Journal article
Nonlinear protein binding of phenytoin in clinical practice: Development and validation of a mechanistic prediction model
British journal of clinical pharmacology, Vol.85(10), pp.2360-2368
10/2019
DOI: 10.1111/bcp.14053
PMID: 31269540
Abstract
To individualize treatment, phenytoin doses are adjusted based on free concentrations, either measured or calculated from total concentrations. As a mechanistic protein binding model may more accurately reflect the protein binding of phenytoin than the empirical Winter-Tozer equation that is routinely used for calculation of free concentrations, we aimed to develop and validate a mechanistic phenytoin protein binding model.
Data were extracted from routine clinical practice. A mechanistic drug protein binding model was developed using nonlinear mixed effects modelling in a development dataset. The predictive performance of the mechanistic model was then compared with the performance of the Winter-Tozer equation in 5 external datasets.
We found that in the clinically relevant concentration range, phenytoin protein binding is not only affected by serum albumin concentrations and presence of severe renal dysfunction, but is also concentration dependent. Furthermore, the developed mechanistic model outperformed the Winter-Tozer equation in 4 out of 5 datasets in predicting free concentrations in various populations.
Clinicians should be aware that the free fraction changes when phenytoin exposure changes. A mechanistic binding model may facilitate prediction of free phenytoin concentrations from total concentrations, for example for dose individualization in the clinic.
Details
- Title: Subtitle
- Nonlinear protein binding of phenytoin in clinical practice: Development and validation of a mechanistic prediction model
- Creators
- Rob Ter Heine - Radboud institute for Health Sciences & Department of Pharmacy, Radboudumc, Nijmegen, The NetherlandsSean P Kane - Department of Pharmacy Practice, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USAAlwin D R Huitema - Department of Pharmacy & Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands & Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The NetherlandsMatthew D Krasowski - Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USAErik M van Maarseveen - Department of Clinical Pharmacy, Division of Laboratory Medicine and Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Resource Type
- Journal article
- Publication Details
- British journal of clinical pharmacology, Vol.85(10), pp.2360-2368
- DOI
- 10.1111/bcp.14053
- PMID
- 31269540
- NLM abbreviation
- Br J Clin Pharmacol
- ISSN
- 0306-5251
- eISSN
- 1365-2125
- Publisher
- England
- Language
- English
- Date published
- 10/2019
- Academic Unit
- Pathology
- Record Identifier
- 9984047777702771
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