The bioavailability of a monoclonal antibody (mAb) or another therapeutic protein after subcutaneous (SC) dosing is challenging to predict from first principles, even if the impact of injection site physiology and drug properties on mAb bioavailability is generally understood. We used a physiologically based pharmacokinetic model to predict pre-systemic clearance after SC administration mechanistically by incorporating the FcRn salvage pathway in antigen-presenting cells (APCs) in peripheral lymph nodes, draining the injection site. Clinically observed data of the removal rate of IgG from the arm as well as its plasma concentration after SC dosing were mostly predicted within the 95% confidence interval. The bioavailability of IgG was predicted to be 70%, which mechanistically relates to macropinocytosis in the draining lymph nodes and transient local dose-dependent partial saturation of the FcRn receptor in the APCs, resulting in higher catabolism and consequently less drug reaching the systemic circulation. The predicted free FcRn concentration was reduced to 40–45%, reaching the minimum 1–2 days after the SC administration of IgG, and returned to baseline after 8–12 days, depending on the site of injection. The model predicted the uptake into APCs, the binding affinity to FcRn, and the dose to be important factors impacting the bioavailability of a mAb.

Aim: Current enoxaparin dosing guidelines in children are based on total body weight. This is potentially inappropriate in obese children as it may overestimate the drug clearance. Current evidence suggests that obese children may require lower initial doses of enoxaparin, therefore the aim of this work was to characterise the pharmacokinetics of enoxaparin in obese children and to propose a more appropriate dosing regimen.Methods: Data from 196 unique encounters of 160 children who received enoxaparin treatment doses were analysed. Enoxaparin concentration was quantified using the chromogenic anti factor Xa (anti‐Xa) assay. Patients provided a total of 552 anti‐Xa samples. Existing published pharmacokinetic (PK) models were fitted and evaluated against our dataset using prediction‐corrected visual predictive check plots (pcVPCs). A PK model was fitted using a nonlinear mixed‐effects modelling approach. The fitted model was used to evaluate the current standard dosing and identify an optimal dosing regimen for obese children.Results: Published models of enoxaparin pharmacokinetics in children did not capture the pharmacokinetics of enoxaparin in obese children as shown by pcVPCs. A one‐compartment model with linear elimination best described the pharmacokinetics of enoxaparin. Allometrically scaled fat‐free mass with an estimated exponent of 0.712 (CI 0.66‐0.76) was the most influential covariate on clearance while linear fat‐free mass was selected as the covariate on volume. Simulations from the model showed that fat‐free mass‐based dosing could achieve the target anti‐Xa activity at steady state in 77.5% and 78.2% of obese and normal‐weight children, respectively, compared to 65.2% and 75.5% for standard total body weight‐based dosing.Conclusions: A population PK model that describes the time course of anti‐Xa activity of enoxaparin was developed in a paediatric population. Based on this model, a unified dosing regimen was proposed that will potentially improve the success rate of target attainment in overweight/obese patients without the need for patient body size categorisation. Therefore, prospective validation of the proposed approach is warranted.