Population Pharmacokinetic Analysis for Plasma and Epithelial Lining Fluid Ceftolozane/Tazobactam Concentrations in Patients With Ventilated Nosocomial Pneumonia

ABSTRACT Telavancin is an investigational bactericidal lipoglycopeptide with a multifunctional mechanism of action, as demonstrated against methicillin-resistant Staphylococcus aureus. While the plasma pharmacokinetics have been described, the extent of the penetration of the drug into the lung, measured by the epithelial lining fluid (ELF), remains unknown. Population modeling and Monte Carlo simulation were employed to estimate the penetration of telavancin into ELF. Plasma and ELF pharmacokinetic data were obtained from 20 healthy volunteers, and the pharmacokinetic samples were assayed by a validated liquid chromatography-tandem mass spectrometry technique. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer. The model parameters were identified in a population pharmacokinetic analysis (BigNPAG). Monte Carlo simulation of 9,999 subjects was performed to calculate the ELF/plasma penetration ratios by estimating the area under the concentration-time curve (AUC) for the drug in ELF (AUCELF) and for the free drug in plasma (free AUCplasma) from zero to infinity after a single dose. After the Bayesian step, the overall fits of the model to the data were good, and plots of predicted versus observed concentrations in plasma and ELF showed slopes and intercepts very close to the ideal values of 1.0 and 0.0, respectively. The median AUCELF/free AUCplasma penetration ratio was 0.73, and the 25th and 75th percentile value ratios were 0.43 and 1.24, respectively. In uninfected lung tissue, the median AUCELF is approximately 75% of the free AUCplasma.

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Use of Population Pharmacokinetic Modeling and Monte Carlo Simulation To Describe the Pharmacodynamic Profile of Cefditoren in Plasma and Epithelial Lining Fluid

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00736-06 ◽

2007 ◽

Vol 52 (6) ◽

pp. 1945-1951 ◽

Cited By ~ 13

Author(s):

Thomas P. Lodise ◽

Martina Kinzig-Schippers ◽

George L. Drusano ◽

Ulrich Loos ◽

Friedrich Vogel ◽

...

Keyword(s):

Monte Carlo Simulation ◽

Monte Carlo ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Epithelial Lining ◽

Target Attainment ◽

Epithelial Lining Fluid ◽

Dosing Interval ◽

Pharmacodynamic Profile

ABSTRACT Cefditoren is a broad-spectrum, oral cephalosporin that is highly active against clinically relevant respiratory tract pathogens, including multidrug-resistant Streptococcus pneumoniae. This study described its pharmacodynamic profile in plasma and epithelial lining fluid (ELF). Plasma and ELF pharmacokinetic data were obtained from 24 patients under fasting conditions. Cefditoren and urea concentrations were determined in plasma and bronchoalveolar lavage fluid by liquid chromatography-tandem mass spectrometry. Concentration-time profiles in plasma and ELF were modeled using a model with three disposition compartments and first-order absorption, elimination, and transfer. Pharmacokinetic parameters were identified in a population pharmacokinetic analysis (big nonparametric adaptive grid with adaptive γ). Monte Carlo simulation (9,999 subjects) was performed with the ADAPT II program to estimate the probability of target attainment at which the free-cefditoren plasma concentrations (88%) protein binding and total ELF concentrations exceeded the MIC for 33% of the dosing interval for 400 mg cefditoren given orally every 12 h. After the Bayesian step, the overall fits of the model to the data were good, and plots of predicted versus observed concentrations for plasma and ELF showed slopes and intercepts very close to the ideal values of 1.0 and 0.0, respectively. In the plasma probability of target attainment analysis, the probability of achieving a time for which free, or unbound, plasma concentration exceeds the MIC of the organism for 33% of the dosing interval was <80% for a MIC of >0.06 mg/liter. Similar to plasma, the probability of achieving a time above the MIC of 33% was <80% for MIC of >0.06 mg/liter in ELF. Cefditoren was found to have a low probability of achieving a bacteriostatic effect against MICs of >0.06 mg/liter, which includes most S. pneumoniae isolates with intermediate susceptibility to penicillin, when given in the fasting state in both plasma and ELF.

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Levofloxacin Penetration into Epithelial Lining Fluid as Determined by Population Pharmacokinetic Modeling and Monte Carlo Simulation

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.2.586-589.2002 ◽

2002 ◽

Vol 46 (2) ◽

pp. 586-589 ◽

Cited By ~ 50

Author(s):

G. L. Drusano ◽

S. L. Preston ◽

M. H. Gotfried ◽

L. H. Danziger ◽

K. A. Rodvold

Keyword(s):

Monte Carlo Simulation ◽

Monte Carlo ◽

Population Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Lung Pathology ◽

Epithelial Lining ◽

Epithelial Lining Fluid ◽

Mean Values ◽

Population Mean

ABSTRACT Levofloxacin was administered orally to steady state to volunteers randomly in doses of 500 and 750 mg. Plasma and epithelial lining fluid (ELF) samples were obtained at 4, 12, and 24 h after the final dose. All data were comodeled in a population pharmacokinetic analysis employing BigNPEM. Penetration was evaluated from the population mean parameter vector values and from the results of a 1,000-subject Monte Carlo simulation. Evaluation from the population mean values demonstrated a penetration ratio (ELF/plasma) of 1.16. The Monte Carlo simulation provided a measure of dispersion, demonstrating a mean ratio of 3.18, with a median of 1.43 and a 95% confidence interval of 0.14 to 19.1. Population analysis with Monte Carlo simulation provides the best and least-biased estimate of penetration. It also demonstrates clearly that we can expect differences in penetration between patients. This analysis did not deal with inflammation, as it was performed in volunteers. The influence of lung pathology on penetration needs to be examined.

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