title: Development of a Physiologically Based Pharmacokinetic Modelling Approach to Predict the Pharmacokinetics of Vancomycin in Critically Ill Septic Patients.
abstract: Sepsis is characterised by an excessive release of inflammatory mediators substantially affecting body composition and physiology, which can be further affected by intensive care management. Consequently, drug pharmacokinetics can be substantially altered. This study aimed to extend a whole-body physiologically based pharmacokinetic (PBPK) model for healthy adults based on disease-related physiological changes of critically ill septic patients and to evaluate the accuracy of this PBPK model using vancomycin as a clinically relevant drug.
  
  
  
  The literature was searched for relevant information on physiological changes in critically ill patients with sepsis, severe sepsis and septic shock. Consolidated information was incorporated into a validated PBPK vancomycin model for healthy adults. In addition, the model was further individualised based on patient data from a study including ten septic patients treated with intravenous vancomycin. Models were evaluated comparing predicted concentrations with observed patient concentration-time data.
  
  
  
  The literature-based PBPK model correctly predicted pharmacokinetic changes and observed plasma concentrations especially for the distribution phase as a result of a consideration of interstitial water accumulation. Incorporation of disease-related changes improved the model prediction from 55 to 88% within a threshold of 30% variability of predicted vs. observed concentrations. In particular, the consideration of individualised creatinine clearance data, which were highly variable in this patient population, had an influence on model performance.
  
  
  
  PBPK modelling incorporating literature data and individual patient data is able to correctly predict vancomycin pharmacokinetics in septic patients. This study therefore provides essential key parameters for further development of PBPK models and dose optimisation strategies in critically ill patients with sepsis.
authors.affiliation: Department of Clinical Pharmacy, Institute of Pharmaceutical and Medical Chemistry, University of Muenster, Corrensstrasse 48, 48149, Muenster, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Radke
authors.affiliation: Department of Pharmacy, University Hospital of Muenster, Muenster, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Horn
authors.affiliation: Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital of Muenster, Muenster, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Lanckohr
authors.affiliation: Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital of Muenster, Muenster, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Ellger
authors.affiliation: Systems Pharmacology CV, Bayer Technology Services GmbH, Leverkusen, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Meyer
authors.affiliation: Systems Pharmacology CV, Bayer Technology Services GmbH, Leverkusen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Eissing
authors.affiliation: Department of Clinical Pharmacy, Institute of Pharmaceutical and Medical Chemistry, University of Muenster, Corrensstrasse 48, 48149, Muenster, Germany. georg.hempel@uni-muenster.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Hempel
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D001798:Blood Proteins / Q000378:metabolism; D016638:Critical Illness; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006400:Hematocrit; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D018805:Sepsis / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D014640:Vancomycin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D001798:Blood Proteins; D014640:Vancomycin; D003577:Cytochrome P-450 Enzyme System