S. Chantel(1), P.Y. Petit(2), P. Martin(1), D. Massignon(3), F. Saulnier(2), M. Benoist(2), S. Granger(2), P. Maire(4,5), R.W. Jelliffe(5), G. Aulagner(1)
(1) Department of Pharmacy, Hôpital Cardiologique, Bron, France; (2) Department of Anaesthesia, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France; (3) Department of Haematology, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France; (4) ADCAPT, Department of Pharmacy, Hôpital A. Charial, Francheville, France; (5) Laboratory of Applied Pharmacokinetics, University of South California, Los Angeles, USA
Introduction: Enoxaparin is usually given for venous thromboembolism prophylaxis in orthopaedic surgery, at a fixed dose of 40 mg subcutaneously once daily, without monitoring of anti-Xa levels. Pharmacokinetic variability of enoxaparin is now well documented in obese patients or in patients with chronic renal failure, but further investigations are required in a general population of in-patients.
Aim: To describe pharmacokinetic interindividual variability of enoxaparin used for venous thromboembolism prophylaxis after total hip replacement.
Methods: Three blood samples for anti-Xa activity measurement were taken in patients receiving enoxaparin during the study. Population pharmacokinetic analysis was performed using the NPEM2 program (version 11.7). A one compartment model was found to be the most suitable model to estimate population parameter values : clearance (Cl), apparent volume of distribution (Vol), elimination constant (Kel), absorption constant (Ka), weight-normalized volume of distribution (Vs=Vol/weight). Individual parameters were estimated by MAP (Maximum A posteriori Probability) Bayesian method. Correlations between each individual parameter value and covariates (body weight, ideal body weight, creatinine clearance) were tested.
Results: A total of 48 patients (men 54%, age 65±13 years, body weight 79±14 kg, creatinine clearance 78±21 ml/min) were included in this study. The population estimates (median ± standard deviation, coefficient of variation) were Cl = 1,18 ± 0,49 L/h (41%), Vol = 4,45 ± 2,08 L (49%), Kel = 0,34 ± 0,21 h-1 (80%), Ka = 1,62 ± 1,53 h-1 (95%), Vs = 0,052 ± 0,029 L/kg (56%). Individual estimated Cl was strongly correlated with body weight (r=0,715, p<0,001), ideal body weight (r=0,692, p<0,001), but not with creatinine clearance (r=0,170, NS). Vol was poorly correlated with body weight (r=0,288, p=0,03) and ideal body weight (r=0,314, p=0,03). Kel was not correlated with creatinine clearance (r=0,095, NS) neither with body weight (r=0,064, NS). Estimated peak activity (Cmax) ranged from 0,13 to 0,56 IU/mL, and was negatively correlated with body weight (r=-0,454, p<0,001). Estimated area under the concentration-time curve (AUC) ranged from 1,62 to 6,25 IU/mL.h.
Conclusion: Enoxaparin exhibits variable interindividual pharmacokinetics in a general population. Body weight is the best covariate which partly explains enoxaparin pharmacokinetic variability. Unfortunately, half of clearance variability remains unexplained.
Reference: PAGE 14 (2005) Abstr 762 [www.page-meeting.org/?abstract=762]
Poster: poster