Anti-Vancomycin monoclonal antibody, clone 4H22

Background and Objectives Teicoplanin is a highly protein-bound antibiotic, increasingly used to treat serious Gram-positive infections in critically ill children. Maturational and pathophysiological intensive care unit-related changes often lead to altered pharmacokinetics. In this study, the objectives were to develop a pediatric population-pharmacokinetic model of unbound and total teicoplanin concentrations, to investigate the impact of plasma albumin levels and renal function on teicoplanin pharmacokinetics, and to evaluate the efficacy of the current weight-based dosing regimen. Methods An observational pharmacokinetic study was performed and blood samples were collected for quantification of unbound and total concentrations of teicoplanin after the first dose and in assumed steady-state conditions. A population-pharmacokinetic analysis was conducted using a standard sequential approach and Monte Carlo simulations were performed for a probability of target attainment analysis using previously published pharmacokinetic-pharmacodynamic targets. Results A two-compartment model with allometric scaling of pharmacokinetic parameters and non-linear plasma protein binding best described the data. Neither the inclusion of albumin nor the renal function significantly improved the model and no other covariates were supported for inclusion in the final model. The probability of target attainment analysis showed that the standard dosing regimen does not satisfactory attain the majority of the proposed targets. Conclusions We successfully characterized the pharmacokinetics of unbound and total teicoplanin in critically ill pediatric patients. The highly variable unbound fraction of teicoplanin could not be predicted using albumin levels, which may support the use of therapeutic drug monitoring of unbound concentrations. Poor target attainment was shown for the most commonly used dosing regimen, regardless of the pharmacokinetic-pharmacodynamic target evaluated.

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 (AUC(0-2)) 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.