- Gorlaeus Laboratories, LMUY00.20
LACDR
Leiden University
Einsteinweg 55
2333 CC Leiden
The Netherlands
- Prof. Elizabeth de Lange has been trained as a chemist, with a specialization in Biophysical Chemistry (Groningen Uni... moreProf. Elizabeth de Lange has been trained as a chemist, with a specialization in Biophysical Chemistry (Groningen University, The Netherlands). She obtained her PhD in Pharmacology (Leiden Academic Center for Drug Research (LACDR), Leiden University, The Netherlands). She currently is the Principal Investigator on Predictive Pharmacology in the Division of Systems Biomedicine.Liesbeth’s ultimate aim is to predict human drug effects and early neurodegenerative disease stage by translational model development on the basis of preclinical and clinical data. To that end she underscores that the rate and extent of the body (biological systems) processes are condition dependent. Therefore, the mutual coherence and time dependencies of biological systems processes should be unraveled by strategic preclinical and clinical experimentation to obtain multilevel and longitudinal data combined with mathematical modelling (Mastermind Research Approach).RESEARCH INTERESTS. Pharmacokinetics, pharmacodynamics, Physiologically based, modelling and simulation, CNS, diseases, neurodegeneration, extracellular vesicles, omic technologiesedit
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For mechanism-based investigations on PK-PD relationships following intranasal administration, the use of advanced animal models and analytical techniques are crucial. As described in this thesis, quantitative information on distinction... more
For mechanism-based investigations on PK-PD relationships following intranasal administration, the use of advanced animal models and analytical techniques are crucial. As described in this thesis, quantitative information on distinction between extent as well as rate of absorption between nose-to-systemic and nose-to-brain distribution can now be obtained. Using plasma prolactin concentrations as a biomarker for dopamine D2 inhibition, a mechanism-based PK-PD model was developed. Most important aspects in this approach were incorporation of target site exposure (brain extracellular fluid) of remoxipride and a biological system response (positive feedback) mechanism on the synthesis of prolactin, thereby increasing the mechanistic insight in modulation of the dopaminergic system in rats. Simulating remoxipride brain extracellular fluid concentrations in humans, allometric scaling and use of independent information on interspecies differences proved that the structural model is applicable in both rats and man.
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Background Very little knowledge exists on the impact of Alzheimer’s disease on the CNS target site pharmacokinetics (PK). Aim To predict the CNS PK of cognitively healthy young and elderly and of Alzheimer’s patients using the... more
Background Very little knowledge exists on the impact of Alzheimer’s disease on the CNS target site pharmacokinetics (PK). Aim To predict the CNS PK of cognitively healthy young and elderly and of Alzheimer’s patients using the physiologically based LeiCNS-PK3.0 model. Methods LeiCNS-PK3.0 was used to predict the PK profiles in brain extracellular (brainECF) and intracellular (brainICF) fluids and cerebrospinal fluid of the subarachnoid space (CSFSAS) of donepezil, galantamine, memantine, rivastigmine, and semagacestat in young, elderly, and Alzheimer’s patients. The physiological parameters of LeiCNS-PK3.0 were adapted for aging and Alzheimer’s based on an extensive literature search. The CNS PK profiles at plateau for clinical dose regimens were related to in vitro IC50 values of acetylcholinesterase, butyrylcholinesterase, N-methyl-D-aspartate, or gamma-secretase. Results The PK profiles of all drugs differed between the CNS compartments regarding plateau levels and fluctuation. ...
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Alzheimer's disease (AD) is a complex disease driven mainly by neuronal loss due to accumulation of intracellular neurofibrillary tangles and amyloid β aggregates in the brain. The diagnosis of AD currently relies on clinical symptoms... more
Alzheimer's disease (AD) is a complex disease driven mainly by neuronal loss due to accumulation of intracellular neurofibrillary tangles and amyloid β aggregates in the brain. The diagnosis of AD currently relies on clinical symptoms while the disease can only be confirmed at autopsy. The few available biomarkers allowing for diagnosis are typically detected many years after the onset of the disease. New diagnostic approaches, particularly in easily-accessible biofluids, are essential. By providing an exhaustive information of the phenotype, metabolomics is an ideal approach for identification of new biomarkers. This review investigates the current position of metabolomics in the field of AD research, focusing on animal and human studies, and discusses the improvements carried out over the past decade.
