Development of Population and Bayesian Models for Applied Use in Patients Receiving Cefepime

Abstract

Background and Objective Understanding pharmacokinetic disposition of cefepime, a β-lactam antibiotic, is crucial for developing regimens to achieve optimal exposure and improved clinical outcomes. This study sought to develop and evaluate a unified population pharmacokinetic model in both pediatric and adult patients receiving cefepime treatment. Methods Multiple physiologically relevant models were fit to pediatric and adult subject data. To evaluate the final model performance, a withheld group of 12 pediatric patients and two separate adult populations were assessed. Results Seventy subjects with a total of 604 cefepime concentrations were included in this study. All adults (n = 34) on average weighed 82.7 kg and displayed a mean creatinine clearance of 106.7 mL/min. All pediatric subjects (n = 36) had mean weight and creatinine clearance of 16.0 kg and 195.6 mL/min, respectively. A covariate-adjusted two-compartment model described the observed concentrations well (population model R 2 , 87.0%; Bayesian model R 2 , 96.5%). In the evaluation subsets, the model performed similarly well (population R 2 , 84.0%; Bayesian R 2 , 90.2%). ConclusionThe identified model serves well for population dosing and as a Bayesian prior for precision dosing.

Population Pharmacokinetics and Target Attainment of Cefepime in Critically Ill Patients and Guidance for Initial Dosing

“…where Peds stands for pediatric group, with a value of 1 for the pediatric study and a value of 0 for the adult ICU group. The results for pediatric simulations and the probability of target attainment (PTA) have been published previously (15)(16)(17)(18). Table 2 shows the parameter estimates for the final model.…”

“…For a CrCl of Ͻ30 ml/min, 1 g every 12 h and 2 g every 24 h (II and EI) had Յ90% PTA at a MIC of 8 mg/liter (21). Another cefepime model, published by Liu and colleagues, included pediatric patients, adult ICU patients, and febrile neutropenic adult cancer patients (18). Both weight and CrCl were included as covariates on V and k el , respectively.…”

“…The final model was used to simulate 2 g cefepime every 8 h infused over 30 min, and a target of 68% fT ϾMIC was evaluated for the first 24 h of therapy. From a MIC of 2 mg/liter to a MIC of 4 mg/liter, the PTA dropped from Ͼ90% to Ͻ80% (18). A third model, developed by Roos et al, included 13 adult ICU patients and used 65% fT ϾMIC as a target (22).…”

Systematic Review and Meta-Analysis of the Effect of Loop Diuretics on Antibiotic Pharmacokinetics

“…Despite important physiologic differences in adult and pediatric populations, furosemide has similar physiologic effects and mechanisms of action in both populations [ 10 ]. Furthermore, after accounting for postnatal age, weight, and kidney function, the pharmacokinetics of drugs in adults and pediatrics may be reliably predicted using a single covariate PK model [ 11 , 12 ]. Therefore, both pediatric and adult populations were included.…”

Pharmacokinetic/Pharmacodynamic Dosage Individualization of Cefepime in Critically Ill Patients: A Case Study

“…This model was based on the analysis of 683 cefepime concentrations collected in 70 patients, including critically ill patients. 12 This was a 2-compartment, 4 parameter model. The original model incorporated the influence of body weight on the central volume of distribution (V1) and that of creatinine clearance and body weight on the elimination rate constant (Ke).…”