Development of a dosage strategy in patients receiving enoxaparin by continuous intravenous infusion using modelling and simulation

Yan Feng, Bruce Green, Stephen B. Duffull, Sandra L. Kane-Gill, Mary B. Bobek, Robert Bies

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Aim: To develop an appropriate dosing strategy for continuous intravenous infusions (CII) of enoxaparin by minimizing the percentage of steady-state anti-Xa concentration (Css) outside the therapeutic range of 0.5-1.2 IU ml-1. Methods: A nonlinear mixed effects model was developed with NONMEM® for 48 adult patients who received CII of enoxaparin with infusion durations that ranged from 8 to 894 h at rates between 100 and 1600 IU h-1. Three hundred and sixty-three anti-Xa concentration measurements were available from patients who received CII. These were combined with 309 anti-Xa concentrations from 35 patients who received subcutaneous enoxaparin. The effects of age, body size, height, sex, creatinine clearance (CrCL) and patient location [intensive care unit (ICU) or general medical unit] on pharmacokinetic (PK) parameters were evaluated. Monte Carlo simulations were used to (i) evaluate covariate effects on Css and (ii) compare the impact of different infusion rates on predicted Css. The best dose was selected based on the highest probability that the Css achieved would lie within the therapeutic range. Results: A two-compartment linear model with additive and proportional residual error for general medical unit patients and only a proportional error for patients in ICU provided the best description of the data. Both CrCL and weight were found to affect significantly clearance and volume of distribution of the central compartment, respectively. Simulations suggested that the best doses for patients in the ICU setting were 50 IU kg-1 per 12 h (4.2 IU kg-1 h-1) if CrCL 50 ml min-1. The best doses for patients in the general medical unit were 60 IU kg-1 per 12 h (5.0 IU kg-1 h-1) if CrCL 50 ml min-1. These best doses were selected based on providing the lowest equal probability of either being above or below the therapeutic range and the highest probability that the Css achieved would lie within the therapeutic range. Conclusions: The dose of enoxaparin should be individualized to the patients' renal function and weight. There is some evidence to support slightly lower doses of CII enoxaparin in patients in the ICU setting.

Original languageEnglish (US)
Pages (from-to)165-176
Number of pages12
JournalBritish Journal of Clinical Pharmacology
Volume62
Issue number2
DOIs
StatePublished - Aug 2006
Externally publishedYes

Fingerprint

Enoxaparin
Intravenous Infusions
Intensive Care Units
Creatinine
Weights and Measures
Medical Errors
Body Height
Body Size
Therapeutics
Linear Models
Pharmacokinetics
Kidney

Keywords

  • Creatinine clearance
  • Enoxaparin
  • NONMEM
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Development of a dosage strategy in patients receiving enoxaparin by continuous intravenous infusion using modelling and simulation. / Feng, Yan; Green, Bruce; Duffull, Stephen B.; Kane-Gill, Sandra L.; Bobek, Mary B.; Bies, Robert.

In: British Journal of Clinical Pharmacology, Vol. 62, No. 2, 08.2006, p. 165-176.

Research output: Contribution to journalArticle

Feng, Yan ; Green, Bruce ; Duffull, Stephen B. ; Kane-Gill, Sandra L. ; Bobek, Mary B. ; Bies, Robert. / Development of a dosage strategy in patients receiving enoxaparin by continuous intravenous infusion using modelling and simulation. In: British Journal of Clinical Pharmacology. 2006 ; Vol. 62, No. 2. pp. 165-176.
@article{208a12cc1a154966a01fad7cc153e69a,
title = "Development of a dosage strategy in patients receiving enoxaparin by continuous intravenous infusion using modelling and simulation",
abstract = "Aim: To develop an appropriate dosing strategy for continuous intravenous infusions (CII) of enoxaparin by minimizing the percentage of steady-state anti-Xa concentration (Css) outside the therapeutic range of 0.5-1.2 IU ml-1. Methods: A nonlinear mixed effects model was developed with NONMEM{\circledR} for 48 adult patients who received CII of enoxaparin with infusion durations that ranged from 8 to 894 h at rates between 100 and 1600 IU h-1. Three hundred and sixty-three anti-Xa concentration measurements were available from patients who received CII. These were combined with 309 anti-Xa concentrations from 35 patients who received subcutaneous enoxaparin. The effects of age, body size, height, sex, creatinine clearance (CrCL) and patient location [intensive care unit (ICU) or general medical unit] on pharmacokinetic (PK) parameters were evaluated. Monte Carlo simulations were used to (i) evaluate covariate effects on Css and (ii) compare the impact of different infusion rates on predicted Css. The best dose was selected based on the highest probability that the Css achieved would lie within the therapeutic range. Results: A two-compartment linear model with additive and proportional residual error for general medical unit patients and only a proportional error for patients in ICU provided the best description of the data. Both CrCL and weight were found to affect significantly clearance and volume of distribution of the central compartment, respectively. Simulations suggested that the best doses for patients in the ICU setting were 50 IU kg-1 per 12 h (4.2 IU kg-1 h-1) if CrCL 50 ml min-1. The best doses for patients in the general medical unit were 60 IU kg-1 per 12 h (5.0 IU kg-1 h-1) if CrCL 50 ml min-1. These best doses were selected based on providing the lowest equal probability of either being above or below the therapeutic range and the highest probability that the Css achieved would lie within the therapeutic range. Conclusions: The dose of enoxaparin should be individualized to the patients' renal function and weight. There is some evidence to support slightly lower doses of CII enoxaparin in patients in the ICU setting.",
keywords = "Creatinine clearance, Enoxaparin, NONMEM, Pharmacokinetics",
author = "Yan Feng and Bruce Green and Duffull, {Stephen B.} and Kane-Gill, {Sandra L.} and Bobek, {Mary B.} and Robert Bies",
year = "2006",
month = "8",
doi = "10.1111/j.1365-2125.2006.02650.x",
language = "English (US)",
volume = "62",
pages = "165--176",
journal = "British Journal of Clinical Pharmacology",
issn = "0306-5251",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - Development of a dosage strategy in patients receiving enoxaparin by continuous intravenous infusion using modelling and simulation

