期刊
CLINICAL PHARMACOLOGY & THERAPEUTICS
卷 112, 期 2, 页码 391-403出版社
WILEY
DOI: 10.1002/cpt.2618
关键词
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资金
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [5R01HD096435]
- Pediatric Trials Network (PTN) through NICHD [HHSN275201000003I]
- National Institute of General Medical Sciences (NIGMS) [T32GM122741]
- American Foundation for Pharmaceutical Education (AFPE)
- Pharm Alliance travel award
- UNC/GSK Pharmacokinetics/Pharmacodynamics Post-Doctoral Fellowship
- NICHD [5R01HD096435-04, 1R01HD102949-01A1, R13HD102136, RL1HD107784]
- National Heart Lung and Blood Institute (NHLBI) [R61/R33HL147833]
- US Food and Drug Administration [R01-FD006099, U18-FD006298]
- US government for his work in pediatric clinical pharmacology [HHSN275201800003I]
Dosing guidance for children with obesity is often unknown and it remains unclear whether children with and without obesity experience equivalent enoxaparin exposure. A physiologically-based pharmacokinetic model was developed to explore the differences in anti-Xa concentration between children with and without obesity. The model showed that weight-normalized clearance was reduced in children with obesity, leading to higher anti-Xa concentrations under weight-based dosing. Fat-free mass weight-based dosing improved enoxaparin exposure across different age groups and obesity status.
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.
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