical Sciences-ABCF, event that will be held at São Paulo, Brazil, Sep 2018
• Binding kinetics in the in vivo context. European Federation of Medicinal Chemistry in de sessie “Time is of the Essence”. Lubjana, Kroatia. Sep 2018
• Mastermind Research Appoaches to predict PKPD- general considerations. Genentech, San Francisco, USA, Jul, 2018
• Mathematical approaches to develop a spatial brain distribution and binding model, based on units. Quantitative Systems Pharmacology UK 2nd Exchange Workshop, Reading UK, Jul, 2018
• 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

Updated on May 20th, 2020

Publications

Published * = corresponding author

1. Qin T, Prins S, Groeneveld GJ, Van Westen G, de Vries HE, Wong YC, Bischoff LJM, de Lange ECM*. Utility of Animal Models to Understand Human Alzheimer’s Disease, Using the Mastermind Research Approach to Avoid Unnecessary Further Sacrifices of Animals. Int J Mol Sci. 2020 Apr 30;21(9). pii: E3158. doi: 10.3390/ijms21093158.

2. Alexander Lebedev, Jonna Nilsson, Joanna Lindström, William Fredborg, Ulrika Akenine, Carolina Hillilä, Pia Andersen, Gabriela Spulber, Elizabeth de Lange, Dirk-Jan van den Berg, Miia Kivipelto, Martin Lövden. Effects of daily L-dopa administration on learning and brain structure in older adults undergoing cognitive training: a randomised clinical trial. Sci Rep. 2020

3. Nicolas JM, de Lange ECM. Mind the Gaps: Ontogeny of Human Brain P-gp and Its Impact on Drug Toxicity. AAPS J. 2019 May 28;21(4):67. doi: 10.1208/s12248-019-0340-z.

4. Vendel E, Rottschäfer V, de Lange ECM*. The need for mathematical modelling of spatial drug distribution within the brain. Fluids Barriers CNS. 2019 May 16;16(1):12. doi: 10.1186/s12987-019-0133-x. Review

5. Puris E, Gynther M, de Lange ECM, Auriola S, Hammarlund-Udenaes M, Huttunen KM, Loryan I. Mechanistic Study on the Use of the l-Type Amino Acid Transporter 1 for Brain Intracellular Delivery of Ketoprofen via Prodrug: A Novel Approach Supporting the Development of Prodrugs for Intracellular Targets. Mol Pharm. 2019 Jul 1;16(7):3261-3274. doi: 10.1021/acs.molpharmaceut.9b00502. Epub 2019 Jun 18

6. Qile M, Beekman HDM, Sprenkeler DJ, Houtman MJC, van Ham WB, Stary-Weinzinger A, Beyl S, Hering S, van den Berg DJ, de Lange ECM, Heitman LH, IJzerman AP, Vos MA, van der Heyden MAG. LUF7244, an allosteric modulator/activator of Kv 11.1 channels, counteracts dofetilide-induced TdP arrhythmia in the chronic atrioventricular block dog model. Br J Pharmacol. 2019 Jul 24. doi: 10.1111/bph.14798.

7. Hu Y, Gaillard PJ, de Lange ECM, Hammarlund-Udenaes M. Targeted Brain Delivery of Methotrexate by Glutathione PEGylated Liposomes: How can the Formulation Make a Difference? Eur J Pharm Biopharm. 2019 Apr 2. pii: S0939-6411(18)31441-3. doi: 10.1016/j.ejpb.2019.04.004.

8. De Witte WEA, Danhof M, van der Graaf PH, de Lange EC. The implications of target saturation for the use of drug-target residence time. Nat Rev Drug Discov. 2018 Dec 28;18(1):82-84.

9. YC Wong, M Centanni, EC de Lange*. A physiologically-based modeling approach to predict dopamine D2 receptor occupancy of antipsychotics in brain: translation from rat to human.J Clin Pharmacol. 2019 May;59(5):731-747. doi: 10.1002/jcph.1365.
10. Van den Brink W, 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.

11. De Lange ECM*, Vd Berg DJ, Bellanti F, Voskuyl RA, Syvänen S. P-glycoprotein protein expression versus functionality at the blood-brain barrier using immunohistochemistry, microdialysis and mathematical modeling. Eur J Pharm Sci. 2018 Aug 23;124:61-70. doi: 10.1016/j.ejps.2018.08.022. [Epub ahead of print]

12. De Witte WEA, Rottschäfer V, Danhof M, van der Graaf PH, Peletier LA, de Lange ECM*. Modelling the delay between pharmacokinetics and EEG effects of morphine in rats: binding kinetic versus effect compartment models. J Pharmacokinet Pharmacodyn. 2018 Aug;45(4):621-635. doi: 10.1007/s10928-018-9593-x. Epub 2018 May 18.

13. De Witte WEA, Rottschäfer V, Danhof M, van der Graaf PH, Peletier LA, de Lange ECM*. Correction to: Modelling the delay between pharmacokinetics and EEG effects of morphine in rats: binding kinetic versus effect compartment models. J Pharmacokinet Pharmacodyn. 2018 Oct;45(5):763. doi: 10.1007/s10928-018-9604-y.

