LB-019 - MODEL-INFORMED DOSE OPTIMIZATION FOR PROPHYLACTIC PIPERACILLIN-TAZOBACTAM IN PERIOPERATIVE PEDIATRIC PATIENTS.

W. Tan¹, K. Irie², C. McIntire³, J. Torres³, R. Jones³, G. Abbie⁴, T. Mizuno^2,5, S. Tang Girdwood³; ¹Cincinnati Children Hospital Medical Center, , , ²Division of Translational and Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, , , ³Cincinnati Children's Hospital Medical Center, , , ⁴abigayle.gibson@cchmc.org, , , ⁵Department of Pediatrics, University of Cincinnati College of Medicine, , .

Background: Current international guidelines recommend that pediatric intraoperative dosing regimen for piperacillin/tazobactam (PTZ) be 90-112.5 mg/kg (80-100 mg/kg as piperacillin (PIP)) administered every 2 hours (Q2H). However, the risk of nephrotoxicity due to elevated PIP exposure underscores the need for optimization of this dosing regimen.

Methods: Thirty-four patients who received perioperative PTZ were identified as part of a prospective study of patients admitted to a pediatric ICU. The patients received 100 mg/kg PTZ Q2H intra-operatively and Q6H post-operatively. Plasma samples were collected via opportunistic sampling. Free PIP concentrations were measured by HPLC. Population PK modeling with 286 concentrations was performed using NONMEM with allometrically scaled weight on clearance and linearly scaled weight on volume. Subsequent simulations were performed to identify dosing regimens to achieve the targets of 100% T>1x or 4x MIC based on free PIP concentrations. The therapeutic goals were to maintain the concentration above 8 mg/L (1x MIC) and above 32 mg/L (4x MIC). Target attainment for >90% of virtual patients was considered adequate. The PK modeling and simulation analyses were completed in October 2023.

Results: A two-compartment model was found to adequately describe the PK data. Creatinine clearance was identified as a significant covariate on clearance. The inclusion of inter-occasion variability for peri- or post-operative occasions significantly improved model fit. Simulations showed that 15 mg/kg PIP Q2H and a 10 mg/kg PIP loading dose followed by 3.125 mg/kg/h continuous infusion would achieve 100 %T>1x MIC. For the target of 100 %T>4x MIC, 55 mg/kg PIP Q2H and a 15 mg/kg PIP loading dose followed by 9.375 mg/kg/h continuous infusion were identified to achieve the goal.

Conclusion: A free PIP PK model was developed for pediatric perioperative patients. Model-informed dosing recommendations were established to ensure target attainment while reducing the risk of high exposure; Q2H doses were much lower than what is recommended in current guidelines. Simulation results indicate that both Q2H and continuous infusion methods are clinically viable options. Future directions include conducting a larger-scale, prospective evaluation of the recommended dosing regimens.