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Population Pharmacokinetics of Levetiracetam in Patients with Traumatic Brain Injury and Subarachnoid Hemorrhage Exhibiting Augmented Renal Clearance

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Abstract

Background and Objective

Patients with severe trauma exhibit augmented renal clearance, which can alter the dosing requirement of renally eliminated drugs. This study aimed to develop a population pharmacokinetic model for levetiracetam in patients with severe traumatic brain injury and aneurysmal subarachnoid hemorrhage, and use it to describe optimal dosing regimens.

Methods

This was a prospective open-label observational study. Critically ill adult patients with severe traumatic brain injury or aneurysmal subarachnoid hemorrhage without renal dysfunction and receiving levetiracetam were eligible. Serial levetiracetam plasma concentrations were analyzed to develop a population pharmacokinetic model and perform dosing simulations.

Results

A two-compartment model best described the concentration–time data from 30 patients. The mean ± standard deviation parameter estimates were bioavailability (F) of 0.8 ± 0.2, absorption rate constant of 2.4 ± 2 h−1, clearance 2.5 ± 1.1 L/h, central volume of distribution 8.9 ± 3.0 L/h, and transfer rate constraints of 1.8 ± 1.1 h−1 from central to peripheral compartments and 0.7 ± 0.3 h−1 from peripheral to central compartments. For the simulated intermittent dosing regimens, on average, the median trough concentration reduced by 50% for every 40-mL/min/1.73 m2 increase in urinary creatinine clearance. Simulated doses of at least 6 g/day were required for some levels of augmented renal clearance.

Conclusions

Patients with severe traumatic brain injury and aneurysmal subarachnoid hemorrhage with augmented renal clearance are at risk of not achieving target levetiracetam plasma concentrations. We suggest dose titration guided by measured creatinine clearance, and/or, therapeutic drug monitoring if available, to minimize the risk of seizures.

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Acknowledgements

Jason A. Roberts acknowledges funding from the Australian National Health and Medical Research Council for a Centre of Research Excellence (APP1099452) and a Practitioner Fellowship (APP1117065).

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Authors and Affiliations

  1. University of Queensland Centre for Clinical Research, The University of Queensland, Building 71/918, Royal Brisbane & Women’s Hospital Campus, Herston, QLD, 4029, Australia

    Fekade Bruck Sime, Jason A. Roberts, Saurabh Pandey, Santosh Adiraju, Suzanne L. Parker, Steven C. Wallis, Jeffrey Lipman & Menino Osbert Cotta

  2. Centre for Translational Anti-Infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia

    Fekade Bruck Sime, Jason A. Roberts & Menino Osbert Cotta

  3. Department of Pharmacy, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia

    Jason A. Roberts

  4. Department of Intensive Care, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia

    Jason A. Roberts, Amelia Livermore, Jenie Butler & Jeffrey Lipman

  5. Division of Anesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France

    Jason A. Roberts & Jeffrey Lipman

  6. Kenneth G. Jamieson Department of Neurosurgery, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia

    Rosalind L. Jeffree

  7. Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia

    Rosalind L. Jeffree

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  1. Fekade Bruck Sime
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  2. Jason A. Roberts
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  4. Saurabh Pandey
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  6. Amelia Livermore
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  9. Steven C. Wallis
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  10. Jeffrey Lipman
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  11. Menino Osbert Cotta
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Corresponding authors

Correspondence to Fekade Bruck Sime or Menino Osbert Cotta.

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Funding

This work was supported by Grants from the Royal Brisbane and Women’s Hospital Foundation and the Intensive Care Foundation, Australia.

Conflict of interest

Fekade Bruck Sime, Jason A. Roberts, Rosalind L. Jeffree, Saurabh Pandey, Santosh Adiraju, Amelia Livermore, Jenie Butler, Suzanne L. Parker, Steven C. Wallis, Jeffrey Lipman, and Menino Osbert Cotta have no conflicts of interest that are directly relevant to the content of this article.

Consent to participate

All study participants provided written informed consent.

Consent for publication

All authors apporved and provided consent for publication.

Ethics approval

The University of Queensland and Royal Brisbane and Women’s Hospital Human Research Ethics Committees granted ethical clearance (Reference 2016000790 and HREC/16/QRBW/154, respectively).

Availability of data and material

Data are available provided that ethical clearance is obtained for additional access/use.

Code availability

The software used is freely available from LAPKB, University of Southern California, no custom code is applicable.

Authors’ contribution

FBS-data analysis, Pop PK modeling, writing manuscript; JAR-conception, review of study design, critical review of manuscript, RLJ-conception, review of study design, critical review of manuscript; SP-assay method development, sample analysis, review of manuscript; SA-assay method development, sample analysis, review of manuscript, AL-data collections, review of manuscript; JB-data collection, review of manuscript, SLP-assay method development, sample analysis, review of manuscript, SCW-assay method development, sample analysis, review of manuscript, JL-conception, critical review of manuscript, MOC-conception, study design, grant acquisition, supervision of data collections, critical review of manuscript.

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Sime, F.B., Roberts, J.A., Jeffree, R.L. et al. Population Pharmacokinetics of Levetiracetam in Patients with Traumatic Brain Injury and Subarachnoid Hemorrhage Exhibiting Augmented Renal Clearance. Clin Pharmacokinet 60, 655–664 (2021). https://doi.org/10.1007/s40262-020-00979-8

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  • DOI: https://doi.org/10.1007/s40262-020-00979-8

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