Optimization of Vancomycin Dosing Regimen in Cancer Patients using Pharmacokinetic/Pharmacodynamic Modeling

Abstract

Background : Gram-positive bacterial infections are considered one of the major causes of mortality and morbidity in patients with cancer. Hence, the challenge lies in regulating the pervasive use of vancomycin in the management of infections facing such patients due to the anomalous vancomycin pharmacokinetics (PKs) and pharmacodynamics (PDs). Inappropriate vancomycin exposure is associated with toxicity, pathogen resistance, and therapeutic failure. Objective : The aim of this study was to estimate vancomycin PK in patients with cancer and without cancer. The standard dosage regimens of vancomycin were then evaluated using data from PK modeling. Methods : In this observational PK study, the data were extracted from a matched patient cohort of those with cancer and those without cancer. Pharmacokinetic analysis was performed using Monolix version 4.4, and the PK parameters were compared in both groups (cancer vs noncancer). The standard and suggested vancomycin dosing regimens were evaluated using PK/PD modeling and Monte Carlo Simulations. Results : In total, 448 blood samples were analyzed from 147 patients enrolled in this study, of which 73 patients had cancer and 74 patients were noncancer patients. In general, no significant differences were observed between the two groups (cancer vs noncancer) in all characteristics except for the vancomycin levels, which were significantly lower in patients with cancer (p = 0.00104). This analysis showed that patients with cancer showed a significantly higher vancomycin clearance than noncancer patients (p = 0.002), whereas the volume of distribution (V) was found to be similar in both groups (p = 0.83).This resulted in most of the patients failing to achieve the target area under the curve from zero to 24 hours (AUC0–2) to the minimum inhibitory concentration. These data showed that a higher maintenance dose of vancomycin is required to achieve the PD target. Conclusions : The findings of this study showed that the patients with cancer have lower levels of vancomycin due to higher clearance than noncancer patients. Thus, higher doses than the standard vancomycin doses may be needed to treat invasive Methicillin-resistant Staphylococcus aureus infections in patients with cancer.