ArticleClinical cancer research : an official journal of the American Association for Cancer Research2024
Mechanistic Modeling of Intrathecal Chemotherapy Pharmacokinetics in the Human Central Nervous System.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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The trial behind it
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Who cites it
7 citing papers in PubMed, 9 citations in OpenAlex.
- Polatuzumab vedotin in CNS lymphoma: proof-of-concept study for blood-brain barrier penetration.Blood advances · 2025Article
- Point/Counterpoint: Intrathecal therapy for patients with leptomeningeal metastases from solid tumors.Neuro-oncology · 2025Article
- The Effect of Injection Parameters on Drug Distribution for Spinal Anesthesia: A Numerical Approach.Journal of clinical medicine · 2025Article
- Young rat vascular endothelial cells promote neurological recovery of stroke aged rat via HIF-1α.iScience · 2025Article
- SpatialCNS-PBPK: An R/Shiny Web-Based Application for Physiologically Based Pharmacokinetic Modeling of Spatial Pharmacokinetics in the Human Central Nervous System and Brain Tumors.CPT: pharmacometrics & systems pharmacology · 2025Article
- Mechanistic Modeling of Spatial Heterogeneity of Drug Penetration and Exposure in the Human Central Nervous System and Brain Tumors.Clinical pharmacology and therapeutics · 2025Article
- The multi-pathway treatment of flavonoids as natural compounds in neurological diseases: achievements, limitations, and prospects.Frontiers in neuroscience · 2025Review
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
purposeThe pharmacokinetics of intrathecally administered antibody or small-molecule drugs in the human central nervous system (CNS) remains poorly understood. This study aimed to provide mechanistic and quantitative perspectives on the CNS pharmacokinetics of intrathecal chemotherapy, by using a physiologically based pharmacokinetic (PBPK) modeling approach. EXPERIMENTAL
designA novel CNS PBPK model platform was developed and verified, which accounted for the human CNS general anatomy and physiologic processes governing drug distribution and disposition. The model was used to predict CNS pharmacokinetics of antibody (trastuzumab) and small-molecule drugs (methotrexate, abemaciclib, tucatinib) following intraventricular injection or intraventricular 24-hour infusion, and to assess the key determinants of drug penetration into the deep brain parenchyma.
resultsIntraventricularly administered antibody and small-molecule drugs exhibited distinct temporal and spatial distribution and disposition in human CNS. Both antibody and small-molecule drugs achieved supratherapeutic or therapeutic concentrations in the cerebrospinal fluid (CSF) compartments and adjacent brain tissue. While intrathecal small-molecule drugs penetrated the deep brain parenchyma to a negligible extent, intrathecal antibodies may achieve therapeutic concentrations in the deep brain parenchyma. Intraventricular 24-hour infusion enabled prolonged CNS exposure to therapeutically relevant concentrations while avoiding excessively high and potentially neurotoxic drug concentrations.
conclusionsCNS PBPK modeling, in line with available clinical efficacy data, confirms the therapeutic value of intrathecal chemotherapy with antibody or small-molecule drugs for treating neoplastic meningitis and warrants further clinical investigation of intrathecal antibody drugs to treat brain parenchyma tumors. Compared with intraventricular injection, intraventricular 24-hour infusion may mitigate neurotoxicity while retaining potential efficacy.
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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.