Letter to the Editor: Lean-Body Mass-Guided Heparin Dosing: A Pharmacokinetic Imperative

Dear Editor,

We read with great interest the recent study by Nguyen et al, ¹ “Adjusted Versus Total Body Weight Dosing for Intravenous Heparin Infusions and Target Attainment in Obese Patients,” which addresses a critical issue in anticoagulation therapy for individuals living with obesity. The authors’ comparison of total body weight (TBW) and adjusted body weight (ABW) dosing for intravenous heparin provides valuable clinical insight, particularly regarding the observed reduction in supratherapeutic heparin correlation values (HCV) with ABW-based dosing.

While the study investigates important aspects, the underlying pharmacokinetic (PK) methodology warrants closer scrutiny. Obesity significantly alters drug pharmacology, particularly through changes in drug clearance (CL) and volume of distribution (V), and to a lesser extent, gastrointestinal transit and absorption. The use of TBW to scale drug doses in patients living with obesity may overestimate clearance and maintenance dosing, given that drug elimination typically occurs primarily in the lean, fat-free portion of the body. Consequently, TBW-based dosing may increase the risk of supratherapeutic exposure and drug toxicity. ²

Alternative body size descriptors, such as ideal body weight (IBW), body surface area, or fat-free mass (FFM), have been proposed to more accurately account for obesity-related pharmacokinetic changes. ² FFM, in particular, accounts for body composition by excluding body fat and has emerged as a preferred scaler in population pharmacokinetic studies.^3,4 Sinha et al ⁵ provide a detailed review and comparison of FFM measurement and prediction methods, offering practical approaches to incorporate lean-body weight into PK modeling. Additionally, FFM has been found to correlate well with heparin clearance in children receiving a single dose of heparin. ³ By focusing on the lean portion of the body, FFM correlates more closely with drug clearance, offering a mechanistic rationale for individualized dose adjustment in patients living with obesity.

The study by Nguyen et al does not appear to incorporate these mechanistic considerations into dosing selection or PK modeling. Incorporating body composition metrics, such as FFM, into future pharmacokinetic and pharmacokinetic-pharmacodynamic (PK-PD) studies could refine dosing strategies, minimize supratherapeutic exposures, and improve safety outcomes. Furthermore, physiologically based pharmacokinetic (PBPK) modeling could offer a predictive framework for evaluating how obesity and dynamic changes in body composition impact heparin disposition and response. ² Lastly, it is worth noting that ABW was originally developed to normalize the volume of distribution of aminoglycosides in patients with excess body weight, and it has not been evaluated as a covariate for the pharmacokinetics of heparin.

In conclusion, while ABW-based heparin dosing may reduce supratherapeutic HCV in patients living with obesity, a deeper understanding of obesity-related pharmacokinetics is critical. Well-designed PK, PK-PD, and PBPK studies incorporating precise body size descriptors, such as FFM, are essential to optimize dosing, minimize toxicity, and guide evidence-based anticoagulation therapy in this growing patient population.

Andrej Belančić
Department of Basic and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia

Almir Fajkić
Department of Pathophysiology, Faculty of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina

Hesham Al-Sallami
College of Pharmacy, Qatar University, Doha, Qatar