Lean body weight should guide enoxaparin dosing in obesity: A response to Roberts et al.

We read with interest the recent article by Roberts et al.1 comparing various body size descriptors with anti-Xa concentrations in obese and non-obese patients treated with enoxaparin. The authors note the weight-adjusted doses of enoxaparin using actual body weight may overdose obese individuals and increase the risk of bleeding. Using the standard dose of 1 mg/kg, the authors assessed the empirical correlation between anti-Xa concentrations and actual body weight (Wt), ideal body weight (IBW) and lean-body weight (LBW), as well as incremental increases (in 10% increments) above IBW and LBW. The authors concluded that the best weight metric for scaling enoxaparin doses in obese individuals was ideal body weight + 40% of weight in excess of ideal body weight. A similar result was found for LBW + 40%. We agree with the authors that using Wt to calculate enoxaparin dose is likely to result in overdosing in obese patients. Indeed, it is disappointing that Wt continues to be used in this population despite the well-documented increased risk of bleeding and the availability of established guidelines recommending dose reductions to improve safety.2 However, we wish to emphasize the need for a mechanistic application of the influence of body weight on drug clearance. The relationship between dose requirements and body weight arises from the strong correlation between drug clearance and body size and composition. Clearance (CL), which determines the maintenance dose at steady state, typically scales to an appropriate descriptor of body size. Wt is often used due to its reasonable correlation to drug metabolism and its ease of measurement. However, for most drugs, metabolism occurs in the non-fat (i.e., lean) portion of the body so the relationship between Wt and CL is nonlinear.3 Consequently, scaling CL by Wt in obese patients overestimates CL leading to over-estimation of maintenance dose and potential drug toxicity (bleeding in the case of enoxaparin). This highlights the need for alternative body size descriptors that better correlate with CL in obese individuals. LBW has become the preferred body size descriptor in population pharmacokinetic studies, and is a better scaler for drug CL than other metrics and is therefore a better predictor of dose requirements.4-6 Adipose tissue, which has no effect on enoxaparin CL, should not be included in dose estimations. Additionally, the use of IBW for dosing in obesity can potentially lead to erroneous dosing due to a bias estimate of drug clearance in this population.4 It has now been 17 years since the randomized-controlled trial by Barras et al., comparing a model-supported7 LBW-based dosing regimen to conventional dosing, was published.8 In that study, patients in the individualized arm experienced significantly fewer bleeding and bruising events without compromising treatment effectiveness. Although evidence demonstrating translation to optimal clinical outcomes remains limited, LBW-based doses in the range of 1.2–1.5 mg/kg have been proposed to correspond to target drug exposure (anti-Xa concentrations) in obese patients.6, 8 This is partially supported by the findings of Roberts et al., who reported that dosing based on LBW + 40% of weight in excess of ideal body weight correlated well with anti-Xa concentration. From a mechanistic perspective, however, IBW does not scale well with drug CL and its use in CL estimation and subsequent dose calculation is therefore likely to result in biased estimates as weight increases.4, 9 There is little justification for continuing an arbitrary dosing method based on Wt in obese patients when mechanism-based dose individualisation can be applied to enoxaparin. With the advent and availability of digital clinical decision support tools, the incorporation of LBW in dose estimations should be achievable.