A whole-body physiologically based pharmacokinetic (WB-PBPK) model of ciprofloxacin: a step towards predicting bacterial killing at sites of infection

Journal of Pharmacokinetics and Pharmacodynamics, Aug 2016

The purpose of this study was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model for ciprofloxacin for ICU patients, based on only plasma concentration data. In a next step, tissue and organ concentration time profiles in patients were predicted using the developed model. The WB-PBPK model was built using a non-linear mixed effects approach based on data from 102 adult intensive care unit patients. Tissue to plasma distribution coefficients (Kp) were available from the literature and used as informative priors. The developed WB-PBPK model successfully characterized both the typical trends and variability of the available ciprofloxacin plasma concentration data. The WB-PBPK model was thereafter combined with a pharmacokinetic–pharmacodynamic (PKPD) model, developed based on in vitro time-kill data of ciprofloxacin and Escherichia coli to illustrate the potential of this type of approach to predict the time-course of bacterial killing at different sites of infection. The predicted unbound concentration–time profile in extracellular tissue was driving the bacterial killing in the PKPD model and the rate and extent of take-over of mutant bacteria in different tissues were explored. The bacterial killing was predicted to be most efficient in lung and kidney, which correspond well to ciprofloxacin’s indications pneumonia and urinary tract infections. Furthermore, a function based on available information on bacterial killing by the immune system in vivo was incorporated. This work demonstrates the development and application of a WB-PBPK–PD model to compare killing of bacteria with different antibiotic susceptibility, of value for drug development and the optimal use of antibiotics .

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A whole-body physiologically based pharmacokinetic (WB-PBPK) model of ciprofloxacin: a step towards predicting bacterial killing at sites of infection

A whole-body physiologically based pharmacokinetic (WB-PBPK) model of ciprofloxacin: a step towards predicting bacterial killing at sites of infection Muhammad W. Sadiq 0 1 2 3 4 5 Elisabet I. Nielsen 0 1 2 3 4 5 Dalia Khachman 0 1 2 3 4 5 Jean-Marie Conil 0 1 2 3 4 5 Bernard Georges 0 1 2 3 4 5 Georges Houin 0 1 2 3 4 5 Celine M. Laffont 0 1 2 3 4 5 Mats O. Karlsson 0 1 2 3 4 5 Lena E. Friberg 0 1 2 3 4 5 0 INRA , Toxalim, Toulouse , France 1 Department of Pharmaceutical Biosciences, Uppsala University , Box 591, 75124 Uppsala , Sweden 2 & Lena E. Friberg 3 Pole d'Anesthesie-Reanimation, Hopital Rangueil , Toulouse , France 4 Laboratoire de Pharmacocinetique et Toxicologie Clinique, Hospital Purpan, Institut Federatif de Biologie , Toulouse , France 5 Universite de Toulouse , Toulouse , France The purpose of this study was to develop a whole-body physiologically based pharmacokinetic (WBPBPK) model for ciprofloxacin for ICU patients, based on only plasma concentration data. In a next step, tissue and organ concentration time profiles in patients were predicted using the developed model. The WB-PBPK model was built using a non-linear mixed effects approach based on data from 102 adult intensive care unit patients. Tissue to plasma distribution coefficients (Kp) were available from the literature and used as informative priors. The developed WB-PBPK model successfully characterized both the typical trends and variability of the available ciprofloxacin plasma concentration data. The WB-PBPK model was thereafter combined with a pharmacokinetic-pharmacodynamic (PKPD) model, developed based on in vitro timekill data of ciprofloxacin and Escherichia coli to illustrate the potential of this type of approach to predict the timecourse of bacterial killing at different sites of infection. The predicted unbound concentration-time profile in extracellular tissue was driving the bacterial killing in the PKPD model and the rate and extent of take-over of mutant bacteria in different tissues were explored. The bacterial killing was predicted to be most efficient in lung and kidney, which correspond well to ciprofloxacin's indications pneumonia and urinary tract infections. Furthermore, a function based on available information on bacterial killing by the immune system in vivo was incorporated. This work demonstrates the development and application of a WBPBPK-PD model to compare killing of bacteria with different antibiotic susceptibility, of value for drug development and the optimal use of antibiotics . Physiologically-based pharmacokinetic; Antibiotic; Modeling; Bacterial infection; Pharmacokinetic-pharmacodynamic; Fluoroquinolone; Informative priors; NONMEM - CVMD iMED, DMPK, Astrazeneca, Mo¨lndal, Sweden Introduction The time-course of the distribution of an antibiotic into an infected tissue can be of critical importance for successful therapy of the infection. Based on the physicochemical properties of a drug and its interaction with different transporters, the rate and extent of distribution differs between tissues [ 1, 2 ]. Sub-therapeutic exposure of an antibiotic at the site of infection may not only result in treatment failure but also emergence of resistance, while higher than therapeutic levels may result in toxicity. Typically, when pharmacokinetic–pharmacodynamic (PKPD) relationships of antibiotics are evaluated, the bacterial killing is assumed to be dependent on a summary variable of the pharmacokinetic (PK) profile in plasma (e.g. peak plasma concentration, area under the plasma concentration–time curve or time period that the plasma concentration exceeds the MIC) [3]. Using the plasma concentration to monitor and drive the antimicrobial effect is practical, but the plasma concentration is not always reflecting the biophase antimicrobial concentration. In addition, the dynamics of the concentrations during the initial treatment period may be critical for a successful outcome. Overlooking that the time-course of concentration in the infected tissue is what is driving the bacterial killing could lead to suboptimal dosing in patients. In the era of increasing antibiotic resistance, new therapies need to be explored for previously untested types of infections. To efficiently get an idea of the potential of these therapies it is important to understand the distribution and exposure time profile of antimicrobials in the target tissues. Whole body physiologically based pharmacokinetic (WB-PBPK) models encompass the distinct feature of describing the distribution of a drug in different tissues and blood in a mechanistic way [ 4–6 ]. Such models have long been used in toxicological risk assessment for different environmental contaminants [ 7 ]. In recent years they have been increasingly applied in different stages of drug discovery and development, and also recognized by regulatory authorities as a valuable tool [ 1, 7–12 ]. WB-PBPK models require two types of input data; physiological paramete (...truncated)


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Muhammad W. Sadiq, Elisabet I. Nielsen, Dalia Khachman, Jean-Marie Conil, Bernard Georges, Georges Houin, Celine M. Laffont, Mats O. Karlsson, Lena E. Friberg. A whole-body physiologically based pharmacokinetic (WB-PBPK) model of ciprofloxacin: a step towards predicting bacterial killing at sites of infection, Journal of Pharmacokinetics and Pharmacodynamics, 2017, pp. 69-79, Volume 44, Issue 2, DOI: 10.1007/s10928-016-9486-9