14. de Witte WEA, Versfelt JW, Kuzikov M, Rolland S, Georgi V, Gribbon P, Gul S, Huntjens D, van der Graaf PH, Danhof M, Fernández-Montalván A, Witt G, de Lange ECM*. In vitro and in silico analysis of the effects of D2 receptor antagonist target binding kinetics on the cellular response to fluctuating dopamine concentrations. Br J Pharmacol. 2018 Nov;175(21):4121-4136. doi: 10.1111/bph.14456. Epub 2018 Sep 21.

15. Hu Y, Gaillard PJ, Rip J, de Lange EC, Hammarlund-Udenaes M. In Vivo Quantitative Understanding of PEGylated Liposome’s Influence on Brain Delivery of Diphenhydramine.Mol Pharm. 2018 Dec 3;15(12):5493-5500. doi: 10.1021/acs.molpharmaceut.8b00611.

16. Hurtado MO, Kohler I, de Lange EC*. Next-generation biomarker discovery in Alzheimer’s disease using metabolomics – from animal to human studies. Bioanalysis. 2018 Sep 1;10(18):1525-1546. doi: 10.4155/bio-2018-0135. Epub 2018 Sep 10.

17. Ketharanathan N, Yamamoto Y, Rohlwink UK, Wildschut ED, Mathôt RAA, de Lange ECM, de Wildt SN, Argent AC, Tibboel D, Figaji AA. Combining Brain Microdialysis and Translational Pharmacokinetic Modeling to Predict Drug Concentrations in Pediatric Severe Traumatic Brain Injury: The Next Step Toward Evidence-Based Pharmacotherapy? J Neurotrauma. 2018 Sep 6. doi: 10.1089/neu.2017.5588. [Epub ahead of print]

18. 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.

19. 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.

20. 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.

21. 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. Expert Opin Drug Discov. 2018 Jun;13(6):539-550. doi: 10.1080/17460441.2018.1446935. Epub 2018 Mar 8.

22. Vendel E, Rottschäfer V, de Lange EC*. Improving the prediction of local drug distribution profiles in the brain with a new 2D mathematical model. Bull Math Biol. 2018 Aug 8. doi: 10.1007/s11538-018-0469-4. [Epub ahead of print]

23. Verbeek J, Eriksson J, Syvänen S, Huisman M, Schuit RC, Molthoff CFM, Voskuyl RA, de Lange EC, Lammertsma AA, Windhorst AD .Synthesis and preliminary preclinical evaluation of fluorine-18 labelled isatin-4-(4-methoxyphenyl)-3-thiosemicarbazone ([18F]4FIMPTC) as a novel PET tracer of P-glycoprotein expression. EJNMMI Radiopharm Chem. 2018 Sep 21;3:11. doi: 10.1186/s41181-018-0046-z. eCollection 2018 Dec.

24. 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.

25. Yamamoto Y, Välitalo PA, Wong YC, Huntjens DR, Proost JH, Vermeulen A, Krauwinkel W, Beukers MW, van den Berg DJ, Hartman RH, Wong YC, Danhof M, Kokkif H, Kokkif M, van Hasselt JGC, de Lange ECM*. Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach. Eur J Pharm Sci. 2018 Jan 15;112:168-179.

26. 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.

27. 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

28. 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

29. 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.

30. 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.

31. 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

32. 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.

33. 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

34. 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]

35. 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

36. 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

37. 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

38. 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]

39. 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

40. 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.

41. 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

42. 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

43. 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

44. 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

45. 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

46. 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.

47. 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

48. 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.

49. 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

50. 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]

51. 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

52. 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

53. 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.

54. 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.

55. 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.

56. 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.

57. 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.

58. 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.

59. 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

60. 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

61. 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.

62. 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

63. 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.

64. 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.

65. 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

66. 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

67. 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

68. 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

69. 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

70. 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

71. 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

72. 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)

73. 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

74. 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

75. 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

76. 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

77. 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

78. 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

79. 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)

80. 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

81. 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.

82. 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

83. 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

84. 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

85. 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.

86. 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

87. 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

88. 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

89. 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

90. 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

91. 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

92. 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

93. 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

94. 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

95. 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

96. 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

97. 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

98. 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

99. 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

100. 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

101. 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

102. 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

103. 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

104. 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

105. 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

106. 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

107. 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

108. 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

109. 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

110. 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

111. 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

112. 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

113. 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.

114. 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

115. 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

116. 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

117. 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

118. 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

119. 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

120. 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

121. 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. 2019

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

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

Updated on May 20th, 2020

Conferences/ Symposia / Courses / Workshop

• Microdialysis Symposium, Berlin, Germany, sept 2021- scientific committee member
• Cerebrovascular Biology Conference, Uppsala, Sweden, Jun 2021- scientific committee member
• Quantitative Systems Pharmacology Conference 2020 (QSPC2020). Leiden, Apr 2021- Organizer /chair
• Course on the Blood-brain barrier and CNS drug distribution. ULLA Summer school 2019- Helsinki- Finland- Jul 2019- Course director
• AAPS-IBBS Workshop “Novel Approaches Targeting and Bypassing Brain Barriers for Effective Delivery of Small and Large Therapeutics” April- May, USA, 2019. Scientific Committee member.
• Dutch Pharmacological Society (NVF). “Personalized treatment”. Rotterdam, Apr 2019. Organizer
• 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