ArticleAntibiotics (Basel, Switzerland)2022
A Minimal Physiologically Based Pharmacokinetic Model to Characterize CNS Distribution of Metronidazole in Neuro Care ICU Patients.
Article in Antibiotics (Basel, Switzerland), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers, 1 of them a synthesis that pooled it.
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Who cites it
3 citing papers in PubMed, 1 synthesis or guideline pooled it, 8 citations in OpenAlex.
- Metronidazole Pharmacokinetics Across Species: Meta-Analysis Integrating Allometric Scaling and Minimal Physiologically-Based Pharmacokinetic Modeling.The AAPS journal · 2025Pooled it
- Effect of traumatic brain injury on the trough concentration of linezolid in patients with hospital-acquired pneumonia.Scientific reports · 2025Article
- Utility of Minimal Physiologically Based Pharmacokinetic Models for Assessing Fractional Distribution, Oral Absorption, and Series-Compartment Models of Hepatic Clearance.Drug metabolism and disposition: the biological fate of chemicals · 2023Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Understanding antibiotic concentration-time profiles in the central nervous system (CNS) is crucial to treat severe life-threatening CNS infections, such as nosocomial ventriculitis or meningitis. Yet CNS distribution is likely to be altered in patients with brain damage and infection/inflammation. Our objective was to develop a physiologically based pharmacokinetic (PBPK) model to predict brain concentration-time profiles of antibiotics and to simulate the impact of pathophysiological changes on CNS profiles. A minimal PBPK model consisting of three physiological brain compartments was developed from metronidazole concentrations previously measured in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) of eight brain-injured patients. Volumes and blood flows were fixed to their physiological value obtained from the literature. Diffusion clearances characterizing transport across the blood-brain barrier and blood-CSF barrier were estimated from system- and drug-specific parameters and were confirmed from a Caco-2 model. The model described well unbound metronidazole pharmacokinetic profiles in plasma, ECF and CSF. Simulations showed that with metronidazole, an antibiotic with extensive CNS distribution simply governed by passive diffusion, pathophysiological alterations of membrane permeability, brain ECF volume or cerebral blood flow would have no effect on ECF or CSF pharmacokinetic profiles. This work will serve as a starting point for the development of a new PBPK model to describe the CNS distribution of antibiotics with more limited permeability for which pathophysiological conditions are expected to have a greater effect.
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