PT-016 - POPULATION PHARMACOKINETIC MODELING TO GUIDE THE OPTIMAL DOSING FOR UNFRACTIONATED HEPARIN IN PEDIATRICS REQUIRING EXTRACORPOREAL MEMBRANE OXYGENATION.

A. Salem¹, T. Smith², J. Wilkes², D. Bailly³, V. Yellepeddi³, M. Gopalakrishnan¹; ¹University of Maryland, Baltimore, MD, USA, ²Intermountain Healthcare Primary Children's Hospital, Salt Lake City, UT, USA, ³University of Utah, Salt Lake City, UT, USA.

Background: Unfractionated heparin (UFH) is the gold standard anticoagulant for pediatrics on extracorporeal membrane oxygenation (ECMO), however, there is a lack of evidence on selecting the optimal dose [1]. We aimed to: (i) develop a population pharmacokinetic (PopPK) model for UFH, measured through anti-factor Xa assay, and (ii) use simulations to optimize starting infusions and dose titrations and enhance reaching the anti-factor Xa therapeutic target (0.3-0.7 IU/mL).

Methods: Retrospective electronic health record data were collected from 218 pediatrics ( < 19 years) who received UFH infusions while on ECMO. The curated data included longitudinal records of anti-factor Xa levels, UFH doses and clinical characteristics. The PopPK model development and simulations were done using nonlinear mixed effect modeling in Pumas v2.1.

Results: A one-compartment PopPK model with time varying clearance (CL) best fit the data. Significant covariates included: weight on CL and volume of distribution, ECMO circuit change on CL and, duration of ECMO on first order rate constant to reach steady state CL. Matching with non-ECMO pediatric patients [2], the typical estimate for steady state CL was 3.4 L/(h·50 kg) [95% confidence interval (CI) = 2.9 - 3.8 L/(h·50 kg)]. Simulations showed that starting infusions of 25 and 15 IU/h/kg for pediatrics < 1 year, and pediatrics ≥1 year, respectively, achieved the therapeutic target in 58% of patients while only 5% were above the target after the initial dose. The proposed UFH titration scheme achieved the target in 77% & 95% of patients while only 5% & 2% were above the target after 24 and 48 hours of treatment, respectively.

Conclusion: A PopPK model of UFH was developed for all pediatrics (neonates to adolescents) on ECMO. The proposed UFH dosing scheme achieved the anti-factor Xa target rapidly and safely.

[1] McMichael, A.B., Ryerson, L.M., Ratano, D., Fan, E., Faraoni, D. and Annich, G.M. 2021 ELSO Adult and Pediatric Anticoagulation Guidelines. ASAIO. J. 68, 303-310 (2021).
[2] Salem, A. M., Niu, T., Li, C., Moffett, B. S., Ivaturi, V., Gopalakrishnan, M. Reassessing the Pediatric Dosing Recommendations for Unfractionated Heparin Using Real‐World Data: A Pharmacokinetic–Pharmacodynamic Modeling Approach. J. Clin. Pharmacol. 62, 733-746 (2022).