Cefepime precision dosing tool: From Standard to Precise Dose Using Nonparametric Population Pharmacokinetics

Abstract

Cefepime is the second most common cephalosporin used in U.S. hospitals. We aim to develop and validate cefepime population pharmacokinetic (PK) model and integrate into precision dosing tool for implementation. Two datasets (680 patients) were used to build cefepime PK model in Pmetrics, and three datasets (34 patients) were used for the validation. A separate application dataset (115 patients) was used for the implementation and validation of a precision dosing tool. The model support points and covariates were used to generate the optimal initial dose (OID). Cefepime PK was described by a two-compartment model including weight and creatinine clearance (CrCl) as covariates. The median rate of elimination was 0.30 hr −1 (adults) and 0.96 hr −1 (pediatrics), central volume of distribution 13.85 L, and rate of transfer from the central to the peripheral compartments 1.22 hr −1 and from the peripheral to the central compartments 1.38 hr −1 . After integration in BestDose, the observed vs. predicted cefepime concentration fit using the application dataset was excellent (R 2 >0.98) and the median difference between observed and what BestDose predicted in a second occasion was 4%. For OID, cefepime 0.5-1g 4-hour infusion q8-24hr with CrCl<70 mL/min was needed to achieve a target range of free trough:MIC 1-4 at MIC 8 mg/L, while continuous infusion was needed for higher CrCl and weight values. In conclusion, we developed and validated a cefepime model for clinical application. The model was integrated in a precision dosing tool for implementation and the median concentration prediction bias was 4%. OID algorithm was provided.