Dosing Strategy for Enoxaparin in Patients with Renal Impairment Presenting with Acute Coronary Syndromes

Green, B., Greenwood, M., Saltisi, D., Westhuyzen, J., Kluver, L., Rowell, J. and Atherton, J. (2005) Dosing Strategy for Enoxaparin in Patients with Renal Impairment Presenting with Acute Coronary Syndromes. British Journal of Clinical Pharmacology, 59 3: 281-290. doi:10.1111/j.1365-2125.2004.02253.x

Author Green, B.
Greenwood, M.
Saltisi, D.
Westhuyzen, J.
Kluver, L.
Rowell, J.
Atherton, J.
Title Dosing Strategy for Enoxaparin in Patients with Renal Impairment Presenting with Acute Coronary Syndromes
Journal name British Journal of Clinical Pharmacology   Check publisher's open access policy
ISSN 0306-5251
Publication date 2005-03-01
Sub-type Article (original research)
DOI 10.1111/j.1365-2125.2004.02253.x
Volume 59
Issue 3
Start page 281
End page 290
Total pages 10
Editor E. J. Begg
J. R. Ritter
M. S. Lennard
Place of publication UK
Publisher Blackwell Publishing
Language eng
Subject 320503 Clinical Pharmacology and Therapeutics
320500 Pharmacology and Pharmaceutical Sciences
730106 Cardiovascular system and diseases
Abstract Background Phase III clinical studies have confirmed that enoxaparin is superior to standard heparin in reducing the rate of recurrent ischaemic events in patients with non-ST elevation acute coronary syndromes. Patients with moderate to severe renal impairment were, however, excluded from these studies. Due to the hydrophilic disposition of enoxaparin, accumulation is likely in patients with renal dysfunction, thereby increasing the risk of haemorrhagic complications if standard weight adjusted treatment doses are used. Arbitrary dose reduction has been reported to increase the risk of ischaemic events, presumably due to inadequate enoxaparin concentrations. Aim The aims of this study were to investigate the influence of glomerular filtration rate (GFR) on the pharmacokinetics of subcutaneously administered enoxaparin, and to develop a practical dosing algorithm in renal impairment that can easily be used at the bedside. Methods Thirty-eight patients, median age 78 years (range 44–87), mean GFR 32 ml min1 (range 16–117) and mean weight 69 kg (range 32–95), presenting with acute coronary syndrome were recruited into the study. Approximately 10 anti-Xa concentrations were taken per patient over their period of therapy. A population pharmacokinetic model was developed using non linear mixed effects modelling techniques, utilizing the software NONMEM. Stochastic simulations were performed to identify the most suitable dosing regimen. Results Three hundred and thirteen anti-Xa concentrations were collected. A two compartment, first order input model was identified as the best baseline model. Covariates found to improve model fitting were GFR as a linear function on clearance (CL) and weight as a linear function on the central volume compartment (Vc). The fraction of drug excreted unchanged (Fu) was estimated at 71%. CL and Vc from the final covariate model were estimated as; CL (l h1) = 0.681 per 4.8 l hr1 (GFR) + 0.229 Vc (l) = 5.22 per 80 kg (total body weight) Conclusions Clearance of enoxaparin was predictably related to GFR estimated using the Cockroft and Gault equation, with ideal body weight used as the size descriptor. According to our model no dosage adjustment from the standard 1.0 mg kg1 12 hourly is required for the first 48 h of treatment. Maintenance doses thereafter can be calculated using standard proportional adjustments based on Fu equal to 0.71.
Keyword Pharmacology & Pharmacy
Kidney Failure
Molecular-weight Heparin
Unstable Angina Patients
Unfractionated Heparin
Timi 11b
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
2006 Higher Education Research Data Collection
School of Pharmacy Publications
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Citation counts: TR Web of Science Citation Count  Cited 41 times in Thomson Reuters Web of Science Article | Citations
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Created: Fri, 21 Dec 2007, 10:23:08 EST by Laura McTaggart on behalf of School of Pharmacy