Use of Real-World Data and Physiologically-Based Pharmacokinetic Modeling to Characterize Enoxaparin Disposition in Children With Obesity

Abstract

Dosing guidance for children with obesity is often unknown despite the fact that nearly 20% of US children are classified as obese. Enoxaparin, a commonly prescribed low-molecular-weight heparin, is dosed based on body weight irrespective of obesity status to achieve maximum concentration within a narrow therapeutic or prophylactic target range. However, whether children with and without obesity experience equivalent enoxaparin exposure remains unclear. To address this clinical question, 2,825 anti-activated factor X (anti-Xa) surrogate concentrations were collected from the electronic health records of 596 children, including those with obesity. Using linear mixed-effects regression models, we observed that 4-hour anti-Xa concentrations were statistically significantly different in children with and without obesity, even for children with the same absolute dose (P = 0.004). To further mechanistically explore obesity-associated differences in anti-Xa concentration, a pediatric physiologically-based pharmacokinetic (PBPK) model was developed in adults, and then scaled to children with and without obesity. This PBPK model incorporated binding of enoxaparin to antithrombin to form anti-Xa and elimination via heparinase-mediated metabolism and glomerular filtration. Following scaling, the PBPK model predicted real-world pediatric concentrations well, with an average fold error (standard deviation of the fold error) of 0.82 (0.23) and 0.87 (0.26) in children with and without obesity, respectively. PBPK model simulations revealed that children with obesity have at most 20% higher 4-hour anti-Xa concentrations under recommended, total body weight-based dosing compared to children without obesity owing to reduced weight-normalized clearance. Enoxaparin exposure was better matched across age groups and obesity status using fat-free mass weight-based dosing.

Figure 1

Box plots of (a, c) observed anti‐Xa concentrations and (b, d) dose‐normalized 4‐hour anti‐Xa concentrations for children with vs. without obesity receiving enoxaparin for (a, b) treatment and (c, d) prophylaxis. Dashed lines represent the target anti‐Xa concentration range for treatment and prophylaxis. The P values for comparing the median concentration in children with vs. without obesity are (a) < 0.001, (b) 0.004, (c) 0.12, and (d) 0.12. Conc, concentration.

Figure 2

Changes in simulated enoxaparin absolute and weight‐normalized (a, c) CL and (b, d) V _d with obesity status for children ages 2 to < 6 years, 6 to < 12 years, and 12–18 years with and without obesity. Simulated children (n = 1,000 per group) received 1 mg/kg subcutaneous doses twice‐daily of enoxaparin. Boxes represent the median and IQR, and whiskers extend to 1.5 × IQR. CL, clearance; IQR, interquartile range; V _d, volume of distribution.

Figure 3

PBPK model‐simulated anti‐Xa 4‐hour concentrations following twice‐daily subcutaneous dosing of 0.2–1.5 mg/kg using (a, b) TBW or (c, d) FFM for children ages 12–18 years (a, c) without and (b, d) with obesity (n = 1,000 children per group). A full range of dosing was simulated to assess both treatment and prophylaxis target therapeutic concentration ranges. Boxes represent the median and IQR, and whiskers extend to 1.5 × IQR. Red and black dashed lines represent the target ranges for treatment (0.6–1.0 IU/mL) and prophylaxis (0.1–0.3 IU/mL) dosing, respectively., Similar plots for children 2 to < 6 and 6 to < 12 years are presented in Figures  S6 and S7 . FFM, fat‐free mass; IQR, interquartile range; IU, international unit; PBPK, physiologically‐based pharmacokinetic; TBW, total body weight.