2007
DOI: 10.1128/aac.00065-07
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Evaluation of Tigecycline Penetration into Colon Wall Tissue and Epithelial Lining Fluid Using a Population Pharmacokinetic Model and Monte Carlo Simulation

Abstract: The objective of these analyses was to assess the penetration of tigecycline into colon wall tissue and epithelial lining fluid (ELF). The analyses included data from subjects without infection (phase 1) and patients with intra-abdominal infections (phase 2/3). Steady-state serum samples were collected from all subjects/ patients (n ‫؍‬ 577), while colon wall specimens (n ‫؍‬ 23) and ELF specimens (n ‫؍‬ 30) were obtained from subjects without infection. Tissue and serum data were simultaneously comodeled by u… Show more

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Cited by 35 publications
(18 citation statements)
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“…However, this experiment simulated a higher concentration of tigecycline than those used in our model, and that concentration was maintained over the entire course of the experiment. Clearly, this is not the concentration-time profile exhibited by tigecycline administered clinically at a dose of 50 mg every 12 h, even in the ELF (12,39,44). To achieve an fAUC exposure in ELF of 3.1 g-h/ml, our model simulated a steady-state tigecycline peak concentration of 0.57 g/ml, followed rapidly by an exponential decline in the concentration to approximately 0.21 g/ml, which was then maintained for the 12-h dosing interval (Fig.…”
Section: Discussionmentioning
confidence: 99%
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“…However, this experiment simulated a higher concentration of tigecycline than those used in our model, and that concentration was maintained over the entire course of the experiment. Clearly, this is not the concentration-time profile exhibited by tigecycline administered clinically at a dose of 50 mg every 12 h, even in the ELF (12,39,44). To achieve an fAUC exposure in ELF of 3.1 g-h/ml, our model simulated a steady-state tigecycline peak concentration of 0.57 g/ml, followed rapidly by an exponential decline in the concentration to approximately 0.21 g/ml, which was then maintained for the 12-h dosing interval (Fig.…”
Section: Discussionmentioning
confidence: 99%
“…Although tigecycline exposures alone resulted in regrowth of the five KPC isolates studied, tigecycline did delay regrowth by approximately 18 h. The lack of effect in this in vitro pharmacodynamic model was disconcerting given the fact that tigecycline has been used clinically against KPC-producing K. pneumoniae, with success, in some reports (27,45). While in vitro modeling attempts to simulate the effect of the antibiotic at achievable concentrations at the site of infection and may be preferable to checkerboard or time-kill studies that analyze only single drug concentrations, it still cannot mimic the contributions of the host immune system, nor can we simulate all scenarios of the extensive variability in ELF penetration portrayed by tigecycline (39). We speculate that these differences likely account for the discrepancy between our observations with tigecycline and what has been demonstrated in case reports.…”
Section: Discussionmentioning
confidence: 99%
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“…Third, in the case of the penetration of anti-TB drugs into ELF, some studies have utilized only one or two ELF sampling time points. The penetration of drug from serum to ELF is a function of time, and the concentration-time profile of antibiotic in blood and ELF may vary substantially in a strongly nonlinear fashion based on lag, i.e., hysteresis (66,87). Thus, examination of concentrations at a single time point in ELF (or any other PK compartment for that matter), as was the case for the published data we used for Monte Carlo simulations, may introduce imprecision.…”
Section: Limitationsmentioning
confidence: 99%