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It is generally accepted that, in conjunction with pharmacokinetics, the first-order rate constant of target dissociation is a major determinant of the time course and duration of in vivo target occupancy. Here we show that the... more
It is generally accepted that, in conjunction with pharmacokinetics, the first-order rate constant of target dissociation is a major determinant of the time course and duration of in vivo target occupancy. Here we show that the second-order rate constant of target association can be equally important. On the basis of the commonly used mathematical models for drug-target binding, it is shown that a high target association rate constant can increase the (local) concentration of the drug, which decreases the rate of decline of target occupancy. The increased drug concentration can also lead to increased off-target binding and decreased selectivity. Therefore, the kinetics of both target association and dissociation need to be taken into account in the selection of drug candidates with optimal pharmacodynamic properties.
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Transport to the brain is important for drugs that have their site of action in the brain compartment. However, drug transport to the brain is limited by the presence of various barriers in the brain. These comprise the blood-brain... more
Transport to the brain is important for drugs that have their site of action in the brain compartment. However, drug transport to the brain is limited by the presence of various barriers in the brain. These comprise the blood-brain barrier (BBB), the blood-cerebro-spinal-fluid barrier (blood-CSF) presented by the choroid plexi, and the brain-CSF (brain-CSF) barrier presented by an epithelial layer (ependyma) covering the circum-ventricular organs (CVO’s). The BBB and the blood-CSF barrier limit the entry of drugs from blood into the brain and the CSF respectively. However, since the surface area of the BBB is about 5000 times larger than the blood-CSF barrier, it is in this context considered as the most important barrier to the brain. It can be considered as a physical, a metabolic and an immunological barrier whose properties are changed during disease (stress) conditions. This may result in increased or decreased paracellular and/or transcellular transport of compounds to the brain. Under such conditions, upregulated transcellular transport may provide a key to target drugs selectively to the BBB and subsequently into the brain. In the BBB Research Group of the Division of Pharmacology, the PK-PD of drug transport to the brain is studied, at the level of the BBB. This comprises the study of the kinetics of drug transport and the effect(s) of disease on drug transport to the brain (Fig. 1).
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Research Interests: Neuroscience, Psychology, Epilepsy, Neuropharmacology, Positron Emission Tomography, and 15 moreMedicine, Brain, Chronic Disease, Female, Animals, Neuroinflammation, Microglia, Drug Resistance, Biomarker, Status Epilepticus, Radiopharmaceuticals, Phenobarbital, Neurosciences, Random Allocation, and Pharmacology and pharmaceutical sciences
Research Interests: Pharmacology, Pharmacokinetics, Medicine, Pharmaceutical, Animals, and 15 moreCorticosterone, Blood sampling, Male, Anesthesia, Central Nervous System, Perfusion, Behavioral Animal Models, Microdialysis, Nasal cavity, Biological markers, Physiological Stress Markers, Intranasal Administration, Radioimmunoassay, Pharmacology and pharmaceutical sciences, and Cmax
Research Interests: Pharmacology, Algorithms, Chemistry, Pharmacokinetics, Medicine, and 15 morePharmaceutical Sciences, Animals, Male, Heart rate, In Vivo, Pharmacodynamics, Propranolol, Protein Binding, Blood Proteins, Agonist, Isoproterenol, Atenolol, Metoprolol, plasma proteins, and Pharmacology and pharmaceutical sciences
In contrast to the impact of plasma protein binding on pharmacokinetics, no quantitative in vivo information is available on its impact on pharmacodynamics. The pharmacokinetic-pharmacodynamic relationship of the model drug... more
In contrast to the impact of plasma protein binding on pharmacokinetics, no quantitative in vivo information is available on its impact on pharmacodynamics. The pharmacokinetic-pharmacodynamic relationship of the model drug S(-)-propranolol was evaluated using mechanism-based estimations of in vivo receptor affinity (K(B,vivo)), under conditions of altered plasma protein binding resulting from different levels of alpha-1-acid glycoprotein (AGP). Male Wistar Kyoto rats with isoprenaline-induced tachycardia received an intravenous infusion of S(-)-propranolol, on postsurgery day 2 (n = 7) and day 7 (n = 8) with elevated and normal plasma protein binding, respectively. Serial blood samples were taken in parallel to heart rate measurements. AGP concentrations at 2 and 7 days postsurgery were 708 +/- 274 and 176 +/- 111 microg/mL (mean +/- SE), respectively. Using nonlinear mixed effects modeling, AGP concentration was a covariate for intercompartmental clearance for the third compartment of the pharmacokinetic model of S(-)-propranolol. Individual values of AGP concentrations ranged between 110 and 1150 microg/mL, and were associated with K(B,vivo) values of S(-)-propranolol from 7.0 to 30 nM. Using the K(B,vivo) for S(-)-propranolol with correction for average values for normal and elevated plasma protein binding, nearly identical values were found. This confirms, strictly quantitative, earlier indications that plasma protein binding restricts the pharmacodynamics of S(-)-propranolol.
