P2202Probability of target attainment of cefepime/enmetazobactam to support dose selection for the treatment of pulmonary infections

05. New antibacterial agents, PK/PD & Stewardship
05b. Pharmacokinetics/pharmacodynamics of antibacterial drugs & therapeutic drug monitoring
J. Quevedo 1, N. Dunkel 1, A. Belley 2, P. Velicitat 2, M. Machacek 3, A. Santerre Henriksen 4, J. Vollmer 3.
1ADVANZ PHARMA UK - London (United Kingdom), 2Allecra therapeutics - St. Louis (France), 3LYO-X AG - Basel (Switzerland), 4Maxel Consulting ApS - Jyllinge (Denmark)

Background

Cefepime/enmetazobactam, a novel beta-lactam/beta-lactamase inhibitor combination for beat-lactam resistant gram-negative infections, met criteria for non-inferiority and superiority compared to piperacillin/tazobactam in a phase 3 study of complicated urinary tract infections (cUTI) and acute pyelonephritis (AP)(1). A joint population pharmacokinetic (PK) model was developed based on the combined phase 1, 2, and 3 studies to characterize cefepime (CEF) and enmetazobactam (EMT) PK in plasma and epithelial lining fluid (ELF) . Using this model, Monte-Carlo simulations were performed to determine the probability of target attainment (PTA) in ELF to support dose selection for the treatment of pulmonary infections caused by gram-negative pathogens.


Methods

Monte-Carlo simulations of 4,000 subjects with normal renal function (estimated glomerular filtration rate of 90 - <150 mL/min/1.73m2) receiving 2 g cefepime/0.5 g enmetazobactam by 2-hour infusion were used to compute the joint PTA (i.e simultaneous attainment of both targets ) in ELF. The ELF population PK was established using observations from 19 healthy volunteers in a phase 1 study(2). The ELF concentrations were described with a time dependent plasma-to-ELF biodistribution coefficient. Nonclinical targets for cefepime (free drug concentration >MIC for 20% of the dosing interval) and enmetazobactam (free drug concentration >threshold concentration of 2 mg/L for 20% of the dosing interval) associated with 2-log10 bioburden reduction in mouse lung infection model were used.


Results

The cefepime/enmetazobactam ELF joint PTA as a function of the MIC for the ELF targets for ≥2-log10 kill on Day 1 and Day 7 are shown in the figure 1. For the 2-log10 kill targets, the joint PTA was ≥99.7% for gram-negative pathogens with an MIC of ≤8 mg/L on Day 1 and 100% on Day 7 of dosing in patients. 


Conclusions

Based on the high PTA for cefepime-enmetazobactam in patients receiving 2g cefepime/0.5g enmetazobactam by 2-hour intravenous infusion, this dose is expected to achieve drug exposure targets associated with the resolution of high organism burdens in pulmonary infections due to a range of gram-negative pathogens including multidrug-resistant Enterobacterales.


Conclusions

Case(s) description

Discussion

References

Joint PTA in ELF at day 1 and day 7

Keyword 1
PK/PD, pharmacology and TDM
Keyword 2
New and non-traditional drugs
Keyword 3
cefepime enmetazobactam
References, word count: 30 words
1. JAMA. 2022 Oct 4;328(13):1304-1314 / 2. Antimicrob Agents Chemother. 2020 Dec 16;65(1):e01468-20

Conflicts of interest


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No