Advanced search
1 file | 852.56 KB

A physiologically based pharmacokinetic perspective on the clinical utility of albumin-based dose adjustments in critically ill patients

Huybrecht T'jollyn (UGent) , An Vermeulen (UGent) , Jan Van Bocxlaer (UGent) and Pieter Colin (UGent)
(2018) CLINICAL PHARMACOKINETICS. 57(1). p.59-69
Author
Organization
Abstract
Introduction: In hypo-albuminemia, the extent of albumin binding of a drug decreases. The resulting change in plasma protein binding only rarely leads to clinically relevant changes in unbound drug exposure. Nevertheless, in the critically ill, a tendency to increase dosing of anti-infective therapy is seen in patients experiencing hypo-albuminemia. To reconcile basic pharmacological principles with current clinical practice, this work presents a pharmacologically-based pharmacokinetic simulation study to emphasize the (lack of) effect of altered plasma protein binding on a drug's concentration-time profile and associated pharmacokinetic parameters. Methods: Four virtual compounds, representing a broad chemical space (low/high clearance/volume of distribution), were created and administered to a virtual population of normal patients and three types of hypo-albuminemic patients in Simcyp (R). The influence of decreased plasma protein binding in hypoalbuminemia on the pharmacokinetic parameters and profiles of these four compounds was investigated. Results: Simulation results showed that while high-clearance compounds suffer from increased unbound exposure with decreased plasma protein binding, the unbound exposure of low-clearance compounds was unaffected. However, for the subset of low-clearance compounds with a small volume of distribution, it appeared that there were still alterations in their plasma concentration-time profiles. Since this may lead to different times above a minimum inhibitory concentration value, this might affect the bacterial killing for some anti-infective drugs. Overall, for any compound involved in the simulations, the unbound exposure did not decrease in plasma protein binding subjects relative to normal plasma protein binding subjects. Discussion: This finding is in line with the few case-controlled studies in the literature. Hence, increasing the dose/dosing frequency seems futile and might reduce the benefit-risk ratio for narrow therapeutic index drugs. Moreover, these simulations indicate that when only total plasma concentrations and derived pharmacokinetic parameters are considered, incorrect conclusions will be drawn.
Keywords
PLASMA-PROTEIN BINDING, IN-VITRO DATA, INDUCED HYPOALBUMINEMIA, ANTIBACTERIAL AGENTS, VIVO, CLEARANCE, RELEVANCE, PHARMACODYNAMICS, ANTIBIOTICS, PREDICTION

Downloads

  • (...).pdf
    • full text
    • |
    • UGent only
    • |
    • PDF
    • |
    • 852.56 KB

Citation

Please use this url to cite or link to this publication:

Chicago
T’jollyn, Huybrecht, An Vermeulen, Jan Van Bocxlaer, and Pieter Colin. 2018. “A Physiologically Based Pharmacokinetic Perspective on the Clinical Utility of Albumin-based Dose Adjustments in Critically Ill Patients.” Clinical Pharmacokinetics 57 (1): 59–69.
APA
T’jollyn, H., Vermeulen, A., Van Bocxlaer, J., & Colin, P. (2018). A physiologically based pharmacokinetic perspective on the clinical utility of albumin-based dose adjustments in critically ill patients. CLINICAL PHARMACOKINETICS, 57(1), 59–69.
Vancouver
1.
T’jollyn H, Vermeulen A, Van Bocxlaer J, Colin P. A physiologically based pharmacokinetic perspective on the clinical utility of albumin-based dose adjustments in critically ill patients. CLINICAL PHARMACOKINETICS. 2018;57(1):59–69.
MLA
T’jollyn, Huybrecht, An Vermeulen, Jan Van Bocxlaer, et al. “A Physiologically Based Pharmacokinetic Perspective on the Clinical Utility of Albumin-based Dose Adjustments in Critically Ill Patients.” CLINICAL PHARMACOKINETICS 57.1 (2018): 59–69. Print.
@article{8548356,
  abstract     = {Introduction: In hypo-albuminemia, the extent of albumin binding of a drug decreases. The resulting change in plasma protein binding only rarely leads to clinically relevant changes in unbound drug exposure. Nevertheless, in the critically ill, a tendency to increase dosing of anti-infective therapy is seen in patients experiencing hypo-albuminemia. To reconcile basic pharmacological principles with current clinical practice, this work presents a pharmacologically-based pharmacokinetic simulation study to emphasize the (lack of) effect of altered plasma protein binding on a drug's concentration-time profile and associated pharmacokinetic parameters. 
Methods: Four virtual compounds, representing a broad chemical space (low/high clearance/volume of distribution), were created and administered to a virtual population of normal patients and three types of hypo-albuminemic patients in Simcyp (R). The influence of decreased plasma protein binding in hypoalbuminemia on the pharmacokinetic parameters and profiles of these four compounds was investigated. 
Results: Simulation results showed that while high-clearance compounds suffer from increased unbound exposure with decreased plasma protein binding, the unbound exposure of low-clearance compounds was unaffected. However, for the subset of low-clearance compounds with a small volume of distribution, it appeared that there were still alterations in their plasma concentration-time profiles. Since this may lead to different times above a minimum inhibitory concentration value, this might affect the bacterial killing for some anti-infective drugs. Overall, for any compound involved in the simulations, the unbound exposure did not decrease in plasma protein binding subjects relative to normal plasma protein binding subjects. 
Discussion: This finding is in line with the few case-controlled studies in the literature. Hence, increasing the dose/dosing frequency seems futile and might reduce the benefit-risk ratio for narrow therapeutic index drugs. Moreover, these simulations indicate that when only total plasma concentrations and derived pharmacokinetic parameters are considered, incorrect conclusions will be drawn.},
  author       = {T'jollyn, Huybrecht and Vermeulen, An and Van Bocxlaer, Jan and Colin, Pieter},
  issn         = {0312-5963},
  journal      = {CLINICAL PHARMACOKINETICS},
  keyword      = {PLASMA-PROTEIN BINDING,IN-VITRO DATA,INDUCED HYPOALBUMINEMIA,ANTIBACTERIAL AGENTS,VIVO,CLEARANCE,RELEVANCE,PHARMACODYNAMICS,ANTIBIOTICS,PREDICTION},
  language     = {eng},
  number       = {1},
  pages        = {59--69},
  title        = {A physiologically based pharmacokinetic perspective on the clinical utility of albumin-based dose adjustments in critically ill patients},
  url          = {http://dx.doi.org/10.1007/s40262-017-0549-x},
  volume       = {57},
  year         = {2018},
}

Altmetric
View in Altmetric
Web of Science
Times cited: