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

Jianguo Li, Mark Lovern, Michelle L Green, Joannellyn Chiu, Diansong Zhou, Craig Comisar, Yuan Xiong, Jeremy Hing, Merran MacPherson, James G Wright, Todd Riccobene, Timothy J Carrothers, Shampa Das, Jianguo Li, Mark Lovern, Michelle L Green, Joannellyn Chiu, Diansong Zhou, Craig Comisar, Yuan Xiong, Jeremy Hing, Merran MacPherson, James G Wright, Todd Riccobene, Timothy J Carrothers, Shampa Das

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).

Trial registration: ClinicalTrials.gov NCT01291602 NCT01430910 NCT01920399 NCT01499290 NCT01500239 NCT01726023 NCT01644643 NCT01595438 NCT01599806 NCT01808092 NCT01624246.

Conflict of interest statement

Jianguo Li and Shampa Das are former employees of and shareholders in AstraZeneca. Diansong Zhou is an employee of and shareholder in AstraZeneca. Mark Lovern, Michelle Green, Craig Comisar, and Yuan Xiong are employees of Certara Strategic Consulting (formerly Quantitative Solutions), and James Wright is an employee of Wright Dose Ltd, both of which received funding from AstraZeneca for support and assistance with the PopPK analyses. Merran MacPherson is a former employee of Wright Dose Ltd. and also holds shares in AstraZeneca. Joannellyn Chiu and Jeremy Hing are former employees of Certara Strategic Consulting. Todd Riccobene and Timothy J. Carrothers are employees of and shareholders in Allergan (formerly Actavis, formerly Forest Laboratories).

© 2018 University of Liverpool. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Prediction‐corrected visual predictive check stratified by population for ceftazidime. Solid lines represent medians and 10th and 90th percentiles of observed data. Shaded regions encompass 90% of the simulated (n = 1,000) values of the predicted medians (red) and 10th and 90th percentiles (blue). Data points represent the observed data (ng/mL). CI, confidence interval; cIAI, complicated intra‐abdominal infection; cUTI, complicated urinary tract infection; non‐VAP, not ventilator‐associated pneumonia; NP, nosocomial pneumonia; Obs, observations; VAP, ventilator‐associated pneumonia.
Figure 2
Figure 2
Prediction‐corrected visual predictive check stratified by population for avibactam. Solid lines represent the median of the observed data. Shaded regions encompass 90% of the simulated (n = 5,000) values of the predicted medians, 5th, and 95th percentiles. Data points represent the observed data (ng/mL). AVI, avibactam; cIAI, complicated intra‐abdominal infection; cUTI, complicated urinary tract infection; non‐VAP, not ventilator‐associated pneumonia; NP, nosocomial pneumonia; VAP, ventilator‐associated pneumonia.
Figure 3
Figure 3
Simulated joint probability of target attainment (PTA) as function of ceftazidime‐avibactam minimum inhibitory concentration (MIC) in 5000 simulated patients with complicated intra‐abdominal infection (cIAI), complicated urinary tract infection (cUTI), or nosocomial pneumonia (NP) with normal renal function receiving ceftazidime‐avibactam 2000‐500 mg every 8 hours. Joint target attainment was defined as 50% fT > 8 mg/L for ceftazidime, and 50% fT > 1 mg/L for avibactam.

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