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

Abstract

Ceftolozane/tazobactam (C/T) is a combination of a novel cephalosporin with tazobactam, recently approved for the treatment of hospital-acquired and ventilator-associated pneumonia. The plasma pharmacokinetics (PK) of a 3-g dose of C/T (2 g ceftolozane and 1 g tazobactam) administered via a 1-hour infusion every 8 hours in adult patients with nosocomial pneumonia (NP) were evaluated in a phase 3 study (ASPECT-NP; NCT02070757). The present work describes the development of population PK models for ceftolozane and tazobactam in plasma and pulmonary epithelial lining fluid (ELF). The concentration-time profiles of both agents were well characterized by 2-compartment models with zero-order input and first-order elimination. Consistent with the elimination pathway, renal function estimated by creatinine clearance significantly affected the clearance of ceftolozane and tazobactam.The central volumes of distribution for both agents and the peripheral volume of distribution for tazobactam were approximately 2-fold higher in patients with pneumonia compared with healthy participants.A hypothetical link model was developed to describe ceftolozane and tazobactam disposition in ELF in healthy participants and patients with pneumonia. Influx (from plasma to the ELF compartment) and elimination (from the ELF compartment) rate constants were approximately 97% lower for ceftolozane and 52% lower for tazobactam in patients with pneumonia versus healthy participants. These population PK models adequately described the plasma and ELF concentrations of ceftolozane and tazobactam, thus providing a foundation for further modeling and simulation, including the probability of target attainment assessments to support dose recommendations of C/T in adult patients with NP.

Outcomes in Participants with Renal Impairment from a Phase 3 Clinical Trial for Ceftolozane/Tazobactam Treatment of Nosocomial Pneumonia (ASPECT-NP)

“…Population PK modeling and simulation for C/T in adult participants with vHABP/VABP was performed, wherein the previously developed plasma population PK models for ceftolozane and tazobactam were refined using PK data from participants with vHABP/VABP from ASPECT-NP (20). In the updated model, CL CR was identified as a significant covariate on clearance (38). Stochastic simulations were performed using the refined population PK model to estimate steady-state plasma ceftolozane and tazobactam exposures in participants who received adjusted dosing regimens based on RI.…”

Ceftolozane/tazobactam probability of target attainment and outcomes in participants with augmented renal clearance from the randomized phase 3 ASPECT-NP trial

“…PTA was assessed using Monte Carlo simulations based on existing population PK models describing plasma concentrations of ceftolozane and tazobactam in patients with HABP/VABP [ 16 ], and the simulations were aimed at dose justification for patients with HABP/VABP and varying degrees of renal impairment and augmented renal clearance by assessing the probability of PK/PD target attainment for ceftolozane and tazobactam. NONMEM (Version 7.3.0; Icon, plc, Dublin, Ireland) was used for Monte Carlo simulations.…”

“…Pulmonary epithelial lining fluid (ELF) ceftolozane and tazobactam concentration data from 2 phase 1 studies, including one conducted in critically ill participants with pneumonia receiving mechanical ventilation, informed the ELF parameters of the population PK models; disposition of ceftolozane and tazobactam in ELF was described by a hypothetical link model with influx and elimination from the ELF compartment. Among the covariates identified in the existing population PK models in patients with HABP/VABP, CrCl was a significant covariate on ceftolozane and tazobactam clearance; weight and pneumonia were covariates on ceftolozane and tazobactam volume of distributions; and pneumonia was a covariate on the influx and elimination rate constants for the ELF compartment [ 16 ].…”

“…For the Monte Carlo simulations, we created a simulated population of patients with characteristics similar to that of participants from previous infectious disease clinical trials [ 16 ]. From this large pool of simulated patients, 1000 patients with paired body weight and CrCl were randomly drawn for each of the following renal function categories to estimate PTA in each of the CrCl ranges: CrCl 80 to 130 mL/min (normal renal function); CrCl > 130 to < 180 mL/min (ARC); CrCl 180 to < 210 mL/min (ARC); and CrCl ≥ 210 mL/min (ARC).…”

The role of tazobactam‐based combinations for the management of infections due to extended‐spectrum β‐lactamase‐producing Enterobacterales: Insights from the Society of Infectious Diseases Pharmacists

“…A higher volume of distribution will ultimately result in lower C max concentrations and potentially compromise PK/PD target attainment. However, these PK changes will also lead to a longer halflife, which depending on achieved C max values, might afford longer time above threshold concentrations 72,73. Additional data followed by robust pharmacokinetic simulations are needed in these specific patient populations to further appreciate the importance of these changes in PK in relation to optimizing tazobactam exposure in combination with ceftolozane.…”