Population Pharmacokinetics and Dose Optimization of Ceftazidime and Imipenem in Patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Abstract

Background: Ceftazidime and imipenem have been increasingly used to treat Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) due to their extended-spectrum covering Pseudomonas aeruginosa. This study aims to describe the population pharmacokinetic (PK) and pharmacodynamic (PD) target attainment for ceftazidime and imipenem in patients with AECOPD.

Methods: We conducted a prospective PK study at Bach Mai Hospital (Viet Nam). A total of 50 (ceftazidime) and 44 (imipenem) patients with AECOPD were enrolled. Population PK analysis was performed using Monolix 2019R1 and Monte Carlo simulations were conducted to determine the optimal dose regimen with respect to the attainment of 60% and 40% fT>MIC for ceftazidime and imipenem, respectively. A dosing algorithm was developed to identify optimal treatment doses.

Results: Ceftazidime and imipenem PK was best described by a one-compartment population model with a volume of distribution and clearance of 23.7 L and 8.74 L/h for ceftazidime and 15.1 L and 7.88 L/h for imipenem, respectively. Cockcroft-Gault creatinine clearance represented a significant covariate affecting the clearance of both drugs. Increased doses with prolonged infusion were found to cover pathogens with reduced susceptibility.

Conclusions: This study describes a novel and versatile three-level dosing algorithm based on patients' renal function and characteristic of the infective pathogen to explore ceftazidime and imipenem optimal regimen for AECOPD.

Keywords: Pseudomonas aeruginosa; acute exacerbations; ceftazidime; chronic obstructive pulmonary disease; dose optimization; imipenem.

Figure 1

Individual ceftazidime. (a) and imipenem (b) clearance estimates versus creatinine clearance estimated according to Cockcroft and Gault. Log transformed values are plotted, with the solid lines and grey shading areas illustrating the linear regression and the 95% confident interval, respectively. The regression equations and respective correlation coefficients (R²) are presented for each plot. Creatinine clearance were estimated by Cockcroft and Gault equation (CLCR_CG).

Figure 2

Basic goodness-of-fit plots from the final covariate model. (a,b) Measured ceftazidime (CAZ) concentrations are plotted against the population (a) or the individually-fitted (b) concentrations. (c,d) Measured imipenem (IMI) concentrations are plotted against the population (c) or the individually-fitted (d) concentrations. The solid lines represent linear regression lines with shade areas illustrating the 95% confident intervals. The regression equations and respective correlation coefficients (R²) are presented.

Figure 3

Visual Predictive Check plot versus time. The grey solid lines indicate the 10th, 50th, and 90th percentiles of the observed data. The grey-black dashed lines indicate the 10th, 50th, and 90th percentiles of simulated data. The shaded grey and pink areas represent 90% prediction intervals from the corresponding percentiles as predicted by the model.

Figure 4

Probability of target attainment (PTA) of ceftazidime with a target of 60% fT>MIC and imipenem with 40% fT>MIC. MIC values based on the recommendation of Clinical and Laboratory Standards Institute 2020 (CLSI 2020); Dose regimens using short-term infusion (SI: 0.5 h), extended infusion (EI: 3 h), and continuous infusion (CI) are simulated. The simulations were stratified based on CLCR_CG.

Figure 5

Proposed dosing algorithm based on the simulation results of ceftazidime and imipenem in Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) to achieve 60% fT>MIC for ceftazidime and 40% fT>MIC for imipenem. MIC: Minimum inhibitory concentration, PA: Pseudomonas aeruginosa, (S): Susceptible; (I): Intermediate resistance, IMI, imipenem; CFZ, ceftazidime; CLCR_CG, Clearance creatinine according to Cockcroft and Gault equation; q6h, q8h, and q12h, dose following 3 h extended infusion with dose interval of 6, 8, or 12 h, respectively; CI, continuous infusion. Created with Biorender.com (accessed on 1 February 2021).