Research Interests: Pharmacology, Chemistry, Pharmacokinetics, Medicine, Pharmaceutical Sciences, and 14 moreAnimals, Male, Heart rate, Glycoproteins, High Pressure Liquid Chromatography, In Vivo, Rats, Pharmacodynamics, Propranolol, Protein Binding, Blood Proteins, Tachycardia, Isoproterenol, and Pharmacology and pharmaceutical sciences
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Purpose. The use of intracerebral microdialysis as a tool to measure the penetration of anticancer agents in brain tumor was investigated.
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Background Changes in blood-brain barrier (BBB) functionality have been implicated in Parkinson's disease. This study aimed to investigate BBB transport of L-DOPA transport in conjunction with its intra-brain conversion, in both... more
Background Changes in blood-brain barrier (BBB) functionality have been implicated in Parkinson's disease. This study aimed to investigate BBB transport of L-DOPA transport in conjunction with its intra-brain conversion, in both control and diseased cerebral hemispheres in the unilateral rat rotenone model of Parkinson's disease. Methods In Lewis rats, at 14 days after unilateral infusion of rotenone into the medial forebrain bundle, L-DOPA was administered intravenously (10, 25 or 50 mg/kg). Serial blood samples and brain striatal microdialysates were analysed for L-DOPA, and the dopamine metabolites DOPAC and HVA. Ex-vivo brain tissue was analyzed for changes in tyrosine hydroxylase staining as a biomarker for Parkinson's disease severity. Data were analysed by population pharmacokinetic analysis (NONMEM) to compare BBB transport of L-DOPA in conjunction with the conversion of L-DOPA into DOPAC and HVA, in control and diseased cerebral hemisphere. Results Plasma pharma...
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The purpose of the present study was to determine whether intracerebral microdialysis can be used for the assessment of local differences in drug concentrations within the brain. Two transversal microdialysis probes were implanted in... more
The purpose of the present study was to determine whether intracerebral microdialysis can be used for the assessment of local differences in drug concentrations within the brain. Two transversal microdialysis probes were implanted in parallel into the frontal cortex of male Wistar rats, and used as a local infusion and detection device respectively. Within one rat, three different concentrations of atenolol or acetaminophen were infused in randomized order. By means of the detection probe, concentration‐time profiles of the drug in the brain were measured at interprobe distances between 1 and 2 mm. Drug concentrations were found to be dependent on the drug as well as on the interprobe distance. It was found that the outflow concentration from the detection probe decreased with increasing lateral spacing between the probes and this decay was much steeper for acetaminophen than for atenolol. A model was developed which allows estimation of kbp/Deff (transfer coefficient from brain to ...
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Background and purpose:The aim was to investigate the influence of biophase distribution including P‐glycoprotein (Pgp) function on the pharmacokinetic‐pharmacodynamic correlations of morphine's actions in rat brain.Experimental... more
Background and purpose:The aim was to investigate the influence of biophase distribution including P‐glycoprotein (Pgp) function on the pharmacokinetic‐pharmacodynamic correlations of morphine's actions in rat brain.Experimental approach:Male rats received a 10‐min infusion of morphine as 4 mg kg−1, combined with a continuous infusion of the Pgp inhibitor GF120918 or vehicle, 10 or 40 mg kg−1. EEG signals were recorded continuously and blood samples were collected.Key results:Profound hysteresis was observed between morphine blood concentrations and effects on the EEG. Only the termination of the EEG effect was influenced by GF120918. Biophase distribution was best described with an extended catenary biophase distribution model, with a sequential transfer and effect compartment. The rate constant for transport through the transfer compartment (k1e) was 0.038 min−1, being unaffected by GF120918. In contrast, the rate constant for the loss from the effect compartment (keo) decreas...
