Modelling the occurrence and severity of enoxaparin-induced bleeding and bruising events.
OBJECTIVE
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.
Barras
Michael A
MA
School of Pharmacy, University of Queensland, Brisbane, Queensland, Australia.
Duffull
Stephen B
SB
Atherton
John J
JJ
Green
Bruce
B
D000925:Anticoagulants / Q000009:adverse effects* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017984:Enoxaparin / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced*; D006801:Humans; D007668:Kidney / Q000187:drug effects; D007674:Kidney Diseases / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009765:Obesity / Q000378:metabolism*; D012307:Risk Factors; D013923:Thromboembolism / Q000188:drug therapy*
D000925:Anticoagulants; D017984:Enoxaparin