A004: Cefepime Population Pharmacokinetics Using Volumetric Absorptive Microsampling in Critically Ill Children With Multiple Organ Dysfunction Syndrome

Statement of Purpose, Innovation or Hypothesis: Cefepime is a broad-spectrum beta-lactam antibiotic commonly used for empiric treatment of sepsis in children. The PK of cefepime in critically ill children has been understudied, in part due to challenges of performing PK studies in this population. Volumetric absorptive microsampling (VAMS) can overcome some barriers to pediatric PK studies by allowing for precisely timed sampling using small blood volumes, but fewer data exist for whole blood sampling (e.g. VAMS) vs plasma. The primary objective of this study was to develop a population PK (popPK) model for cefepime in critically ill children with MODS using VAMS. Our secondary objective was to compare cefepime PK using VAMS to a published popPK model of plasma cefepime in critically ill children.

Description of Methods & Materials: We conducted a multi-center prospective study of cefepime PK in pediatric MODS. Children ( < 18 years) participating in a larger study of children with MODS in the ICU (PARADIGM; R01HD095976; PI: Hall) were eligible. Children on CRRT were excluded from analyses. Up to 15 PK samples were collected over 3 consecutive days, along with pertinent covariate data. Parametric popPK modeling was performed using Monolix version 2023R1. Ultimate covariate inclusion was based on improvements in objective function value and physiological viability. After model development, we then re-parameterized the model to be consistent with a published popPK model of cefepime in critically ill children (de Cacqueray 2022) to understand how PK using VAMS (whole blood) compare to a model developed with plasma samples.

Data & Results: Twenty-one subjects were included with a median age of 10y (range: 5m-17y) and a median weight of 32 kg (range: 6 kg-150 kg). One participant was on ECMO. Median PELOD-2 score (severity of illness indicator) and eGFR on the first day of PK sampling were 7 (range 0-13) and 100 ml/min/1.73m² (range 23-327), respectively. A two-compartment base model with allometric scaling best described the data. Of the covariates tested, GFR (calculated using CKiD Under 25 [U25] equation) and TNF-α (natural log-transformed) significantly improved estimation of CL. Final parameter estimates of our model are shown in Table 1. Observed versus predicted concentrations are shown in Figure 1. For comparison to the historical plasma cefepime model, we parametrized our data as a one compartment model with allometric scaling normalized to a weight of 9 kg; eGFR (calculated using Schwartz equation) was included as a covariate on clearance. Final estimates for CL (1.21 vs 1.61 L/h) and volume (4.80 vs 8.57 L) were comparable between the published model and our study population, respectively.

Interpretation, Conclusion or Significance: In critically ill children with MODS, GFR and TNF-α significantly impacted cefepime CL. The PK parameters of cefepime in our study population using VAMS was similar to the previously published parameters for plasma cefepime in critically ill children using plasma, although our population was older and exclusively had MODS. Our findings suggest that VAMS is a viable alternative to plasma sampling for both the performance of pediatric PK studies and therapeutic drug monitoring of cefepime.

Citations/References: 1. de Cacqueray, N., Hirt, D., Zheng, Y., Bille, E., Leger, P. L., Rambaud, J., Toubiana, J., Chosidow, A., Vimont, S., Callot, D., Chouchana, L., Béranger, A., Tréluyer, J. M., Benaboud, S., & Oualha, M. (2022). Cefepime population pharmacokinetics and dosing regimen optimization in critically ill children with different renal function. Clinical microbiology and infection: the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 28(10), 1389.e1–1389.e7. https://doi.org/10.1016/j.cmi.2022.05.007 2. Pierce, C. B., Muñoz, A., Ng, D. K., Warady, B. A., Furth, S. L., & Schwartz, G. J. (2021). Age- and sex-dependent clinical equations to estimate glomerular filtration rates in children and young adults with chronic kidney disease. Kidney international, 99(4), 948–956. https://doi.org/10.1016/j.kint.2020.10.047