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Research Interests: Pharmacology, Biochemistry, Neuroscience, Sociology, Biophysics, and 15 moreChemistry, Hematology, Mental Health, Biotechnology, Pharmacokinetics, Drug delivery, Cell Biology, Medicine, Blood brain barrier, Liposome, Microdialysis, In Vivo, PEG Ratio, Molecular Pharmaceutics, and Pharmacology and pharmaceutical sciences
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Alzheimer’s disease (AD) is an aging-related neurodegenerative disease, leading to the progressive loss of memory and other cognitive functions. As there is still no cure for AD, the growth in the number of susceptible individuals... more
Alzheimer’s disease (AD) is an aging-related neurodegenerative disease, leading to the progressive loss of memory and other cognitive functions. As there is still no cure for AD, the growth in the number of susceptible individuals represents a major emerging threat to public health. Currently, the pathogenesis and etiology of AD remain poorly understood, while no efficient treatments are available to slow down the degenerative effects of AD. Metabolomics allows the study of biochemical alterations in pathological processes which may be involved in AD progression and to discover new therapeutic targets. In this review, we summarized and analyzed the results from studies on metabolomics analysis performed in biological samples of AD subjects and AD animal models. Then this information was analyzed by using MetaboAnalyst to find the disturbed pathways among different sample types in human and animal models at different disease stages. We discuss the underlying biochemical mechanisms in...
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The bidirectional pulsatile movement of cerebrospinal fluid (CSF), instead of the traditionally believed unidirectional and constant CSF circulation, has been demonstrated. In the present study, the structure and parameters of the CSF... more
The bidirectional pulsatile movement of cerebrospinal fluid (CSF), instead of the traditionally believed unidirectional and constant CSF circulation, has been demonstrated. In the present study, the structure and parameters of the CSF compartments were revisited in our comprehensive and validated central nervous system (CNS)-specific, physiologically based pharmacokinetic (PBPK) model of healthy rats (LeiCNS-PK3.0). The bidirectional and site-dependent CSF movement was incorporated into LeiCNS-PK3.0 to create the new LeiCNS-PK“3.1” model. The physiological CSF movement rates in healthy rats that are unavailable from the literature were estimated by fitting the PK data of sucrose, a CSF flow marker, after intra-CSF administration. The capability of LeiCNS-PK3.1 to describe the PK profiles of other molecules was compared with that of the original LeiCNS-PK3.0 model. LeiCNS-PK3.1 demonstrated superior description of the CSF PK profiles of a range of small molecules after intra-CSF admi...
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This review addresses questions on how to accomplish successful central nervous system (CNS) drug delivery (i.e., having the right concentration at the right CNS site, at the right time), by understanding the rate and extent of... more
This review addresses questions on how to accomplish successful central nervous system (CNS) drug delivery (i.e., having the right concentration at the right CNS site, at the right time), by understanding the rate and extent of blood‐brain barrier (BBB) transport and intra‐CNS distribution in relation to CNS target site(s) exposure. To this end, we need to obtain and integrate quantitative and connected data on BBB using the Combinatory Mapping Approach that includes in vivo and ex vivo animal measurements, and the physiologically based comprehensive LEICNSPK3.0 mathematical model that can translate from animals to humans. For small molecules, slow diffusional BBB transport and active influx and efflux BBB transport determine the differences between plasma and CNS pharmacokinetics. Obviously, active efflux is important for limiting CNS drug delivery. Furthermore, liposomal formulations of small molecules may to a certain extent circumvent active influx and efflux at the BBB. Interes...
