H. Xu, D. Zhou, J. Li, N. Al-Huniti; AstraZeneca, Waltham, MA

BACKGROUND: Aztreonam (ATM) is a mainly renally excreted (~ 65%) monobactam antibiotic with high activity against gram-negative microorganisms. The aim of this analysis was to understand the impact of renal impairment on ATM exposure and to evaluate dose regimen for patients with renal impairment.
METHODS: Literature data were extracted from two trials where individual level of serum concentrations of ATM and demographics were available from healthy and renal impairment patients after IV bolus injection of 1 g ATM (1,2). Population pharmacokinetic (PK) model of ATM was developed using NONMEM VII. Simulation of probability of PK/PD traget attainment (PTA) was performed for 1,000 subjects using a PK/PD target of 50% free ATM concentration above minimum inhibitory concentration (50% fT>MIC) for modified maintainence doses for each of moderate [CRCL: 10-30 mL/min], severe renal impairment patients [CRCL <10 mL/min] and normal renal function [CRCL >80ml/min] suggested by AZACTAM® label (3).
RESULTS: A two-compartment model adequately described ATM PK. Creatinine clearance and body weight were identified as significant covariates impacting ATM clearance and central volume, respectively. The PTA simulation was conducted with 0.5 h infusion of 1 g loading dose for all patients and maintenance dose of 1 g, 0.5 g and 0.25 g every 8 h for 7 days for patients with normal renal function, moderate and severe renal impairment, respectively. The PTA for PK/PD target of 50% fT>MIC of 4 µg/mL is 95.2%, 99.2% and 99.1% for normal, moderate and severe renal impairment patients, respectively.
CONCLUSION: The population PK modeling and PTA simulation support adequate PTAs at ATM’s breakpoint for Enterobacteriaceae (4 µg/mL) from AZACTAM® label for dose adjustment in patients with moderate and severe renal impairment.