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

TL;DR

This study examines how vancomycin exposure relates to kidney injury in children with multiple organ dysfunction syndrome, finding that current dosing ranges may lead to kidney damage.

Contribution

The study provides a population pharmacokinetic model and identifies exposure thresholds for vancomycin associated with acute kidney injury in critically ill children.

Findings

Children with MODS had widely varying vancomycin AUCs, with ICU-emergent AKI occurring within the current therapeutic range.

An AUC24-48 of 465.8 mg*hr/L best identified AKI with 100% sensitivity.

The Proulx score for MODS was the only significant factor associated with AKI in multivariate analysis.

Abstract

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.

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).

Observed vs. (A) population and (B) individual predictions for the model.

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.

Sensitivity and specificity rates of specific AUC values.

Logistic regression analysis for stage 1 AKI.

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).

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.

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.

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