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A key challenge in the development of central nervous system drugs is the availability of drug target specific blood‐based biomarkers. As a new approach, we applied cluster‐based pharmacokinetic/pharmacodynamic (PK/PD) analysis in brain... more
A key challenge in the development of central nervous system drugs is the availability of drug target specific blood‐based biomarkers. As a new approach, we applied cluster‐based pharmacokinetic/pharmacodynamic (PK/PD) analysis in brain extracellular fluid (brainECF) and plasma simultaneously after 0, 0.17, and 0.86 mg/kg of the dopamine D2/3 agonist quinpirole (QP) in rats. We measured 76 biogenic amines in plasma and brainECF after single and 8‐day administration, to be analyzed by cluster‐based PK/PD analysis. Multiple concentration‐effect relations were observed with potencies ranging from 0.001–383 nM. Many biomarker responses seem to distribute over the blood‐brain barrier (BBB). Effects were observed for dopamine and glutamate signaling in brainECF, and branched‐chain amino acid metabolism and immune signaling in plasma. Altogether, we showed for the first time how cluster‐based PK/PD could describe a systems‐response across plasma and brain, thereby identifying potential blo...
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Background: Cognitive aging creates major individual and societal burden, motivating search for treatment and preventive care strategies. Behavioural interventions can improve cognitive performance in older age, but effects are small.... more
Background: Cognitive aging creates major individual and societal burden, motivating search for treatment and preventive care strategies. Behavioural interventions can improve cognitive performance in older age, but effects are small. Basic research has implicated dopaminergic signaling in plasticity. We investigated whether transient enhancement of dopaminergic neurotransmission via administration of L-dopa improves effects of cognitive training on performance. Methods: Participants for this randomised, parallel-group, double-blind, placebo-controlled trial were recruited via newspaper advertisements. Inclusion criteria were: age of 65-75 years, Mini-Mental State Examination score >25, absence of serious medical conditions. Eligible subjects were randomly allocated to either receive 100/25mg L-dopa/benserazide or placebo prior to each of twenty cognitive training sessions administered during a four-week period. Participants and staff were masked to group assignment. Primary outc...
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Research Interests: Pharmacology, Biochemistry, Neuroscience, Sociology, Biophysics, and 15 moreChemistry, Hematology, Mental Health, Biotechnology, Pharmacokinetics, Drug delivery, Cell Biology, Medicine, Blood brain barrier, Liposome, Microdialysis, In Vivo, PEG Ratio, Molecular Pharmaceutics, and Pharmacology and pharmaceutical sciences
Because biological systems behave as networks, multi-biomarker approaches increasingly replace single biomarker approaches in drug development. To improve the mechanistic insights into CNS drug effects, a plasma neuroendocrine fingerprint... more
Because biological systems behave as networks, multi-biomarker approaches increasingly replace single biomarker approaches in drug development. To improve the mechanistic insights into CNS drug effects, a plasma neuroendocrine fingerprint was identified using multi-biomarker pharmacokinetic/pharmacodynamic (PK/PD) modelling. Short- and long-term D receptor activation was evaluated using quinpirole as a paradigm compound. Rats received 0, 0.17 or 0.86 mg·kg of the D agonist quinpirole i.v. Quinpirole concentrations in plasma and brain extracellular fluid (brain ), as well as plasma concentrations of 13 hormones and neuropeptides, were measured. Experiments were performed at day 1 and repeated after 7-day s.c. drug administration. PK/PD modelling was applied to identify the in vivo concentration-effect relations and neuroendocrine dynamics. The quinpirole pharmacokinetics were adequately described by a two-compartment model with an unbound brain -to-plasma concentration ratio of 5. Th...
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Target binding kinetics influence the time course of the drug effect (pharmacodynamics) both I) directly, by affecting the time course of target occupancy, driven by the pharmacokinetics of the drug, competition with endogenous ligands... more
Target binding kinetics influence the time course of the drug effect (pharmacodynamics) both I) directly, by affecting the time course of target occupancy, driven by the pharmacokinetics of the drug, competition with endogenous ligands and target turnover, and II) indirectly, by affecting signal transduction and homeostatic feedback. For dopamine D antagonists, it has been hypothesized that fast receptor binding kinetics cause fewer side effects, because part of the dynamics of the dopaminergic system is preserved by displacement of these antagonists. Target binding kinetics of D antagonists and signal transduction after dopamine and D antagonist exposure were measured in vitro. These data were integrated by mechanistic modeling, taking into account competitive binding of endogenous dopamine and the antagonist, the turnover of the second messenger cyclic adenosine monophosphate (cAMP), and negative feedback by phosphodiesterase turnover. The proposed signal transduction model succes...
