PBPK model of methotrexate in cerebrospinal fluid ventricles using a combined microdialysis and MRI acquisition
Nolwenn Brandhonneur1, Fanny Noury2, Arnaud Bruyère1
1Université de Rennes 1, Rennes, France; Laboratoire de Pharmacie Galénique, Biopharmacie et Pharmacie Clinique, IRSET U1085, Rennes, France.
Abstract:
The objective of the study was to evaluate the distribution of methotrexate (MTX) in cerebrospinal fluid (CSF) lateral ventricles and in cisterna magna after 3rd intraventricular CSF administration in a rabbit model. MTX or gadolinium chelate (Gd-DOTA) was administered in the 3rd ventricle with a local microdialysis to study the pharmacokinetics at the site of administration and with a simultaneous magnetic resonance imaging (MRI) acquisition in the 3rd ventricle, the lateral ventricles and in the cisterna magna. A specific CSF Physiologically Based Pharmacokinetic (PBPK) model was then extrapolated for MTX from Gd-DOTA data. The relative contribution of elimination and distribution processes to the overall disposition of MTX and Gd-DOTA in the 3rd ventricle was similar (i.e., around 60% for CLE and 40% for CLI) suggesting that Gd-DOTA was a suitable surrogate marker for MTX disposition in ventricular CSF. The PBPK predictions for MTX both in CSF of the 3rd ventricle and in plasma were in accordance with the in vivo results. The present study showed that the combination of local CSF microdialysis with MRI acquisition of the brain ventricles and a PBPK model could be a useful methodology to estimate the drug diffusion within CSF ventricles after direct brain CSF administration. Such a methodology would be of interest to clinicians for a rationale determination and optimization of drug dosing parameters in the treatment of leptomeningeal metastases.
Insights
This study shows that gadolinium chelate (Gd-DOTA) can predict methotrexate (MTX) distribution in cerebrospinal fluid (CSF) after intraventricular administration. This method aids in optimizing drug dosing for brain metastases.
Area of Science:
- Pharmacokinetics
- Neuroscience
- Medical Imaging
Background:
- Accurate drug distribution in cerebrospinal fluid (CSF) is crucial for treating leptomeningeal metastases.
- Methotrexate (MTX) is a key chemotherapeutic agent, but its CSF pharmacokinetics require precise understanding.
- Direct intraventricular administration necessitates robust methods for evaluating drug disposition within the brain's ventricular system.
Purpose of the Study:
- To evaluate the distribution of methotrexate (MTX) in the CSF of lateral ventricles and cisterna magna after third intraventricular administration in a rabbit model.
- To assess the utility of gadolinium chelate (Gd-DOTA) as a surrogate marker for MTX distribution.
- To validate a physiologically based pharmacokinetic (PBPK) model for MTX in the CSF.
Main Methods:
- Administered MTX or Gd-DOTA into the third ventricle of rabbits.
- Utilized local microdialysis for pharmacokinetic analysis at the administration site.
- Performed simultaneous magnetic resonance imaging (MRI) of the ventricles and cisterna magna.
- Developed and extrapolated a CSF PBPK model from Gd-DOTA data for MTX.
Main Results:
- Gd-DOTA demonstrated similar distribution and elimination kinetics to MTX in the ventricular CSF, validating its use as a surrogate marker.
- The PBPK model accurately predicted MTX concentrations in both the third ventricle CSF and plasma.
- The combined approach of microdialysis, MRI, and PBPK modeling proved effective for assessing drug diffusion in CSF ventricles.
Conclusions:
- Gd-DOTA serves as a reliable surrogate for studying MTX pharmacokinetics in the ventricular CSF.
- The integrated methodology of microdialysis, MRI, and PBPK modeling is valuable for understanding drug distribution after intraventricular administration.
- This approach can inform rational drug dosing strategies for treating leptomeningeal metastases.
More Related Videos
05:43Real-Time Dynamic Collection of Hippocampal Extracellular Fluid from Conscious Rats Using a Microdialysis System
Published on: October 21, 2022
08:40Positron Emission Tomography Imaging for In Vivo Measuring of Myelin Content in the Lysolecithin Rat Model of Multiple Sclerosis
Published on: February 28, 2021
