Evaluation of Aztreonam Dosing Regimens in Patients With Normal and Impaired Renal Function: A Population Pharmacokinetic Modeling and Monte Carlo Simulation Analysis

Abstract

Aztreonam is a monocyclic β-lactam antibiotic often used to treat infections caused by Enterobacteriaceae or Pseudomonas aeruginosa. Despite the long history of clinical use, population pharmacokinetic modeling of aztreonam in renally impaired patients is not yet available. The aims of this study were to assess the impact of renal impairment on aztreonam exposure and to evaluate dosing regimens for patients with renal impairment. A population model describing aztreonam pharmacokinetics following intravenous administration was developed using plasma concentrations from 42 healthy volunteers and renally impaired patients from 2 clinical studies. The final pharmacokinetic model was used to predict aztreonam plasma concentrations and evaluate the probability of pharmacodynamic target attainment (PTA) in patients with different levels of renal function. A 2-compartment model with first-order elimination adequately described aztreonam pharmacokinetics. The population mean estimates of aztreonam clearance, intercompartmental clearance, volume of distribution of the central compartment, and volume of distribution of the peripheral compartment were 4.93 L/h, 9.26 L/h, 7.43 L, and 6.44 L, respectively. Creatinine clearance and body weight were the most significant variables to explain patient variability in aztreonam clearance and volume of distribution, respectively. Simulations using the final pharmacokinetic model resulted in a clinical susceptibility break point of 4 and 8 mg/L, respectively, based on the clinical use of 1- and 2-g loading doses with the same or reduced maintenance dose every 8 hours for various renal deficiency patients. The population pharmacokinetic modeling and PTA estimation support adequate PTAs (>90% PTA) from the aztreonam label for dose adjustment of aztreonam in patients with moderate and severe renal impairment.

Population Pharmacokinetic Modeling With Enterohepatic Circulation for AZD3241 in Healthy Subjects and Patients With Multiple System Atrophy

“…Model evaluation was guided by several assessment methods, including visual inspection of diagnostic plots, successful convergence of the model, changes in OFV, precision of parameter estimates, and plausibility of parameter estimates. The final model of AZD3241 was evaluated using nonparametric bootstrap approach with 1000 replicate bootstrap datasets . The predictive performance of the final model was also assessed with dose‐normalized visual predictive check (VPC) by simulating 1000 new datasets …”

“…The final model of AZD3241 was evaluated using nonparametric bootstrap approach with 1000 replicate bootstrap datasets. 7,8 The predictive performance of the final model was also assessed with dose-normalized visual predictive check (VPC) by simulating 1000 new datasets. 7 Population PK analysis was carried out using NON-MEM (version 7.3.0, ICON, Ellicott City, Maryland).…”

Simplified Aztreonam Dosing in Patients with End-Stage Renal Disease: Results of a Monte Carlo Simulation

“…To improve patient outcomes, dosing should be optimized based on pharmacodynamic parameters; updates to the interpretative breakpoints for aztreonam by the Clinical and Laboratory Standards Institute (CLSI) are based on the likelihood of achieving Ն50% free-drug time above the MIC (fT MIC ) (3)(4)(5). Furthermore, the manufacturer's recommendations for aztreonam dosing in patients with creatinine clearance (CL CR ) values of Ͻ10 ml/min/1.73 m 2 state that the dose should be 25% of the normal dose administered with the same interval; this typically results in a dose of 250 mg or 500 mg administered every 8 h, with a supplemental dose of 125 mg or 250 mg administered after hemodialysis (HD) in severe infections (1,6). However, it is not known whether simpler, post-HD dosing once daily or thrice weekly can reliably achieve pharmacodynamic goals, given that the half-life of aztreonam is prolonged in renal dysfunction (1,6).…”

“…Furthermore, the manufacturer's recommendations for aztreonam dosing in patients with creatinine clearance (CL CR ) values of Ͻ10 ml/min/1.73 m 2 state that the dose should be 25% of the normal dose administered with the same interval; this typically results in a dose of 250 mg or 500 mg administered every 8 h, with a supplemental dose of 125 mg or 250 mg administered after hemodialysis (HD) in severe infections (1,6). However, it is not known whether simpler, post-HD dosing once daily or thrice weekly can reliably achieve pharmacodynamic goals, given that the half-life of aztreonam is prolonged in renal dysfunction (1,6). Therefore, we conducted a Monte Carlo simulation (MCS) using a population pharmacokinetic model developed with data from patients with normal or impaired renal function, including patients with CL CR values of Ͻ10 ml/min/1.73 m 2 , to determine the probability of target attainment (PTA) with simplified aztreonam dosing (once daily or thrice weekly) (6).…”

“…However, it is not known whether simpler, post-HD dosing once daily or thrice weekly can reliably achieve pharmacodynamic goals, given that the half-life of aztreonam is prolonged in renal dysfunction (1,6). Therefore, we conducted a Monte Carlo simulation (MCS) using a population pharmacokinetic model developed with data from patients with normal or impaired renal function, including patients with CL CR values of Ͻ10 ml/min/1.73 m 2 , to determine the probability of target attainment (PTA) with simplified aztreonam dosing (once daily or thrice weekly) (6).…”