P-1237. Vancomycin Population Pharmacokinetics and Toxicity-Exposure Relationships in Children with Multiple Organ Dysfunction Syndrome

Abstract Background Vancomycin (VAN) is a first line antibiotic for severe gram-positive bacterial infections in pediatrics but is associated with exposure-dependent kidney injury. In children with multiple organ dysfunction syndrome (MODS), most initial VAN dosing is guided via weight-based approaches. We developed a population pharmacokinetic (popPK) model for children with MODS to evaluate the relationship between acute kidney injury (AKI) and VAN exposures (area under the concentration-time curve [AUC]).Table 1.Population PK parameter fixed effects estimates and random effects (i.e. between subject variability) for central volume of distribution(V1), clearance (CL), beta coefficients on weight adjusted (individual weight/28.4kg) for V1 and CL, peripheral volume of distribution (V2), and intercompartmental bi-directional flow (Q).Figure 1.Observed vs. (A) population and (B) individual predictions for the model. Methods We conducted a multi-center prospective observational PK study (AMPLE) embedded in a larger study of critically ill children with MODS (PARADIGM). Up to 15 PK samples were collected via volumetric absorptive microsampling over 3 days. Parametric popPK modeling was performed using Monolix 2024R1. Covariate inclusion was based on objective function and physiologic relevance. VAN AUC0-24 and AUC24-48 for each child were calculated using Empiric Bayes Estimates in Simulx 2024R1. AKI was considered a 0.3 mg/dL or 50% increase from ICU baseline. Sensitivity and specificity for classifying AKI at each AUC was calculated. A stepwise multivariate analysis determined factors (including AUC) associated with AKI.Figure 2.Sensitivity and specificity rates of specific AUC values.Table 2.Logistic regression analysis for stage 1 AKI. Results 66 subjects were included (median age of 10 y [range: 1 m – 17 y], median weight of 30 kg [range: 3 – 214]). A two-compartment model with clearance adjusted for allometric scaling (weight0.75) and glomerular function (calculated using CKiD Under 25 [U25] equation) best described the data (Table 1, Fig. 1). Median AUC0-24 and AUC24-48 were 454 mg*hr/L (range: 194-1569) and 505 (range: 8-1994), respectively. 7 total subjects met criteria for ICU-emergent AKI. An AUC24-48 of 465.8 mg*hr/L maintained the best sensitivity (100%) whereas at AUCs ≥ 545.5 mg*hr/L sensitivity dropped to ≤ 20% (Fig. 2). In the multivariate analysis only the Proulx score for classifying MODS was significant for AKI (6.68 OR, 95% CI 1.1 – 40.8, Table 2). Conclusion Children with MODS had widely varying AUCs. AUCs ≥ 465.8 best identified AKI. In children with MODS, ICU-emergent AKI occurred within the current targeted therapeutic range. AUCs should be maintained as low as feasible. Disclosures Nathaniel J. Rhodes, PharmD MS, Apothecademy, LLC: Advisor/Consultant Mark Hall, MD FCCM, Abbvie: Advisor/Consultant|Kiadis: Licensing income unrelated to this submission|Partner Therapeutics: Partner Therapeutics provides study drug for a clinical trial for which I am PI. This trial is unrelated to the submitted abstract|Sobi: Sobi provides study drug for a clinical trial for which I am PI. This trial is unrelated to the submitted abstract Kevin J. Downes, MD, Paratek Pharmaceuticals, Inc.: Grant/Research Support|Veloxis Pharmaceuticals, Inc.: Grant/Research Support Marc H. Scheetz, PharmD, MSc, Doseme: Advisor/Consultant|other: Additional not relevant to this abstract. If more information is needed about unrelated relationships, I can provide it.