Article date: November 2009
By: Michael A. Barras, Stephen B. Duffull, John J. Atherton, Bruce Green, in Volume 68, Issue 5, pages 700-711
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
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.
DOI: 10.1111/j.1365-2125.2009.03518.x
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