The integrated use of pharmacokinetic and pharmacodynamic models for the definition of breakpoints

Infection
H Stass, A Dalhoff

Abstract

For fluoroquinolones AUC/MIC ratios are known to correlate with clinical outcomes for patients suffering from respiratory tract infections (RTI) and complicated skin and skin structure infections (cSSSI). This paper describes the results of a population PK/PD analysis followed by Monte Carlo simulations to estimate clinical outcome and the microbiological breakpoints for a 400 mg once-daily moxifloxacin (MFX) treatment schedule. Based on PK data from 416 subjects, a non-compartmental population PK model was developed first to describe the expected exposure (AUC) distribution in humans. Height and gender were the main population covariates with moderate influence on PK variability. Albumin, bilirubin, and creatinine clearance (as derived from serum creatinine according to Cockroft and Gault) had a mild effect on AUC. Residual unexplained variability of AUC was low (13.1%). To describe the PD function the MIC distribution pattern of more than 3,000 isolates of S. pneumoniae as the representative pathogen for RTI (MIC90, range: 0.125; 0.006-4 mg/l) was built into the population PK/PD model for RTI, while 126 isolates of methicillin-susceptible Staphylococcus aureus strains (MIC90, range: 0.125; 0.03-4 mg/l) were the basis for the ...Continue Reading

Citations

Sep 28, 2010·European Journal of Clinical Pharmacology·Jolanta Majcher-PeszynskaUNKNOWN Moxifloxacin-DFI Study Group
Jul 7, 2011·The Journal of Antimicrobial Chemotherapy·Martin G KeesThomas Horbach
Oct 12, 2011·The Journal of Antimicrobial Chemotherapy·Julie De SmetKoen Boussery
Sep 2, 2010·Antimicrobial Agents and Chemotherapy·Julien PoissyNicolas Veziris
Mar 12, 2013·Expert Review of Clinical Pharmacology·Ashit TrivediBernd Meibohm
Jun 15, 2007·Infectious Disease Clinics of North America·Itzhak Brook
Dec 10, 2013·British Journal of Clinical Pharmacology·Pieter ColinKoen Boussery
Jul 16, 2008·Journal of Infection and Chemotherapy : Official Journal of the Japan Society of Chemotherapy·Kazuro IkawaTaijiro Sueda

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