Modelling the occurrence and severity of enoxaparin‐induced bleeding and bruising events

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Enoxaparin is an effective anticoagulant used to treat thromboembolic diseases. • Dose individualization of enoxaparin based on renal impairment and lean body weight reduces bleeding and bruising end‐points for renally compromised and obese subjects. • Scant data exist that quantify the dose–exposure–adverse event relationship for enoxaparin, especially in subjects with renal impairment and/or obesity. WHAT THIS STUDY ADDS • The occurrence and severity of a bleeding or bruising event is described as a function of both cumulative enoxaparin AUC and subject age. • When compared with conventional (product label) dosing, dose individualization of enoxaparin based on lean body weight and renal function reduces the probability of a bleeding or bruising event. AIMS To develop a population pharmacokinetic–pharmacodynamic model to describe the occurrence and severity of bleeding or bruising as a function of enoxaparin exposure. METHODS Data were obtained from a randomized controlled trial ( n = 118) that compared conventional dosing of enoxaparin (product label) with an individualized dosing regimen. Anti‐Xa concentrations were sampled using a sparse design and the size, location and type of bruising and bleeding event, during enoxaparin therapy, were collected daily. A population pharmacokinetic–pharmacodynamic analysis was performed using nonlinear mixed effects techniques. The final model was used to explore how the probability of events in patients with obesity and/or renal impairment varied under differing dosing strategies. RESULTS Three hundred and forty‐nine anti‐Xa concentrations were available for analysis. A two‐compartment first‐order absorption and elimination model best fit the data, with lean body weight describing between‐subject variability in clearance and central volume of distribution. A three‐category proportional‐odds model described the occurrence and severity of events as a function of both cumulative enoxaparin AUC (cAUC) and subject age. Simulations showed that individualized dosing decreased the probability of a bleeding or major bruising event when compared with conventional dosing, which was most noticeable in subjects with obesity and renal impairment. CONCLUSIONS The occurrence and severity of a bleeding or major bruising event to enoxaparin, administered for the treatment of a thromboembolic disease, can be described as a function of both cAUC and subject age. Individualized dosing of enoxaparin will reduce the probability of an event.