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An important question in drug discovery is how to overcome the significant challenge of high drug attrition rates due to lack of efficacy and safety. A missing link in the understanding of determinants for drug efficacy is the relation... more
An important question in drug discovery is how to overcome the significant challenge of high drug attrition rates due to lack of efficacy and safety. A missing link in the understanding of determinants for drug efficacy is the relation between drug-target binding kinetics and signal transduction, particularly in the physiological context of (multiple) endogenous ligands. We hypothesized that the kinetic binding parameters of both drug and endogenous ligand play a crucial role in determining cellular responses, using the NK1 receptor as a model system. We demonstrated that the binding kinetics of both antagonists (DFA and aprepitant) and endogenous agonists (NKA and SP) have significantly different effects on signal transduction profiles, i.e. potency values, in vitro efficacy values and onset rate of signal transduction. The antagonistic effects were most efficacious with slowly dissociating aprepitant and slowly associating NKA while the combination of rapidly dissociating DFA and ...
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Atenolol, a hydrophilic beta blocker, has been used as a model drug for studying passive permeability of biological membranes such as the blood-brain barrier (BBB) and the intestinal epithelium. However, the extent of S-atenolol (the... more
Atenolol, a hydrophilic beta blocker, has been used as a model drug for studying passive permeability of biological membranes such as the blood-brain barrier (BBB) and the intestinal epithelium. However, the extent of S-atenolol (the active enantiomer) distribution in brain has never been evaluated, at equilibrium, to confirm that no transporters are involved in its transport at the BBB. To assess whether S-atenolol, in fact, depicts the characteristics of a low passive permeable drug at the BBB, a microdialysis study was performed in rats to monitor the unbound concentrations of S-atenolol in brain extracellular fluid (ECF) and plasma during and after intravenous infusion. A pharmacokinetic model was developed, based on the microdialysis data, to estimate the permeability clearance of S-atenolol into and out of brain. In addition, the nonspecific binding of S-atenolol in brain homogenate was evaluated using equilibrium dialysis. The steady-state ratio of unbound S-atenolol concentr...
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A considerable number of approved drugs show non-equilibrium binding characteristics, emphasizing the potential role of drug residence times for in vivo efficacy. Therefore, a detailed understanding of the kinetics of association and... more
A considerable number of approved drugs show non-equilibrium binding characteristics, emphasizing the potential role of drug residence times for in vivo efficacy. Therefore, a detailed understanding of the kinetics of association and dissociation of a target-ligand complex might provide crucial insight into the molecular mechanism-of-action of a compound. This deeper understanding will help to improve decision making in drug discovery, thus leading to a better selection of interesting compounds to be profiled further. In this review, we highlight the contributions of the Kinetics for Drug Discovery (K4DD) Consortium, which targets major open questions related to binding kinetics in an industry-driven public-private partnership.
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CC Chemokine Receptor 2 (CCR2) and its endogenous ligand CCL2 are involved in a number of diseases, including atherosclerosis. Several CCR2 antagonists have been developed as potential therapeutic agents, however their in vivo clinical... more
CC Chemokine Receptor 2 (CCR2) and its endogenous ligand CCL2 are involved in a number of diseases, including atherosclerosis. Several CCR2 antagonists have been developed as potential therapeutic agents, however their in vivo clinical efficacy was limited. In this report, we aimed to determine whether 15a, an antagonist with a long residence time on the human CCR2, is effective in inhibiting the development of atherosclerosis in a mouse disease model. First, radioligand binding assays were performed to determine affinity and binding kinetics of 15a on murine CCR2. To assess the in vivo efficacy, western-type diet fed apoE(-/-) mice were treated daily with 15a or vehicle as control. Treatment with 15a reduced the amount of circulating CCR2(+) monocytes and the size of the atherosclerotic plaques in both the carotid artery and the aortic root. We then showed that the long pharmacokinetic half-life of 15a combined with the high drug concentrations ensured prolonged CCR2 occupancy. The...
