ArticleFrontiers in pharmacology2016
A Humanized Clinically Calibrated Quantitative Systems Pharmacology Model for Hypokinetic Motor Symptoms in Parkinson's Disease.
Article in Frontiers in pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 38 citations in OpenAlex.
- Quantitative Systems Pharmacology Development and Application in Neuroscience.Handbook of experimental pharmacology · 2025Review
- Computational neurosciences and quantitative systems pharmacology: a powerful combination for supporting drug development in neurodegenerative diseases.Journal of pharmacokinetics and pharmacodynamics · 2024Review
- Advancing precision medicine therapeutics for Parkinson's utilizing a shared quantitative systems pharmacology model and framework.Frontiers in systems biology · 2024Article
- A quantitative systems pharmacology model for simulating OFF-Time in augmentation trials for Parkinson's disease: application to preladenant.Journal of pharmacokinetics and pharmacodynamics · 2022Article
- Hallmarks of neurodegenerative disease: A systems pharmacology perspective.CPT: pharmacometrics & systems pharmacology · 2022Review
- A Computational Platform Integrating a Mechanistic Model of Crohn's Disease for Predicting Temporal Progression of Mucosal Damage and Healing.Advances in therapy · 2022Article
- Recent Advances in Translational Pharmacokinetics and Pharmacodynamics Prediction of Therapeutic Antibodies Using Modeling and Simulation.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Quantitative systems pharmacology in neuroscience: Novel methodologies and technologies.CPT: pharmacometrics & systems pharmacology · 2021Review
- Toward Predicting Impact of Common Genetic Variants on Schizophrenia Clinical Responses With Antipsychotics: A Quantitative System Pharmacology Study.Frontiers in neuroscience · 2021Article
- Salvaging CNS Clinical Trials Halted Due to COVID-19.CPT: pharmacometrics & systems pharmacology · 2020Article
- Quantitative Systems Pharmacology for Neuroscience Drug Discovery and Development: Current Status, Opportunities, and Challenges.CPT: pharmacometrics & systems pharmacology · 2020Article
- A modeling informed quantitative approach to salvage clinical trials interrupted due to COVID-19.Alzheimer's & dementia (New York, N. Y.) · 2020Article
- Development of Prodrugs for PDT-Based Combination Therapy Using a Singlet-Oxygen-Sensitive Linker and Quantitative Systems Pharmacology.Journal of clinical medicine · 2019Review
- Applications of Quantitative Systems Pharmacology in Model-Informed Drug Discovery: Perspective on Impact and Opportunities.CPT: pharmacometrics & systems pharmacology · 2019Article
- Incorporating Placebo Response in Quantitative Systems Pharmacology Models.CPT: pharmacometrics & systems pharmacology · 2019Article
- Blood-Based Biomarkers of Quinpirole Pharmacology: Cluster-Based PK/PD and Metabolomics to Unravel the Underlying Dynamics in Rat Plasma and Brain.CPT: pharmacometrics & systems pharmacology · 2019Article
- Mathematical Biology Models of Parkinson's Disease.CPT: pharmacometrics & systems pharmacology · 2019Review
- Biomarker-Drug and Liquid Biopsy Co-development for Disease Staging and Targeted Therapy: Cornerstones for Alzheimer's Precision Medicine and Pharmacology.Frontiers in pharmacology · 2019Article
- Predicting parkinsonism side-effects of antipsychotic polypharmacy prescribed in secondary mental healthcare.Journal of psychopharmacology (Oxford, England) · 2018Article
- Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology.CPT: pharmacometrics & systems pharmacology · 2018Article
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3 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
The current treatment of Parkinson's disease with dopamine-centric approaches such as L-DOPA and dopamine agonists, although very successful, is in need of alternative treatment strategies, both in terms of disease modification and symptom management. Various non-dopaminergic treatment approaches did not result in a clear clinical benefit, despite showing a clear effect in preclinical animal models. In addition, polypharmacy is common, sometimes leading to unintended effects on non-motor cognitive and psychiatric symptoms. To explore novel targets for symptomatic treatment and possible synergistic pharmacodynamic effects between different drugs, we developed a computer-based Quantitative Systems Pharmacology (QSP) platform of the closed cortico-striatal-thalamic-cortical basal ganglia loop of the dorsal motor circuit. This mechanism-based simulation platform is based on the known neuro-anatomy and neurophysiology of the basal ganglia and explicitly incorporates domain expertise in a formalized way. The calculated beta/gamma power ratio of the local field potential in the subthalamic nucleus correlates well (R (2) = 0.71) with clinically observed extra-pyramidal symptoms triggered by antipsychotics during schizophrenia treatment (43 drug-dose combinations). When incorporating Parkinsonian (PD) pathology and reported compensatory changes, the computer model suggests a major increase in b/g ratio (corresponding to bradykinesia and rigidity) from a dopamine depletion of 70% onward. The correlation between the outcome of the QSP model and the reported changes in UPDRS III Motor Part for 22 placebo-normalized drug-dose combinations is R (2) = 0.84. The model also correctly recapitulates the lack of clinical benefit for perampanel, MK-0567 and flupirtine and offers a hypothesis for the translational disconnect. Finally, using human PET imaging studies with placebo response, the computer model predicts well the placebo response for chronic treatment, but not for acute treatment in PD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.