Population Pharmacokinetics of High-Dose, Prolonged-Infusion Cefepime in Adult Critically Ill Patients with Ventilator-Associated Pneumonia

Abstract

ABSTRACT A population pharmacokinetic model of cefepime was constructed from data from adult critical care patients with ventilator-associated pneumonia (VAP). A total of 32 patients treated with high-dose cefepime, 2 g every 8 h (3-h infusion) or a renal function-adjusted equivalent dose, were randomized into two groups—26 for the initial model and 6 for model validation. Serum samples of cefepime were collected at steady state. Nonparametric adaptive grid population modeling was employed using a two-compartment K slope pharmacokinetic model relating the elimination rate constant ( K 10 ) to renal function, as defined by creatinine clearance (CL CR ), and central distribution volume ( V 1 ) to total body weight (TBW). The final model was described by the following equations: K 10 = 0.0027 × CL CR + 0.071 h −1 and V 1 = TBW × 0.21 liter/kg. The median intercompartmental transfer constants K 12 and K 21 were 0.780 h −1 and 0.472 h −1 , respectively. Using these median parameter estimates, the bias, precision, and coefficient of determination for the initial model were 11.3 μg/ml, 24.0 μg/ml, and 26%, respectively. The independent validation group displayed a bias, precision, and coefficient of determination of −1.64 μg/ml, 17.1 μg/ml, and 62%, respectively. Time-concentration profiles were assessed for various dosing regimens, using 5,000-patient Monte Carlo simulations. Among the regimens, the likelihoods of 2 g every 8 h (3-h infusion) achieving free drug concentrations above the MIC for 50% of the dosing interval were 91.8%, 78.1%, and 50.3% for MICs of 8, 16, and 32 μg/ml, respectively. This study provides a pharmacokinetic model capable of predicting cefepime concentrations in critically ill patients with VAP.