Reassessing the Pediatric Dosing Recommendations for Unfractionated Heparin Using Real‐World Data: A Pharmacokinetic–Pharmacodynamic Modeling Approach

Abstract

Optimal pediatric dosing of unfractionated heparin (UFH) is challenging because of the paucity of clinical outcome and pharmacokineticpharmacodynamic (PK/PD) studies in pediatrics. This study aimed to: (i) develop a PK/PD model for UFH, quantified by anti-factor Xa assay, and the UFH effect, measured by activated partial thromboplastin time (aPTT); and (ii) use simulations to evaluate pediatric UFH infusions for achieving the anti-factor Xa (0.3-0.7 IU/mL) therapeutic target. Electronic health record data were retrospectively collected from 633 patients aged <19 years admitted to Texas Children's Hospital. The PK/PD model was developed using a 70% (training)/30% (testing) split-sample approach. A 1-compartment PK model with linear elimination adequately described the UFH PK. An allometrically scaled body weight on clearance (CL) and volume of distribution (Vd) with an age-dependent maturation function of extracellular water on Vd were the covariates identified. Comparable with literature, the typical values for CL and Vd were 3.28 L/(h•50 kg) and 8.83 L/50 kg, respectively. A linear model adequately described the UFH-aPTT relationship with an estimated slope of 150 seconds/(IU/mL). Simulations of the currently recommended starting infusions (28 IU/h/kg for pediatrics <1 year old or 20 IU/h/kg for pediatrics >1 year old) showed that the anti-factor Xa therapeutic target was achieved only in 15.3%, 14.6%, 36.9%, and 45.11% of subjects in the age groups of <1 year, 1-6 years, 6-12 years, and 12-19 years, respectively. In conclusion, the UFH anti-factor Xa target is not achieved initially, especially in young pediatrics, suggesting the need to optimize UFH dosing to achieve higher therapeutic success.

Pharmacokinetic Modeling Using Real‐World Data to Optimize Unfractionated Heparin Dosing in Pediatric Patients on Extracorporeal Membrane Oxygenation and Evaluate Target Achievement–Clinical Outcomes Relationship

“…20 The estimated typical steady-state CL value was consistent between ECMO and non-ECMO settings. 25,26,29,30 However, the consistency between CL under ECMO and non-ECMO conditions contradicts with a prior ECMO study in infants (n = 5), where UFH CL was approximately doubled during the ECMO session compared to after the decannulation procedure. 12 Considering the physicochemical properties, heparin is a hydrophilic drug that reduces the susceptibility of sequestration by ECMO circuits.…”

“…Interestingly, the recommendations from the study are similar to the published American College of Chest Physicians guidelines on the UFH starting infusion in non-ECMO pediatric patients (28 IU/h/kg for patients aged 1 year or younger and 20 IU/h/kg for patients aged older than 1 year), although some recent studies suggested starting infusions up to 33 IU/h/kg for younger children. 14,18,30,37 The proposed dose titration schemes (regimens 3, 4, and 5) were efficient in terms of increasing the percentage of patients within the antifactor Xa therapeutic target and lowering the percentage above the target compared to the current hospital protocol. Regimens 3 and 4 could be more practical for implementation given the complexity of regimen 5 in terms of dose adjustments based on the timing on ECMO.…”

Heparin Dosing Regimen Optimization in Veno-Arterial Extracorporeal Membrane Oxygenation: A Pharmacokinetic Analysis

“…To our knowledge, this is the first study to perform a PK analysis of UFH in adult VA-ECMO patients using a nonlinear mixed-effects modeling approach. Among the previous studies that investigated UFH PK [ 18 , 19 , 20 , 21 , 22 , 23 ], only a few focused on cardiopulmonary bypass (CPB) [ 21 , 22 ] or ECMO [ 23 ]. Similar analyses were performed in adult patients undergoing CPB for cardiac surgery, using either anti-activated factor II (anti-IIa) [ 21 ] or anti-Xa [ 22 ] assays.…”

A validated LC-MS/MS method for determination of antiviral prodrug molnupiravir in human plasma and its application for a pharmacokinetic modeling study in healthy Egyptian volunteers

“…Different absorption and disposition structural PK models were explored to fit NHC concentration time profiles as described previously [16] . Log-normal distribution was used to describe inter-individual variabilities (IIV) on PK parameters and multiple residual error models such as additive, proportional and combined error models were tried to describe the data [17] .…”