Jurij Zdovc, Carla Ferreira Santos, Nuno Silva, José Augusto Guimarães Morais, Paulo Paixão
Faculty of Pharmacy, Universidade de Lisboa
Objectives: Vancomycin has been used and still is being used as an effective antibiotic. Nevertheless, there is still a need to gather data and improve approaches to improve the correlation between a patient’s pathophysiologic characteristics and vancomycin pharmacokinetics. Since it is often used as a »drug of last resort» against Gram-positive bacteria, individually adjusted treatment is of utmost importance to achieve an efficient treatment. This is a critical need because of the increasing resistance of bacteria in the past years. The aim of the study was to analyze and clarify the influence of personal characteristics on the pharmacokinetics of vancomycin and to provide a population pharmacokinetic model through which one could adjust and optimize dosing in an individual patient.
Methods: This was a retrospective study of concentration-versus-time data for vancomycin in plasma on a population of 33 critically ill patients from the Hospital Center Tondela – Viseu. The data from the patients’ medical histories was analyzed by a population pharmacokinetic approach (nonlinear mixed effects modeling) using Adapt 5. The significant covariates were detected by means of an ANOVA test and then analyzed in relation to the base model. We used »forward selection» process to construct and choose the best fitting model. The expectation-maximization algorithm was used to adjust the data to the model and obtain the maximum likelihood of the parameters. A validation of the model with the lowest Bayesian Information Criterion was performed using bootstrapping with substitution (n=50).
Results: The best pharmacokinetic model consisted of a one-compartment linear model with additive residual unknown variability and total body weight and renal function as covariates describing a between-subject variability (BSV). The volume of distribution was 64.9 L with a BSV of 66.6% and was proportionally associated to the total body weight (78.8 ± 17.0 kg). The clearance of vancomycin was 4.02 L/h with a BSV of 30.6% and was associated with creatinine clearance as a marker of renal function (128 ± 50.5 ml/min; Cockcroft-Gault equation). Residual unknown variability was 2.96 mg/L. The model was shown to be robust, since no 95% confidence intervals included zero and the results were within that interval.
Conclusions: The study showed that the total body weight and renal function play an important role in the individualized therapy with vancomycin and that the dosing regime should be adjusted accordingly in order to achieve an optimized treatment.
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Reference: PAGE 25 (2016) Abstr 5837 [www.page-meeting.org/?abstract=5837]
Poster: Methodology - Covariate/Variability Models