ArticleJournal of pharmacokinetics and pharmacodynamics2021
Lumbar cerebrospinal fluid-to-brain extracellular fluid surrogacy is context-specific: insights from LeiCNS-PK3.0 simulations.
Article in Journal of pharmacokinetics and pharmacodynamics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Intranasal drug delivery to the brain for neurodegenerative diseases: Current efforts and challenges in delivery platforms and modeling.Advanced drug delivery reviews · 2026Review
- Defining Safe and Effective Cefazolin Dosing Regimens for MSSA Infections in the CNS: Leveraging Sparse Real-World Data and PBPK Modeling.European journal of drug metabolism and pharmacokinetics · 2026Article
- Simulation-based assessment of the P-glycoprotein expression-activity relationship shows a drug and system dependency.Journal of pharmacokinetics and pharmacodynamics · 2026Article
- Revisiting Acyclovir Dosing for Adult Viral Encephalitis Using a Full Bayesian LeiCNS PBPK Modeling Approach.Clinical pharmacokinetics · 2025Article
- Reliability of in vitro data for the mechanistic prediction of brain extracellular fluid pharmacokinetics of P-glycoprotein substrates in vivo; are we scaling correctly?Journal of pharmacokinetics and pharmacodynamics · 2025Article
- Prediction of the Extent of Blood-Brain Barrier Transport Using Machine Learning and Integration into the LeiCNS-PK3.0 Model.Pharmaceutical research · 2025Article
- Do P-glycoprotein-mediated drug-drug interactions at the blood-brain barrier impact morphine brain distribution?Journal of pharmacokinetics and pharmacodynamics · 2025Article
- Active CNS delivery of oxycodone in healthy and endotoxemic pigs.Fluids and barriers of the CNS · 2024Article
- Predictions of Bedaquiline Central Nervous System Exposure in Patients with Tuberculosis Meningitis Using Physiologically based Pharmacokinetic Modeling.Clinical pharmacokinetics · 2024Article
- CNS Viral Infections-What to Consider for Improving Drug Treatment: A Plea for Using Mathematical Modeling Approaches.CNS drugs · 2024Review
- Interspecies Brain PBPK Modeling Platform to Predict Passive Transport through the Blood-Brain Barrier and Assess Target Site Disposition.Pharmaceutics · 2024Article
- Active Uptake of Oxycodone at Both the Blood-Cerebrospinal Fluid Barrier and The Blood-Brain Barrier without Sex Differences: A Rat Microdialysis Study.Pharmaceutical research · 2023Article
- Using the LeiCNS-PK3.0 Physiologically-Based Pharmacokinetic Model to Predict Brain Extracellular Fluid Pharmacokinetics in Mice.Pharmaceutical research · 2023Article
- Population Pharmacokinetic Analysis of Rifampicin in Plasma, Cerebrospinal Fluid, and Brain Extracellular Fluid in South African Children with Tuberculous Meningitis.Antimicrobial agents and chemotherapy · 2023Article
- Physiologically Based Modelling Framework for Prediction of Pulmonary Pharmacokinetics of Antimicrobial Target Site Concentrations.Clinical pharmacokinetics · 2022Article
- Revisiting Cerebrospinal Fluid Flow Direction and Rate in Physiologically Based Pharmacokinetic Model.Pharmaceutics · 2022Article
- Unbound Brain-to-Plasma Partition Coefficient, KPharmaceutical research · 2022Article
- Drug Distribution in Brain and Cerebrospinal Fluids in Relation to ICPharmaceutical research · 2022Article
- The Extension of the LeiCNS-PK3.0 Model in Combination with the "Handshake" Approach to Understand Brain Tumor Pathophysiology.Pharmaceutical research · 2022Article
- Understanding the Blood-Brain Barrier and Beyond: Challenges and Opportunities for Novel CNS Therapeutics.Clinical pharmacology and therapeutics · 2022Review
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Authors and funding
4 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Predicting brain pharmacokinetics is critical for central nervous system (CNS) drug development yet difficult due to ethical restrictions of human brain sampling. CNS pharmacokinetic (PK) profiles are often altered in CNS diseases due to disease-specific pathophysiology. We previously published a comprehensive CNS physiologically-based PK (PBPK) model that predicted the PK profiles of small drugs at brain and cerebrospinal fluid compartments. Here, we improved this model with brain non-specific binding and pH effect on drug ionization and passive transport. We refer to this improved model as Leiden CNS PBPK predictor V3.0 (LeiCNS-PK3.0). LeiCNS-PK3.0 predicted the unbound drug concentrations of brain ECF and CSF compartments in rats and humans with less than two-fold error. We then applied LeiCNS-PK3.0 to study the effect of altered cerebrospinal fluid (CSF) dynamics, CSF volume and flow, on brain extracellular fluid (ECF) pharmacokinetics. The effect of altered CSF dynamics was simulated using LeiCNS-PK3.0 for six drugs and the resulting drug exposure at brain ECF and lumbar CSF were compared. Simulation results showed that altered CSF dynamics changed the CSF PK profiles, but not the brain ECF profiles, irrespective of the drug's physicochemical properties. Our analysis supports the notion that lumbar CSF drug concentration is not an accurate surrogate of brain ECF, particularly in CNS diseases. Systems approaches account for multiple levels of CNS complexity and are better suited to predict brain PK.
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