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In this tutorial, we introduce basic concepts in dynamical systems analysis, such as phase-planes, stability, and bifurcation theory, useful for dissecting the behavior of complex and nonlinear models. A precursor-pool model with positive... more
In this tutorial, we introduce basic concepts in dynamical systems analysis, such as phase-planes, stability, and bifurcation theory, useful for dissecting the behavior of complex and nonlinear models. A precursor-pool model with positive feedback is used to demonstrate the power of mathematical analysis. This model is nonlinear and exhibits multiple steady states, the stability of which is analyzed. The analysis offers insight into model behavior and suggests useful parameter regions, which simulations alone could not.
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Research Interests: Biology, Pharmacokinetics, Medicine, Brain, Humans, and 15 morePharmaceutical, Blood brain barrier, Animals, Male, Central Nervous System, Human Brain, Morphine, Theoretical Models, Rats, Wistar Rats, Acetaminophen, Tissue distribution, Translational model, Human prediction, and Pharmacology and pharmaceutical sciences
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For the pharmacotherapy of neurodegenerative diseases, drugs have to pass the blood–brain barrier (BBB). Many changes in BBB properties in neurodegeneration have been reported. Furthermore, the BBB seems to play an important role in the... more
For the pharmacotherapy of neurodegenerative diseases, drugs have to pass the blood–brain barrier (BBB). Many changes in BBB properties in neurodegeneration have been reported. Furthermore, the BBB seems to play an important role in the disease initiation and or progression. While information on unbound drug concentrations in plasma and brain are needed to decipher BBB transport properties and target site concentrations, and changes thereof in disease conditions, surprisingly, only a very limited number of BBB transport studies in neurodegeneration have been performed on the basis of the unbound drug, and even fewer have taken into account disease conditions and/or measurements of an effect parameter. For better understanding and treatment, a much more integrative and translational pharmacometric research approach is needed, instead of studying neurodegenerative components in isolation. As the human brain is not accessible for sampling, we have to rely on animal models and translational approaches.
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The aim of this investigation was to develop a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model for the biological system prolactin response following a dopamine inhibition challenge using remoxipride as a paradigm compound.... more
The aim of this investigation was to develop a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model for the biological system prolactin response following a dopamine inhibition challenge using remoxipride as a paradigm compound. After assessment of baseline variation in prolactin concentrations, the prolactin response of remoxipride was measured following (1) single intravenous doses of 4, 8 and 16 mg/kg and (2) following double dosing of 3.8 mg/kg with different time intervals. The mechanistic PK-PD model consisted of: (i) a PK model for remoxipride concentrations in brain extracellular fluid; (ii) a pool model incorporating prolactin synthesis, storage in lactotrophs, release into- and elimination from plasma; (iii) a positive feedback component interconnecting prolactin plasma concentrations and prolactin synthesis; and (iv) a dopamine antagonism component interconnecting remoxipride brain extracellular fluid concentrations and stimulation of prolactin release. The most important findings were that the free brain concentration drives the prolactin release into plasma and that the positive feedback on prolactin synthesis in the lactotrophs, in contrast to the negative feedback in the previous models on the PK-PD correlation of remoxipride. An external validation was performed using a dataset obtained in rats following intranasal administration of 4, 8, or 16 mg/kg remoxipride. Following simulation of human remoxipride brain extracellular fluid concentrations, pharmacodynamic extrapolation from rat to humans was performed, using allometric scaling in combination with independent information on the values of biological system specific parameters as prior knowledge. The PK-PD model successfully predicted the system prolactin response in humans, indicating that positive feedback on prolactin synthesis and allometric scaling thereof could be a new feature in describing complex homeostatic mechanisms.
