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

center dot Enoxaparin is an effective anticoagulant used to treat thromboembolic diseases. center dot Dose individualization of enoxaparin based on renal impairment and lean body weight reduces bleeding and bruising end-points for renally compromised and obese subjects. center dot 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 center dot The occurrence and severity of a bleeding or bruising event is described as a function of both cumulative enoxaparin AUC and subject age. center dot 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.