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Pkpd antibiotics

M J E Brill, A N Kristoffersson, C Zhao, E I Nielsen, L E Friberg
BACKGROUND: Deriving suitable dosing regimens for antibiotic combination therapy poses several challenges as the drug interaction can be highly complex, the traditional pharmacokinetic-pharmacodynamic (PKPD) index methodology cannot be applied straightforwardly, and exploring all possible dose combinations is unfeasible. Therefore, semi-mechanistic PKPD models developed based on in vitro single and combination experiments can be valuable to suggest suitable combination dosing regimens...
December 8, 2017: Clinical Microbiology and Infection
David D Khan, Pernilla Lagerbäck, Christer Malmberg, Anders N Kristoffersson, Erik Wistrand-Yuen, Cao Sha, Otto Cars, Dan I Andersson, Diarmaid Hughes, Elisabet I Nielsen, Lena E Friberg
Predicting competition between antibiotic-susceptible wild-type (WT) and less susceptible mutant (MT) bacteria is valuable for understanding how drug concentrations influence the emergence of resistance. Pharmacokinetic/pharmacodynamic (PK/PD) models predicting the rate and extent of takeover of resistant bacteria during different antibiotic pressures can thus be a valuable tool in improving treatment regimens. The aim of this study was to evaluate a previously developed mechanism-based PK/PD model for its ability to predict in vitro mixed-population experiments with competition between Escherichia coli (E...
March 2018: International Journal of Antimicrobial Agents
Elisabet I Nielsen, David D Khan, Sha Cao, Ulrika Lustig, Diarmaid Hughes, Dan I Andersson, Lena E Friberg
Background: Pharmacokinetic/pharmacodynamic (PKPD) models developed based on data from in vitro time-kill experiments have been suggested to contribute to more efficient drug development programmes and better dosing strategies for antibiotics. However, for satisfactory predictions such models would have to show good extrapolation properties. Objectives: To evaluate if a previously described mechanism-based PKPD model was able also to predict drug efficacy for higher bacterial densities and across bacterial strains...
November 1, 2017: Journal of Antimicrobial Chemotherapy
Muhammad W Sadiq, Elisabet I Nielsen, Dalia Khachman, Jean-Marie Conil, Bernard Georges, Georges Houin, Celine M Laffont, Mats O Karlsson, Lena E Friberg
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...
April 2017: Journal of Pharmacokinetics and Pharmacodynamics
David D Khan, Lena E Friberg, Elisabet I Nielsen
OBJECTIVES: For antibiotics, extensive animal PKPD studies are often performed to evaluate the PK/PD driver for subsequent use when recommending dosing regimens. The aim of this work was to evaluate a PKPD model, developed based on in vitro time-kill data for colistin, in predicting the relationships between PK/PD indices and the bacterial killing previously observed in mice. METHODS: An in silico PKPD model for Pseudomonas aeruginosa exposed to colistin was previously developed based on static in vitro time-kill data...
July 2016: Journal of Antimicrobial Chemotherapy
Anders N Kristoffersson, Pascale David-Pierson, Neil J Parrott, Olaf Kuhlmann, Thierry Lave, Lena E Friberg, Elisabet I Nielsen
PURPOSE: Antibiotic dose predictions based on PK/PD indices rely on that the index type and magnitude is insensitive to the pharmacokinetics (PK), the dosing regimen, and bacterial susceptibility. In this work we perform simulations to challenge these assumptions for meropenem and Pseudomonas aeruginosa. METHODS: A published murine dose fractionation study was replicated in silico. The sensitivity of the PK/PD index towards experimental design, drug susceptibility, uncertainty in MIC and different PK profiles was evaluated...
May 2016: Pharmaceutical Research
Colette Calmelet, John Hotchkiss, Philip Crooke
A study of the process of pharmacokinetics-pharmacodynamics (PKPD) of antibiotics and their interaction with bacteria during peritoneal dialysis associated peritonitis (PDAP) is presented. We propose a mathematical model describing the evolution of bacteria population in the presence of antibiotics for different peritoneal dialysis regimens. Using the model along with experimental data, clinical parameters, and physiological values, we compute variations in PD fluid distributions, drug concentrations, and number of bacteria in peritoneal and extra-peritoneal cavities...
December 2014: Mathematical Biosciences and Engineering: MBE
Elisabet I Nielsen, Lena E Friberg
Pharmacokinetic-pharmacodynamic (PKPD) modeling and simulation has evolved as an important tool for rational drug development and drug use, where developed models characterize both the typical trends in the data and quantify the variability in relationships between dose, concentration, and desired effects and side effects. In parallel, rapid emergence of antibiotic-resistant bacteria imposes new challenges on modern health care. Models that can characterize bacterial growth, bacterial killing by antibiotics and immune system, and selection of resistance can provide valuable information on the interactions between antibiotics, bacteria, and host...
July 2013: Pharmacological Reviews
Elisabet I Nielsen, Otto Cars, Lena E Friberg
A pharmacokinetic-pharmacodynamic (PKPD) model that characterizes the full time course of in vitro time-kill curve experiments of antibacterial drugs was here evaluated in its capacity to predict the previously determined PK/PD indices. Six drugs (benzylpenicillin, cefuroxime, erythromycin, gentamicin, moxifloxacin, and vancomycin), representing a broad selection of mechanisms of action and PK and PD characteristics, were investigated. For each drug, a dose fractionation study was simulated, using a wide range of total daily doses given as intermittent doses (dosing intervals of 4, 8, 12, or 24 h) or as a constant drug exposure...
October 2011: Antimicrobial Agents and Chemotherapy
Kenny J Watson, William P Gorczyca, John Umland, Ying Zhang, Xian Chen, Sunny Z Sun, Bernard Fermini, Mark Holbrook, Piet H Van Der Graaf
INTRODUCTION: Delayed ventricular repolarisation is manifested electrocardiographically in a prolongation of the QT interval. Such prolongation can lead to potentially fatal Torsades de Pointes. Moxifloxacin is a fluoroquinolone antibiotic which has been associated with QT prolongation and, as a result, is recommended by the regulatory authorities as a positive control in thorough QT studies performed to evaluate the potential of new chemical entities to induce QT prolongation in humans...
May 2011: Journal of Pharmacological and Toxicological Methods
Elisabet I Nielsen, Otto Cars, Lena E Friberg
We have previously described a general semimechanistic pharmacokinetic-pharmacodynamic (PKPD) model that successfully characterized the time course of antibacterial effects seen in bacterial cultures when exposed to static concentrations of five antibacterial agents of different classes. In this PKPD model, the total bacterial population was divided into two subpopulations, one growing drug-susceptible population and one resting drug-insensitive population. The drug effect was included as an increase in the killing rate of the drug-susceptible bacteria with a maximum-effect (E(max)) model...
April 2011: Antimicrobial Agents and Chemotherapy
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