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Population pharmacodynamic model for low molecular weight heparin nadroparin in morbidly obese and non-obese patients using anti-Xa levels as endpoint

  • Pharmacodynamics
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Abstract

Purpose

In absence of specific dosing guidelines, the optimal dose of low molecular weight heparins for thrombosis prophylaxis in morbidly obese patients (BMI > 40 kg/m2) remains unknown. In order to guide dosing in this patient group, a pharmacodynamics model is developed for nadroparin in morbidly obese and non-obese patients using anti-Xa levels as an endpoint, thereby characterizing the influence of excessive body weight on different pharmacodynamic model parameters.

Methods

Twenty-eight morbidly obese and seven non-obese patients receiving 5700 IU and 2850 IU subcutaneous (s.c.) nadroparin for surgery, respectively, were included with a mean total body weight (TBW) of 135 kg (range 72–252 kg). Up to 11 anti-Xa levels were collected from the start until 24 h after nadroparin administration. Population pharmacodynamic modelling with covariate analysis was performed using NONMEM.

Results

In a two-compartment pharmacodynamic model with baseline endogenous anti-Xa levels, the effect of nadroparin was found to be delayed and could be best described using a transit compartment. TBW was the most predictive covariate for clearance (CL = 23.0 mL/min × (TBW/70)), while lean body weight (LBW) proved the most predictive covariate for central volume of distribution (V1 = 7.0 L × (LBW/60)).

Conclusions

A pharmacodynamic model was developed characterizing anti-Xa levels after s.c. administration of nadroparin in patients weighing between 72 and 252 kg with TBW and LBW as the major determinants for clearance and volume of distribution, respectively.

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Acknowledgments

The authors would like to thank Koos Dubbeldam for the laboratory assessments and Brigitte Bliemer and Silvia Samson for their enthusiastic support in this study.

Contributions of authors statement

Jeroen Diepstraten executed the study, participated in the design and informed consent, analysed data and wrote manuscript. Esther J.H. Janssen executed the study and participated in informed consent and analysing the data. Christian M. Hackeng analysed the blood samples and participated in the design and preparation of the manuscript. Eric P.A. van Dongen participated in the design, informed consent and preparation of the manuscript. René J. Wiezer participated in the design, informed consent and preparation of the manuscript. Bert van Ramshorst was the principal investigator who designed and supervised the study and participated in analysing the data and preparation of the manuscript. Catherijne A.J. Knibbe was the principal investigator who designed, supervised the study, analysed data and participated in preparation of the manuscript.

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Authors and Affiliations

  1. Department of Clinical Pharmacy, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands

    Jeroen Diepstraten, Esther J. H. Janssen & Catherijne A. J. Knibbe

  2. Department of Clinical Chemistry, St. Antonius Hospital, Nieuwegein, The Netherlands

    Christian M. Hackeng

  3. Department of Anesthesiology, Intensive Care and Pain Management, St. Antonius Hospital, Nieuwegein, The Netherlands

    Eric P. A. van Dongen

  4. Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands

    René J. Wiezer & Bert van Ramshorst

  5. Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands

    Catherijne A. J. Knibbe

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  1. Jeroen Diepstraten
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Corresponding author

Correspondence to Catherijne A. J. Knibbe.

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Diepstraten, J., Janssen, E.J.H., Hackeng, C.M. et al. Population pharmacodynamic model for low molecular weight heparin nadroparin in morbidly obese and non-obese patients using anti-Xa levels as endpoint. Eur J Clin Pharmacol 71, 25–34 (2015). https://doi.org/10.1007/s00228-014-1760-4

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  • DOI: https://doi.org/10.1007/s00228-014-1760-4

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