Bruce Green(1), John Atherton(2), Justin Westhuyzen(2),Leeanne Kluver(2),David Saltisi(2)
(1) School of Pharmacy, University of Queensland, Australia, (2) Royal Brisbane Hospital, Queensland, Australia
Background: A dose adjustment strategy for enoxaparin in patients with renal impairment has recently been added to the product label in Australia. The recommendation is 100 IU/kg twice daily if estimated glomerular filtration rate (GFR) is >30ml/min, and 100 IU/kg daily if GFR is equal to or below this value. It is not known what impact this dosing strategy has on concentration time profiles of enoxaparin.
Aim:To undertake a population pharmacokinetic study to determine a suitable dosing strategy for patients with varying degrees of renal impairment.
Methods:
Patients admitted to the Royal Brisbane Hospital with Acute Coronary Syndrome were eligible for enrolment in the study. Patients recruited had varying degrees of renal function, and administered doses of enoxaparin ranged from 50 to 100 IU/kg (100 IU = 1mg) twice daily according to current guidelines. Approximately 10 blood samples to determine anti Xa concentration were taken per patient. A population pharmacokinetic model to describe the data was developed using FOCE with INTERACTION in NONMEM (version 5). Estimates of renal and non renal clearance were used to develop a dosing strategy for patients with varying degrees of renal function. This dosing strategy was tested by simulating a concentration time profile using the final covariate model in NONMEM. One hundred bootstrapped datasets were simulated. The optimal dose model was defined as that which could rapidly achieve the desired enoxaparin concentration range of 500 to 1000 IU/L.Results: Thirty-five patients were recruited in the study with an estimated glomerular filtration rate (GFR) that ranged from 17 to 92 ml/min. A two compartment first order input model with log normal between subject variability (BSV) on clearance (CL), central volume compartment (Vc) and basal anti Xa activity, with additive and proportional residual variance was found to be the most suitable baseline structural model. The final covariate model included estimated GFR on CL according to the method described by Cockroft and Gault but where ideal body weight was used as the weight descriptor. The central volume compartment Vc was best described by total body weight. Fraction excreted unchanged was estimated at 75% and total clearance described by:
Total CL (L/hr) = 0.681/4.80 * (GFR) + 0.229
Using simulation experiments, the variable dosing regimen determined from the above equation appeared to predict desirable enoxaparin concentrations between 500 and 1000 IU/L after 7 days. A loading dose strategy of 100 IU/kg twice daily for 3 days, followed by an individualised dosing strategy dependent upon renal function appeared optimal. Simulations using manufacturer dosing guidelines did not appear to attain efficacious concentrations for those with an estimated GFR <30ml/min. Those above 30ml/min appeared satisfactory for the first three days, although accumulation appeared to occur thereafter.
Conclusions: Current dose guidelines for enoxaparin in patients with renal impairment do not seem to result in a desirable concentration time profile of 500 to 1000 IU/L. This appears rapidly achievable by giving 100 IU/kg twice daily for 3 days, then dose individualising based on renal function.
Reference: PAGE 12 (2003) Abstr 394 [www.page-meeting.org/?abstract=394]
Poster: poster