title: 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.
authors.affiliation: Quantitative Clinical Pharmacology, AstraZeneca, Waltham, MA, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Xu
authors.affiliation: Quantitative Clinical Pharmacology, AstraZeneca, Waltham, MA, USA.
authors.forename: Wangda
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Quantitative Clinical Pharmacology, AstraZeneca, Waltham, MA, USA.
authors.forename: Diansong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Quantitative Clinical Pharmacology, AstraZeneca, Waltham, MA, USA.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Li
authors.affiliation: Quantitative Clinical Pharmacology, AstraZeneca, Waltham, MA, USA.
authors.forename: Nidal
authors.initials: N
authors.lastname: Al-Huniti
mesh_terms: D000328:Adult; D000367:Age Factors; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001398:Aztreonam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001827:Body Height; D001835:Body Weight; D002986:Clinical Trials as Topic; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D051437:Renal Insufficiency / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D003404:Creatinine; D001398:Aztreonam
keywords: NONMEM; aztreonam; pharmacokinetics; probability of target attainment; renal