AU - Feng, Yan

AU - Green, Bruce

AU - Duffull, Stephen B.

AU - Kane-Gill, Sandra L.

AU - Bobek, Mary B.

AU - Bies, Robert

PY - 2006/8

Y1 - 2006/8

N2 - Aim: To develop an appropriate dosing strategy for continuous intravenous infusions (CII) of enoxaparin by minimizing the percentage of steady-state anti-Xa concentration (Css) outside the therapeutic range of 0.5-1.2 IU ml-1. Methods: A nonlinear mixed effects model was developed with NONMEM® for 48 adult patients who received CII of enoxaparin with infusion durations that ranged from 8 to 894 h at rates between 100 and 1600 IU h-1. Three hundred and sixty-three anti-Xa concentration measurements were available from patients who received CII. These were combined with 309 anti-Xa concentrations from 35 patients who received subcutaneous enoxaparin. The effects of age, body size, height, sex, creatinine clearance (CrCL) and patient location [intensive care unit (ICU) or general medical unit] on pharmacokinetic (PK) parameters were evaluated. Monte Carlo simulations were used to (i) evaluate covariate effects on Css and (ii) compare the impact of different infusion rates on predicted Css. The best dose was selected based on the highest probability that the Css achieved would lie within the therapeutic range. Results: A two-compartment linear model with additive and proportional residual error for general medical unit patients and only a proportional error for patients in ICU provided the best description of the data. Both CrCL and weight were found to affect significantly clearance and volume of distribution of the central compartment, respectively. Simulations suggested that the best doses for patients in the ICU setting were 50 IU kg-1 per 12 h (4.2 IU kg-1 h-1) if CrCL 50 ml min-1. The best doses for patients in the general medical unit were 60 IU kg-1 per 12 h (5.0 IU kg-1 h-1) if CrCL 50 ml min-1. These best doses were selected based on providing the lowest equal probability of either being above or below the therapeutic range and the highest probability that the Css achieved would lie within the therapeutic range. Conclusions: The dose of enoxaparin should be individualized to the patients' renal function and weight. There is some evidence to support slightly lower doses of CII enoxaparin in patients in the ICU setting.

AB - Aim: To develop an appropriate dosing strategy for continuous intravenous infusions (CII) of enoxaparin by minimizing the percentage of steady-state anti-Xa concentration (Css) outside the therapeutic range of 0.5-1.2 IU ml-1. Methods: A nonlinear mixed effects model was developed with NONMEM® for 48 adult patients who received CII of enoxaparin with infusion durations that ranged from 8 to 894 h at rates between 100 and 1600 IU h-1. Three hundred and sixty-three anti-Xa concentration measurements were available from patients who received CII. These were combined with 309 anti-Xa concentrations from 35 patients who received subcutaneous enoxaparin. The effects of age, body size, height, sex, creatinine clearance (CrCL) and patient location [intensive care unit (ICU) or general medical unit] on pharmacokinetic (PK) parameters were evaluated. Monte Carlo simulations were used to (i) evaluate covariate effects on Css and (ii) compare the impact of different infusion rates on predicted Css. The best dose was selected based on the highest probability that the Css achieved would lie within the therapeutic range. Results: A two-compartment linear model with additive and proportional residual error for general medical unit patients and only a proportional error for patients in ICU provided the best description of the data. Both CrCL and weight were found to affect significantly clearance and volume of distribution of the central compartment, respectively. Simulations suggested that the best doses for patients in the ICU setting were 50 IU kg-1 per 12 h (4.2 IU kg-1 h-1) if CrCL 50 ml min-1. The best doses for patients in the general medical unit were 60 IU kg-1 per 12 h (5.0 IU kg-1 h-1) if CrCL 50 ml min-1. These best doses were selected based on providing the lowest equal probability of either being above or below the therapeutic range and the highest probability that the Css achieved would lie within the therapeutic range. Conclusions: The dose of enoxaparin should be individualized to the patients' renal function and weight. There is some evidence to support slightly lower doses of CII enoxaparin in patients in the ICU setting.

KW - Creatinine clearance

KW - Enoxaparin

KW - NONMEM

KW - Pharmacokinetics

UR - http://www.scopus.com/inward/record.url?scp=33748267733&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33748267733&partnerID=8YFLogxK

U2 - 10.1111/j.1365-2125.2006.02650.x

DO - 10.1111/j.1365-2125.2006.02650.x

M3 - Article

C2 - 16842391

AN - SCOPUS:33748267733

VL - 62

SP - 165

EP - 176

JO - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

SN - 0306-5251

IS - 2

ER -