Population pharmacokinetics of ceftazidime in burn patients

Abstract

Aim: The aim of this study was to characterize, via a population pharmacokinetic approach, the pharmacokinetics of ceftazidime in burn patients who were not in the acute post-injury phase.

Methods: The development of the pharmacokinetic model was based on data from therapeutic drug monitoring (41 patients, 94 samples). The estimation of population pharmacokinetic parameters and the selection of covariates (age, gender, body weight, size of burn and creatinine plasma concentration) that could affect the pharmacokinetics were performed with a nonlinear mixed effect modelling method.

Results: No relationship between covariates and the pharmacokinetic parameters was established with the exception of an inverse-linear relationship between creatinine plasma concentration and ceftazidime total clearance. The total clearance of ceftazidime was 2.72 l h-1[coefficient variation (CV) = 56.3%] and the distribution volume of the central compartment was 0.28 l kg-1 (CV = 13.2%) The transfer rate constants (k12, k 21) between the central and peripheral compartments were 0.06718 h-1 (CV = 87.2%) and 0.001823 h-1 (CV = 82.7%), respectively. From these parameters, the total ceftazidime volume of distribution (10.64 l kg-1) was calculated.

Conclusion: The population parameters were different from those obtained in a previous study performed in fewer patients and in the early period after burn injury. In our study, the lower ceftazidime clearance could be explained by the relative decrease in ceftazidime elimination in relation to the burn area, and the higher ceftazidime volume of distribution in the presence of interstitial oedema, which could act as a reservoir from which ceftazidime returns slowly to the circulation.

Figure 1

Ceftazidime plasma concentrations vs time in 41 burn patients. Concentrations were normalized to the mean daily dose per kg.

Figure 2

Relationship between C_obs and C_pred. C_obs are observed concentrations (mg l⁻¹) and C_pred are concentrations (mg l⁻¹) predicted by the two-compartment model in Figure 2A and a two-compartment model integrating creatinine plasma concentration in Figure 2B. The straight-line equation (- - -) obtained by linear regression is C_pred= 24.9 + 0.60 × C_obs in Figure 2A and C_pred= 14 + 0.76 × C_obs in Figure 2B.

Figure 2

Relationship between C_obs and C_pred. C_obs are observed concentrations (mg l⁻¹) and C_pred are concentrations (mg l⁻¹) predicted by the two-compartment model in Figure 2A and a two-compartment model integrating creatinine plasma concentration in Figure 2B. The straight-line equation (- - -) obtained by linear regression is C_pred= 24.9 + 0.60 × C_obs in Figure 2A and C_pred= 14 + 0.76 × C_obs in Figure 2B.

Figure 3

Relationship between (C_obs-C_pred)/C_pred and C_pred. C_obs are observed concentrations (mg l⁻¹) and C_pred are concentrations (mg l⁻¹) predicted by the two-compartment model in Figure 3A and a two-compartment model integrating creatinine plasma concentration in Figure 3B. The equation obtained by linear regression is (C_obs-C_pred)/C_pred= 0.154–0.0038 × C_pred in Figure 3A and (C_obs-C_pred)/C_pred= 0.120–0.0024 × C_obs in Figure 3B.

Figure 3

Relationship between (C_obs-C_pred)/C_pred and C_pred. C_obs are observed concentrations (mg l⁻¹) and C_pred are concentrations (mg l⁻¹) predicted by the two-compartment model in Figure 3A and a two-compartment model integrating creatinine plasma concentration in Figure 3B. The equation obtained by linear regression is (C_obs-C_pred)/C_pred= 0.154–0.0038 × C_pred in Figure 3A and (C_obs-C_pred)/C_pred= 0.120–0.0024 × C_obs in Figure 3B.