Ceftazidime‐Avibactam Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Across Adult Indications and Patient Subgroups

Abstract

Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination for the treatment of serious infections caused by resistant gram-negative pathogens. Population pharmacokinetic (PopPK) models were built to incorporate pharmacokinetic (PK) data from five phase III trials in patients with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), or nosocomial (including ventilator-associated) pneumonia. Ceftazidime and avibactam pharmacokinetics were well-described by two-compartment disposition models, with creatinine clearance (CrCL) the key covariate determining clearance variability. Steady-state ceftazidime and avibactam exposure for most patient subgroups differed by ≤ 20% vs. healthy volunteers. Probability of PK/pharmacodynamic (PD) target attainment (free plasma ceftazidime > 8 mg/L and avibactam > 1 mg/L for ≥ 50% of dosing interval) was ≥ 94.9% in simulations for all patient subgroups, including indication and renal function categories. No exposure-microbiological response relationship was identified because target exposures were achieved in almost all patients. These modeling results support the approved ceftazidime-avibactam dosage regimens (2000-500 mg every 8 hours, adjusted for CrCL ≤ 50 mL/min).

Dalbavancin Population Pharmacokinetic Modeling and Target Attainment Analysis

“…The modeling is often performed in an iterative fashion as new data emerge, from initial dose selection to dose adjustment in important subpopulations through final dose justification and the establishment of in vitro susceptibility criteria (break points). [14][15][16][17][18][19] The overall methodological approach consists of 4 steps: (1) identification of appropriate pharmacokinetic/pharmacodynamic (PK/PD) targets from preclinical experiments (in vitro, in vivo) 15 ;…”

Selecting the dosage of ceftazidime–avibactam in the perfect storm of nosocomial pneumonia

“…The final model parameter estimates are shown in the Supplementary Materials. Prediction-corrected visual predictive checks confirmed that the various model iterations reflected the observed data [32,68]. These models were used in Monte Carlo simulations to support and Data sourced from study conducted by Flamm et al [57] validate dosage selection, with simulation methods summarized in the Supplementary Materials.…”

“…The phase III trials all included sparse PK sampling schedules, and at various stages during the development program, additional patient PK and covariate data were incorporated into updated iterations of the ceftazidime and avibactam population PK models to evaluate the performance of the selected dose by assessing model predictions versus actual exposures. These analyses provided assurance that the selected regimen would provide adequate exposures for various clinically important patient subgroups, including patients with NP/VAP [31][32][33], and also supported selection of dosage adjustments for renal function [34,35]. In conjunction with microbiological surveillance data and data from in vitro and animal models, the simulations also supported determination of ceftazidime-avibactam MIC susceptibility breakpoints [36].…”

“…Population PK modeling and PTA analyses to guide dosage selection for NP and VAP Population PK models were developed for ceftazidime and avibactam using patient PK data from clinical trials and [55] updated as additional data were generated throughout the clinical development program, with key iterations including two early phase I-II models [64,65], two interim phase I-III models [66,67], and a final model [32], with each new iteration incorporating all previously available data; the model iterations have been reviewed in detail by Das et al (2019) [68], and details of the final model, including NONMEM codes, as well as descriptions of the model construction, selection of covariates, and model evaluation, have been reported by Li et al (2019) [32]. Ceftazidime and avibactam plasma concentration-time data were analyzed using nonlinear mixed-effects modeling, which described the PK of both ceftazidime and avibactam as a two-compartment disposition model with first-order elimination from a central compartment following intravenous infusion, parameterized by clearance (CL), volume of the central compartment (V c ), intercompartmental clearance (Q), and volume of the peripheral compartment (V p ) [32]. The final model parameter estimates are shown in the Supplementary Materials.…”

“…These models were used in Monte Carlo simulations to support and Data sourced from study conducted by Flamm et al [57] validate dosage selection, with simulation methods summarized in the Supplementary Materials. Based on the in vitro and in vivo studies described above, free plasma PK/PD targets of 50% fT > 8 mg/L for ceftazidime (8 mg/L was selected as it was the ceftazidime-avibactam MIC 90 for the target species, P. aeruginosa, and higher than the MIC 90 for species of the Enterobacteriaceae, as described above) and 50% fT > C T 1 mg/L for avibactam (see [33] for a review of PK/PD target selection), to be attained simultaneously in each simulated patient, were used in PTA analyses to guide dosage selection based on achievement of > 90% joint PTA [31,32,68].…”