Population Pharmacokinetics of Enoxaparin in Neonates and Infants

Background – Enoxaparin is an anticoagulant used for preventing and treating venous thromboembolism. However, there is limited information on optimal enoxaparin dosing and an absence of evidence-based dosage regimens in neonates and infants, especially in critically ill patients. This project aims to develop a population pharmacokinetic model to describe the anti-factor Xa (anti-Xa) activity-time profile and to identify sources of variation in anti-Xa activity following enoxaparin subcutaneous administration in neonates and infants.Method – Anti-Xa activity, dosing, demographic and clinical covariates were obtained from the electronic health records of neonates and infants admitted between 2016 to 2021 for cardiac indications to the intensive care unit Riley Hospital for Children at Indiana University Health in Indianapolis, IN. Demographic data included date of birth, body weight, and laboratory measurements for serum creatinine (SCr), hemoglobin, and platelet count. PK modeling was performed using NONMEM 7.4 and Pirana 2.10 with the FOCE-I method. Goodness-of-fit plots were generated using xpose package in R 4.3. Stepwise covariate modeling was used for covariate selection based on model objective function value, relative standard error, BIC, and condition number. Results – This analysis included 499 patients with a median age of 2.2 (IQR, 0.9 – 4.9) mos, 24098 enoxaparin doses, and 2721 plasma samples analyzed for anti-Xa activity. The PK of enoxaparin was best characterized by a one-compartment model with first-order absorption and elimination. Inter- and intra-individual variability were modeled exponentially, and proportionally, respectively. The model that fit the data best integrated weight scaled allometrically with exponents of 0.75 and 1.0 on apparent clearance (CL/F) and apparent volume of distribution (Vd/F), respectively. The estimated population CL/F, Vd/F, and Ka were 1.27 L/h/70 kg (95% CI: 1.17 to 1.37), 26.9 L/70 kg (95% CI: 23.2 to 30.6), and 0.77 h-1 (95% CI: 0.36 to 1.18), respectively. The disposition of enoxaparin using anti-Xa activity as a surrogate was influenced by SCr and postnatal age (PNA). The Vd/F was notably affected by PNA, with higher exposure observed as age increased until about 1.5 mos PNA, at which point the effect plateaus. The final model incorporated SCr on CL/F using a power function with estimated effect of -0.21 (95% CI: -0.31 to -0.09). A piecewise function was used to model PNA on Vd/F with an inflection point of 1.5 mos, and an estimated effect of -0.57 (95% CI: -0.77 to -0.37).Conclusions – The estimated CL/F, and Vd/F of enoxaparin in neonates and infants in this study are higher than reported values in adults (CL/F ≈ 0.74 L/h, Vd/F ≈ 5.0 L). The inverse relationship between SCr and CL/F indicates dose adjustment may be required in this population. Additionally, pediatric patients less than 1.5 mos of age require higher body-weight adjusted doses of enoxaparin than older infants and adults.Citations: N/A