Defining the Role of Macrophages in Local Moxifloxacin Tissue Concentrations using Biopsy Data and Whole-Body Physiologically Based Pharmacokinetic Modelling
- 1 January 2009
- journal article
- Published by Springer Science and Business Media LLC in Clinical Pharmacokinetics
- Vol. 48 (3), 181-187
- https://doi.org/10.2165/00003088-200948030-00004
Abstract
Objective: This study used a whole-body physiologically based pharmacokinetic (WB-PBPK) model for moxifloxacin, plus in vitro and in vivo literature data on its interaction with macrophages, to interpret biopsy results generated from patients undergoing primarily colorectal surgery. Methods: A WB-PBPK model was developed using PK-Sim® software and refined using observed plasma profiles. The model was assessed by comparing predictions of unbound interstitial concentrations with in vivo data from a microdialysis study. Results: Incorporating in vitro data on the percentage volume of macrophages in a colorectal resection (8.1%) plus the in vivo kinetic and accumulation potential of moxifloxacin in macrophages into the WB-PBPK model, biopsy concentrations and kinetics were predicted and compared with observed data. The WB-PBPK model accurately described adipose and muscle interstitial unbound concentrations. The predicted biopsy concentrations (including interstitial, intracellular, vascular space and macrophages) were slightly greater than the observed values, although the kinetic (i.e. observed biopsy half-life = 21 hours) was similar to that of moxifloxacin in macrophages (20.8 hours) and thus similar to the predicted biopsy half-life. A reduction in the predicted biopsy concentrations to match the observed data required a decrease in the volume fraction of macrophages from 8.1% to 3.6%. Conclusion: When plasma concentrations are known, WB-PBPK is a method to determine interstitial and intracellular concentrations. In this study, integration of biopsy data with WB-PBPK allowed for generation and testing of hypotheses to determine the reason for the observed biopsy kinetics. This type of translational modelling may lead to a better understanding of the anti-infective pharmacokinetic/pharmacodynamic relationship.Keywords
This publication has 36 references indexed in Scilit:
- Cellular Accumulation and Activity of Quinolones in Ciprofloxacin-Resistant J774 MacrophagesAntimicrobial Agents and Chemotherapy, 2006
- Impaired Target Site Penetration of Vancomycin in Diabetic Patients following Cardiac SurgeryAntimicrobial Agents and Chemotherapy, 2006
- Factors influencing the intracellular activity of fluoroquinolones: a study using levofloxacin in a Staphylococcus aureus THP-1 monocyte modelJournal of Antimicrobial Chemotherapy, 2006
- Pharmacodynamic Evaluation of the Intracellular Activities of Antibiotics against Staphylococcus aureus in a Model of THP-1 MacrophagesAntimicrobial Agents and Chemotherapy, 2006
- Development and Evaluation of a Generic Physiologically Based Pharmacokinetic Model for ChildrenClinical Pharmacokinetics, 2006
- Tissue Penetration of Cefpodoxime and Cefixime in Healthy SubjectsThe Journal of Clinical Pharmacology, 2005
- MicrodialysisClinical Pharmacokinetics, 2005
- Impact of Neutropenia on Tissue Penetration of Moxifloxacin and Sparfloxacin in Infected MiceDrugs, 1999
- Distribution and Tissue Penetration of MoxifloxacinDrugs, 1999
- Some suggestions for measuring predictive performanceJournal of Pharmacokinetics and Biopharmaceutics, 1981