Research Interests: Pharmacology, Chemistry, Medicine, Dopamine, Humans, and 13 moreProlactin, Circadian Rhythm, Pharmaceutical Sciences, Animals, Male, Rats, Pharmacodynamics, Wistar Rats, Cross-Over Studies, Dopamine antagonists, Pharmacokinetics and pharmacodynamics, Random Allocation, and Pharmacology and pharmaceutical sciences
Background: Raclopride is a selective antagonist of the dopamine D2 receptor. It is one of the most frequently used in vivo D2 tracers (at low doses) for assessing drug-induced receptor occupancy (RO) in animals and humans. It is also... more
Background: Raclopride is a selective antagonist of the dopamine D2 receptor. It is one of the most frequently used in vivo D2 tracers (at low doses) for assessing drug-induced receptor occupancy (RO) in animals and humans. It is also commonly used as a pharmacological blocker (at high doses) to occupy the available D2 receptors and antagonize the action of dopamine or drugs on D2 in preclinical studies. The aims of this study were to comprehensively evaluate its pharmacokinetic (PK) profiles in different brain compartments and to establish a PK-RO model that could predict the brain distribution and RO of raclopride in the freely moving rat using a LC −MS based approach.
Methods: Rats (n = 24) received a 10-min IV infusion of non-radiolabeled raclopride (1.61 μmol/kg, i.e. 0.56 mg/kg). Plasma and the brain tissues of striatum (with high density of D2 receptors) and cerebellum (with negligible amount of D2 receptors) were collected. Additional microdialysis experiments were performed in some rats (n = 7) to measure the free drug concentration in the extracellular fluid of the striatum and cere-bellum. Raclopride concentrations in all samples were analyzed by LC −MS. A population PK-RO model was constructed in NONMEM to describe the concentration-time profiles in the unbound plasma, brain extracellular fluid and brain tissue compartments and to estimate the RO based on raclopride-D2 receptor binding kinetics.
Results: In plasma raclopride showed a rapid distribution phase followed by a slower elimination phase. The striatum tissue concentrations were consistently higher than that of cerebellum tissue throughout the whole experimental period (10 −h) due to higher non-specific tissue binding and D2 receptor binding in the striatum. Model-based simulations accurately predicted the literature data on rat plasma PK, brain tissue PK and D2 RO at different time points after intravenous or subcutaneous administration of raclopride at tracer dose (RO < 10%), sub-pharmacological dose (RO 10%−30%) and pharmacological dose (RO > 30%).
Conclusion: For the first time a predictive model that could describe the quantitative in vivo relationship between dose, PK and D2 RO of raclopride in non-anesthetized rat was established. The PK-RO model could facilitate the selection of optimal dose and dosing time when raclopride is used as tracer or as pharmacological blocker in various rat studies. The LC −MS based approach, which doses and quantifies a non-radiolabeled tracer, could be useful in evaluating the systemic disposition and brain kinetics of tracers.
Methods: Rats (n = 24) received a 10-min IV infusion of non-radiolabeled raclopride (1.61 μmol/kg, i.e. 0.56 mg/kg). Plasma and the brain tissues of striatum (with high density of D2 receptors) and cerebellum (with negligible amount of D2 receptors) were collected. Additional microdialysis experiments were performed in some rats (n = 7) to measure the free drug concentration in the extracellular fluid of the striatum and cere-bellum. Raclopride concentrations in all samples were analyzed by LC −MS. A population PK-RO model was constructed in NONMEM to describe the concentration-time profiles in the unbound plasma, brain extracellular fluid and brain tissue compartments and to estimate the RO based on raclopride-D2 receptor binding kinetics.
Results: In plasma raclopride showed a rapid distribution phase followed by a slower elimination phase. The striatum tissue concentrations were consistently higher than that of cerebellum tissue throughout the whole experimental period (10 −h) due to higher non-specific tissue binding and D2 receptor binding in the striatum. Model-based simulations accurately predicted the literature data on rat plasma PK, brain tissue PK and D2 RO at different time points after intravenous or subcutaneous administration of raclopride at tracer dose (RO < 10%), sub-pharmacological dose (RO 10%−30%) and pharmacological dose (RO > 30%).
Conclusion: For the first time a predictive model that could describe the quantitative in vivo relationship between dose, PK and D2 RO of raclopride in non-anesthetized rat was established. The PK-RO model could facilitate the selection of optimal dose and dosing time when raclopride is used as tracer or as pharmacological blocker in various rat studies. The LC −MS based approach, which doses and quantifies a non-radiolabeled tracer, could be useful in evaluating the systemic disposition and brain kinetics of tracers.