Population Pharmacokinetics and Target Attainment Analysis of Vancomycin after Intermittent Dosing in Adults with Cystic Fibrosis

Abstract

ABSTRACTVancomycin is the first-line agent to treat pulmonary infections caused by methicillin-resistantStaphylococcus aureus(MRSA) in people with cystic fibrosis (PwCF). However, there is no consensus on vancomycin dosing in this population among health institutions, and there is large variability in dosing regimens across the United States. In this study, we characterized the pharmacokinetics (PK) of vancomycin in PwCF using a population PK approach. The clinical PK data to develop the population PK model was obtained from vancomycin therapeutic monitoring data from PwCF undergoing treatment for infections due to MRSA. The population PK model was then used to perform comprehensive Monte Carlo simulations to evaluate the probability of target attainment (PTA) of 12 different dosing scenarios. The area under the curve to minimum inhibitory concentration ratio (AUC/MIC) ≥ 400 mg*h/L was used as a target for PTA analysis. A total of 181 vancomycin plasma concentrations were included in the analysis. A onecompartment model with first-order elimination best described the data. Weight significantly influenced the vancomycin PK (p< 0.05). In the final model, clearance was estimated as 5.52 L/h/70 kg, and the volume of distribution was 31.5 L/70 kg. The PTA analysis showed that at lower MIC levels (MIC = 1), doses greater than and equal to 1000 mg every 8 hours and 1250 mg every 12 hours resulted in >90% PTA. The PTA results from this study may potentially inform the design of vancomycin dosing regimens to treat pulmonary infections due to MRSA in PwCF.