PT-012 - FROM PICU TO NICU: REFINING MATURATION FACTOR FOR MEROPENEM CLEARANCE.

R. Morales Junior¹, W. Tan², T. Mizuno³, S. Tang-Girdwood⁴; ¹Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, ²Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, ³Cincinnati Children's Hospital, Cincinnati, OH, USA, ⁴Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Background: We previously developed a PopPK model for meropenem in pediatric intensive care unit patients (Morales Junior et al, 2024). Briefly, it is a two-compartment model that incorporates allometric body weight scaling, estimated glomerular filtration rate (GFR) on clearance and cumulative percentage of fluid balance on the central volume of distribution. Due to the absence of neonates our cohort, we adopted the post-menstrual age at which 50% of adult GFR is reached (PMA50: 47.7 weeks) and the Hill coefficient (3.4) from a previously established sigmoid hyperbolic model describing the GFR maturation with age (Rhodin et al, 2009). We aim to refine these estimates to effectively describe the maturation of meropenem clearance using an external dataset comprising of neonates and infants.

Methods: A dataset of 175 neonates and young infants, with 797 plasma meropenem concentrations, was obtained from regulations.gov website. The maturation factor parameters for the meropenem PopPK model were re-estimated using Monolix, while keeping all other parameters fixed from the original model. Due to missing data, the percentage of fluid balance values for the patients in the dataset was assumed to be 0. The concordance between the model predictions and observations was visually assessed using goodness of fit (GOF) plots and a prediction-corrected visual predictive check (pcVPC). A bootstrap analysis with 1,000 replicates was conducted, and the 95% CI for the maturation factor parameter estimates were computed.

Results: The new estimates for the maturation factor were a PMA50 of 36.9 weeks (RSE 4.3%) and a Hill coefficient of 1.8 (RSE 27.7%). Bootstrap results for the PMA50 (36.1 weeks, CI: 34.3 - 39.8) and the Hill coefficient (1.9, CI: 1.2 - 2.5) confirmed the final model's stability. The pcVPC showed observed data falling within the prediction intervals, and the GOF plots (Figure 1) show no evident trends or model misspecification.

Conclusion: The revised model, with updated maturation factor, can effectively capture the variability in meropenem concentrations in neonates and young infants. The results support the use of this updated model for Monte Carlo simulations and Model-Informed Precision Dosing for these young patients, potentially optimizing dosing strategies.