Younghee Jung (1), Dong-Hwan Lee (2), Hyoung Soo Kim (3)
(1) Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Republic of Korea, (2) Department of Clinical Pharmacology, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea, (3) Department of Thoracic and Cardiovascular Surgery, Hallym University College of Medicine, Chuncheon, Republic of Korea
Objectives: There is no literature on population pharmacokinetics (PK) of vancomycin in Korean patients receiving extracorporeal membrane oxygenation (ECMO) therapy. The aim of this study was to develop a population PK model for vancomycin in Korean ECMO patients.
Methods: A total of 22 adult patients with 194 vancomycin concentrations were included in this analysis. A single 1000 mg dose of vancomycin was infused over the course of 1 hour. After starting the first infusion, arterial blood samples of 3 ml each were collected at 0, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours or 0, 1, 1.5, 2, 3, 4, 10, 16, 24 hours over a single dosing interval of each patient. A population PK model for vancomycin was developed using a nonlinear mixed effect modeling. Age, sex, creatinine clearance (CLCR), body weight, and ECMO type were tested as potential covariates in the PK model. Model selection was based on NONMEM (Ver 7.4, Icon Development Solutions) objective function values (OFVs), relative standard errors (RSE) for parameter estimates, diagnostic goodness-of-fit (GOF) plots, and visual predictive check (VPC). The probability of target attainment (PTA) for PK/PD index for vancomycin, a ratio of the area under the concentration-time curve at steady-state over 24 h to MIC (AUC/MIC), [1-4] was compared by applying the vancomycin break point distribution of MICs for methicillin-resistant Staphylococcus aureus set by the European Committee on Antimicrobial Susceptibility Testing. To evaluate the steady-state concentration-time profiles of vancomycin for the current dosing regimen and the need for dose adjustment in patients on ECMO, a 10,000-subject Monte Carlo simulation was performed using the final PK parameter estimates [5,6]. The treatment target is AUC/MIC ≥ 400 for vancomycin and the PTA should be greater than 90% for a regimen to be considered optimal [7-9].
Results: Among the 22 patients (17 males, 5 females). 19 patients received veno-arterial (VA) ECMO and three patients received veno-venous (VV) ECMO. The population PK of vancomycin was best described by a three-compartment model with a proportional residual error model, although vancomycin PK were usually explained by a two-compartment model [10-13]. The typical value (RSE) for the total clearance (CL) was estimated to be 4.01 L/h (7.51%), the central volume of distribution (V1) was 8.01 L (8.43%), the intercompartmental clearance between V1 and the second compartment (V2) was 4.95 L/h (5.27%), V2 was 15.4 L (8.53%), the intercompartmental clearance between the V1 and the third compartment (V3) was 9.09 L/h (10.0%) and V3 was 6.21 L (14.0). The proportional residual variability was 6.64%. CLCR significantly influenced CL. The proposed equation to estimate CL was CL = 4.01 × (1 + 0.00752 × (CLCR – 56.75)). ECMO type was also a significant covariate for Q2. The typical values of Q2 were 4.95 L/h and 6.23 L/h for VA and VV, respectively. The residual plots showed no trend in the residuals and the observed concentrations were evenly distributed about the line of identity in the GOF plots. The VPC plot showed that most of the observations are overlaid within 90% prediction interval of simulated concentrations and observed 5th, 50th, and 95th percentiles are overlaid with the 95% confidence intervals of the simulated 5th, 50th, and 95th percentiles. The current regimen was suboptimal when the MIC was equal to or greater than 1 mg/L according to the Monte Carlo simulation.
Conclusions: A three-compartment population PK model successfully describes vancomycin PK profiles in Korean ECMO patients. Our results suggest that current vancomycin dosing regimens might be insufficient, especially when the MICs of pathogens are ≥1 mg/mL Maximally effective dosing regimens of vancomycin in patients on ECMO should be determined according to personalized dosing, using PK/PD models and therapeutic drug monitoring.
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Reference: PAGE () Abstr 9236 [www.page-meeting.org/?abstract=9236]
Poster: Drug/Disease Modelling - Infection