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 using the BigNPAG program, and a four-compartment, open model with zero-order intravenous input and first-order elimination was employed. To examine the full range of tissue penetration and the associated probabilities of occurrence, a 9,999-subject Monte Carlo simulation was performed with two outputs, one for ELF penetration and one for colon wall tissue penetration. Data were well fit using models described above, with all r 2 values above 0.95. For subjects without infection, the median (5th and 95th percentiles) colon wall and ELF penetration ratios were 1.73 (0.160 and 199) and 1.15 (0.561 and 5.23), respectively. Simulation results predict that tissue penetration varies considerably and likely explain unexpected clinical outcomes for those patients infected with strains at margins of the MIC distribution.

In Vitro Pharmacodynamics of Simulated Pulmonary Exposures of Tigecycline Alone and in Combination against Klebsiella pneumoniae Isolates Producing a KPC Carbapenemase

“…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.…”

“…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.…”

“…Steady-state serum concentrations were calculated using mean pharmacokinetic parameters from this study and a two-compartment model in WinNonLin Professional, version 5.0.1 (Pharsight Corporation, Mountain View, CA). To estimate the pulmonary exposure of tigecycline, and because the pharmacodynamic parameter that drives efficacy for tigecycline is AUC/MIC, serum concentrations were increased proportionally to achieve an AUC that was approximately 115% of that in serum (12,39). This yielded a 12-h target AUC of approximately 3.1 g-h/ml.…”

“…1A (44). For these calculations, we assumed that the median area under the curve (AUC) for ELF over the dosing interval was 115% of that in serum, as observed in a population pharmacokinetic analysis of ELF data from healthy volunteers (39). Steady-state serum concentrations were calculated using mean pharmacokinetic parameters from this study and a two-compartment model in WinNonLin Professional, version 5.0.1 (Pharsight Corporation, Mountain View, CA).…”

An Oracle: Antituberculosis Pharmacokinetics-Pharmacodynamics, Clinical Correlation, and Clinical Trial Simulations To Predict the Future

“…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.…”