Abstract
Background and Objective: Pediatric dosing of enoxaparin was derived based on extrapolation of the adult therapeutic range to children. However, a large fraction of children do not achieve therapeutic anticoagulation with initial dosing. We aim to use real-world anti-Xa data obtained from children receiving enoxaparin per standard of care to characterize the population pharmacokinetics (PopPK).Author names: Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Also, kindly confirm the details in the metadata are correct.The author names are accurately presented and the metadata are correct. Methods: A PopPK analysis was performed using NONMEM, and a stepwise covariate modeling approach was applied for the covariate selection. The final PopPK model, developed with data from 1293 patients ranging in age from 1 day to 18 years, was used to simulate enoxaparin subcutaneous dosing for prophylaxis and treatment based on total body weight (0–18 years, TBW) or fat-free mass (2–18 years, FFM). Simulated exposures in children with obesity (body mass index percentile ≥95th percentile) were compared with those without obesity. Results: A linear, one-compartment PopPK model that included allometric scaling using TBW (<2 years) or FFM (≥2 years) characterized the enoxaparin pharmacokinetic data. In addition, serum creatinine was identified as a significant covariate influencing clearance. Simulations indicated that in patients aged <2 years, the recommended 1.5 mg/kg TBW-based dosing achieves therapeutic simulated concentrations. In pediatric patients aged ≥2 years, the recommended 1.0 mg/kg dose resulted in exposures more comparable in children with and without obesity when FFM weight-based dosing was applied. Conclusion: Using real-world data and PopPK modeling, enoxaparin’s pharmacokinetics were characterized in pediatric patients. Using FFM and twice-daily dosing might reduce the risk of overdosing, especially in children with obesity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 999-1014 |
| Number of pages | 16 |
| Journal | Clinical Pharmacokinetics |
| Volume | 63 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2024 |
Funding
Pediatric Trials Network (PTN) Steering Committee Members: Daniel K. Benjamin Jr., Kanecia Zimmerman, Phyllis Kennel, Cheryl Alderman, Zoe Sund, Kylie Opel, and Rose Beci, Duke Clinical Research Institute, Durham, NC; Chi Dang Hornik, Duke University Medical Center, Durham, NC; Gregory L. Kearns, Scottsdale, AZ; Matthew Laughon, University of North Carolina at Chapel Hill, Chapel Hill, NC; Ian M. Paul, Penn State College of Medicine, Hershey, PA; Janice Sullivan, University of Louisville, Louisville, KY; Kelly Wade, Children\u2019s Hospital of Philadelphia, Philadelphia, PA; Paula Delmore, Wichita Medical Research and Education Foundation, Wichita, KS; Leanne West, International Children\u2019s Advocacy Network; Susan Abdel-Rahman. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): Ravinder Anand, Elizabeth Payne, Lily Chen, Gina Simone, Kathleen O'Connor, Jennifer Cermak, and Lawrence Taylor, The Emmes Company, LLC (Data Coordinating Center). PTN Publications Committee: Thomas Green (Chair), Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, IL; Danny Benjamin; Perdita Taylor-Zapata; Kelly Wade; Greg Kearns; Ravinder Anand; Ian Paul; Julie Autmizguine; Edmund Capparelli; Kanecia Zimmerman; Rachel Greenberg; Cheryl Alderman; Terren Green. The PTN Data Repository sites principal investigator (study team) are as follows: Andrew Atz (Leslie Lenert, John Clark, and Kalyan Chundru), Medical University of South Carolina, Charleston, SC, USA; Catherine Bendel (Brian Harvey and Sonya Grillo), University of Minnesota, Minneapolis, MN, USA; Francis Chan (Stephanie Fan), Lorma Linda University, Lorma Linda, CA, USA; Kevin Downes and Robert Grundmeier (Mark Ramos and Shawn O\u2019Connor, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA; Benjamin Fogel, Penn State University, University Park, PA, USA; Debbie Gipson (Samara Attala, Richard Eickstadt, Erin Kaleba, Don Liamini, Jamie Estill, Jeremy Jared, and Peter Bow), University of Michigan, Ann Arbor, MI, USA; Matt Laughon (Jennifer Talbert and Cindy Clark), University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Michael Miller, William Muller, Ann and Robert H. Lurie Childrens Hospital of Chicago, Chicago, IL, USA; Michael Smith (Janice Sullivan, Steve Heilman, KP Singh, Satish Vuyyuri, Jeff Schwitters, and Don Stone), University of Louisville and Norton Healthcare, Louisville, KY, USA. We would like to acknowledge Terren Green for providing editorial support. This research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) under award 5R01HD096435. The enoxaparin pediatric data were collected by the Pediatric Trials Network (PTN) through NICHD contract HHSN275201000003I (Principal Investigator (PI): Daniel K. Benjamin, Jr.). F.O.C. and V.E.H. were supported through a University of North Carolina at Chapel Hill/GlaxoSmithKline (GSK) Pharmacokinetics/Pharmacodynamics Fellowship. J.G.G. received research support from a National Institute of General Medical Sciences (NIGMS) funded T32 program (T32GM122741), a Fred Eshelman Pre-Doctoral Fellowship in Pharmaceutical Sciences from the American Foundation for Pharmaceutical Education (AFPE), and a PharmAlliance travel award. D.G. received research support from the NICHD (5R01HD096435 and 1R01HD102949). The content is solely the authors\u2019 responsibility and does not necessarily represent the official views of the National Institutes of Health.
ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)
