Population Pharmacokinetic Model for Vancomycin Used in Open Heart Surgery: Model-Based Evaluation of Standard Dosing Regimens

Abstract

The purpose of this study was to investigate the population pharmacokinetics of vancomycin in patients undergoing open heart surgery. In this observational pharmacokinetic study, multiple blood samples were drawn over a 48-h period of intravenous vancomycin in patients who were undergoing open heart surgery. Blood samples were analyzed using an Architect i4000SR immunoassay analyzer. Population pharmacokinetic models were developed using Monolix 4.4 software. Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. A total of 168 blood samples were analyzed from 28 patients. The pharmacokinetics of vancomycin are best described by a two-compartment model with between-subject variability in clearance (CL), the volume of distribution of the central compartment (V₁), and volume of distribution of the peripheral compartment (V₂). The CL and the V₁ of vancomycin were related to creatinine CL (CL_CR), body weight, and albumin concentration. Dosing simulations showed that standard dosing regimens of 1 and 1.5 g failed to achieve the PK-PD target of AUC_0-24/MIC > 400 for an MIC of 1 mg/liter, while high weight-based dosing regimens were able to achieve the PK-PD target. In summary, the administration of standard doses of 1 and 1.5 g of vancomycin two times daily provided inadequate antibiotic prophylaxis in patients undergoing open heart surgery. The same findings were obtained when 15- and 20-mg/kg doses of vancomycin were administered. Achieving the PK-PD target required higher doses (25 and 30 mg/kg) of vancomycin.

Keywords: Monte Carlo simulation; PK-PD; open heart surgery; population pharmacokinetics; prophylaxis; vancomycin.

FIG 1

GOF plots obtained from the final model for vancomycin. (A) Individual predictions of vancomycin versus observed concentrations. (B) Population predictions of vancomycin versus observed concentrations. (C) Weighted residuals versus time since last dose. (D) Weighted residuals versus population predicted concentrations.

FIG 2

Predicted-corrected visual predictive check (pcVPC) for vancomycin concentration versus time based on 1,000 Monte Carlo simulations. The solid green line represents the 10th, 50th, and 90th percentiles of the observed data. The shaded regions represent the 90% confidence intervals around the 10th, 50th, and 90th percentiles of the simulated data. The observed plasma concentrations are represented by blue circles.

FIG 3

Target attainment analysis for vancomycin (AUC_0–24/MIC > 400) for all of the various dosing regimens at different MICs.