1406. Augmented Renal Clearance Using Aminoglycoside Population-Based Pharmacokinetic Modeling with Bayesian Estimation in Children in the Pediatric Intensive Care Unit

Abstract

BackgroundAugmented renal clearance (ARC) in critically ill pediatric patients has been evaluated in limited studies. We evaluated ARC using clearance of aminoglycosides (CLAMINO) derived from population-based pharmacokinetic modeling.MethodsA retrospective, cohort study was conducted at two pediatric hospitals in patients who received aminoglycosides from 1999 to 2016. ARC was defined as a CLAMINO of ≥130 mL/minute/1.73 m2 within the first 24 hours of therapy. Pharmacokinetic (PK) models with nonparametric parameter estimation were constructed using Pmetrics in R, with the ultimate model selected by Akaike score and rule of parsimony. Covariate modifiers considered included: age, total body weight (TBW), serum creatinine (SCr) and sex. Noncompartmental analysis was performed on the Bayesian posteriors from the first dose to generate CLAMINO within the first 24 hours and other PK exposure metrics (i.e., area under the curve for first 24 hours [AUC24], maximum concentration [CMAX]). Summary of patient demographics and statistical analysis were performed using GraphPad Prism version 7.ResultsARC was identified in 34 of 117 (29%) subjects using 275 aminoglycoside serum concentrations. A two-compartment model fit the data well (See Figure 1: Population [a], Bayesian [b]). Allometric scaling of CLAMINO utilized a fixed exponent of 0.75 and volume of distribution (VD) scaling utilized a fixed exponent of 1 in the final model. The final population model for CLAMINO (L/hour) was 3.45 × (TBW/40)0.75 + 0.05 × 10(SCr/AGE) and VD was 10.64 × (TBW/40)1. Median age and baseline SCr were similar in those with and without ARC (13 [IQR 10–16] vs. 11.0 [5.0–15.0] years, P = 0.11, and 0.37 [0.27–0.49] vs. 0.38 [0.28–0.50] mg/dL, P = 0.67, respectively). Median TBW was found to be significantly higher in those with vs. without ARC (44.9 [26.9–61.7] vs. 34 [17.6–54.9] kg P = 0.04). Median 24 hours CLAMINO was also found to be significantly higher in those with vs. without ARC (147.3 [138.7–163.9] vs. 94.5 [79.4–112.9], mL/minute/1.73 m2, P < 0.001). Patients with vs. without ARC had significantly lower AUC24 and CMAX (40.7 [33.3–54.4] vs. 55.7[46.7–66.4] mg hour/L, P ≤ 0.001 and 5.06 [4.11–6.76] vs. 6.32 [5–7.44], µg/mL, P = 0.01).ConclusionThe incidence of ARC observed was similar to adult studies. Patients that exhibited ARC had lower AUC24 and CMAX; thus, higher doses may be warranted. Disclosures All authors: No reported disclosures.