Variability in Meropenem Distribution and Clearance in Children with Sepsis: Population-Based Pharmacokinetics with Assessment of Renal Biomarkers.

Abstract

Background and objective: Meropenem dosing to achieve therapeutic exposure in critically ill children with sepsis is challenging due to a spectrum of renal function, from augmented renal clearance (ARC) to acute kidney injury (AKI). The objective of this study was to define meropenem plasma concentrations and pharmacodynamic exposure metrics in children with septic shock during the first 3 days of PICU hospitalization.

Methods: We prospectively evaluated meropenem clearance (CL_MERO) and volume of distribution (V_1-MERO), innovatively assessing renal biomarkers (serum creatinine [SCr], serum cystatin C [SCys], and neutrophil gelatinase-associated lipocalin [SNgal]), in infants aged ≥ 4 weeks and children on intravenous (IV) meropenem 20 mg/kg every 8 h from 2019 to 2023. Cases with sepsis were matched to controls without sepsis.

Results: Analysis included 27 participants (19 cases and 8 controls) with 309 meropenem serum concentrations. Median age was 11.8 (range 0.6-19.6) years, weight 36.3 (7.2-98.0) kg, SCr 0.33 (0.09-2.57) mg/dL, SCys 451.1 (178.3-1824.1) ng/mL, and SNgal 180.7 (23.2-1403.0) ng/mL. A 2-compartment, population pharmacokinetic (PK) model via NONMEM best described data, with weight on V_MERO and allometric scaling on CL_MERO. Using the final model with SCys in V_1-MERO and estimated glomerular filtration rate (eGFR)-MS in CL_MERO, the median V_1-MERO was 0.23 (range 0.07-0.57) L/kg and CL_MERO 0.15 (0.05-0.49) L/h/kg, with eGFR-MS 139 (23-365) mL/min/1.73 m² from AKI to ARC. Meropenem clearance, V_1-MERO and eGFR-MS were significantly decreased in cases versus controls, with higher variability of eGFR-MS in cases.

Conclusion: Wide variation in meropenem concentrations in children with sepsis as compared to those without sepsis prompt close monitoring of GFR and drug concentrations in this population.