Pharmacokinetic variability of the absorption of enoxaparin used subcutaneously for venous thromboembolism prophylaxis
Chantel, S.(1,2), P. Martin(1,2), P.Y. Petit (3), D. Massignon(4), X. Dode(1), P. Maire (5), R.W. Jelliffe(6), G. Aulagner(1,2)
(1) Department of Pharmacy, Hôpital Cardiologique, Bron, France, (2) EA 3452, University H. Poincaré, Nancy, France, (3) Department of Anaesthesia, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France, (4) Department of Haematology, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France, (5) ADCAPT, Department of Pharmacy, Hôpital A. Charial, Francheville, France, (6) Laboratory of Applied Pharmacokinetics, University of South California, Los Angeles, USA
Introduction: The use of enoxaparin for the prophylaxis of venous thromboembolism (VTE) after orthopaedic surgery leads to an important pharmacokinetic variability, particularly for the absorption of the drug. The aim of this study was to determine the influence of morphological patients’ characteristics on the absorption (absorbed fraction - Fa, absorption constant - Ka) of enoxaparin used subcuteaneously for VTE prophylaxis in orthopaedic surgery.
Patients and methods: Sixty-nine patients (57 for total hip replacement, 12 for total knee replacement) were treated with subcutaneous enoxaparin, 4000 IU od at 7 am. Enoxaparin was administered according to the recommendations for the method of administration of the summary of product characteristics of Lovenox® (Sanofi-Aventis).
Three blood samples for anti-Xa activity measurement were taken in each patient. Population pharmacokinetic analysis was performed using the NPEM2 program (version 11.7), with a one-compartment linear model which was found the best to describe the distribution of pharmacokinetic parameters in the population.
Individual parameters (Fa, Ka, clearance) were estimated by MAP (Maximum A posteriori Probability) Bayesian method. Correlations between each individual parameter value and the patient’s covariates (weight, height, body mass index - BMI, body surface area - BSA, overweight, …) were tested.
Results - Discussion: Thirty-eight men and 31 women were included (age 65±13 years, body weight 79±14 kg, BMI 28±4 kg/m²). Nineteen patients (28%) were considered to be obese patients (BMI >30 kg/m²).
The population estimates (mean ± standard deviation, coefficient of variation) were Ka = 0.484 ± 0.330 h-1 (68%), Fa = 0.713 ± 0.206 (29%), Cl = 0.983 ± 0.449 (46%). Ka was not correlated with any covariate as body weight, body mass index or overweight. In contrast, Fa was negatively correlated with body weight (r=-0.282, p=0,02) and with body surface area (r=-0.308, p=0.02), indicating that enoxaparin is absorbed in a lesser fraction in the heaviest patients than in the lightest. Moreover, Fa is higher in non obese patients than in the obese ones (0.748 vs. 0.641, p=0.03).
The multiple regression analysis shows that the clearance is mainly explained by 2 independent factors: the body weight (p=0,03) and the absorbed fraction (p<0,001).
Conclusion: The absorption of enoxaparin is clearly related to the patients’ weight, and could explain why the body exposure to the drug is lesser in the heaviest patients than in the lightest ones. Therefore, a weight-adapted dose may reduce the pharmacokinetic variability of enoxaparin.