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Clinical Pharmacokinetic Monitoring of Free Valproic Acid Levels: A Systematic Review

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Abstract

Background

Current guidelines recommend therapeutic drug monitoring as a critical component of valproic acid (VPA) therapy. Due to high protein binding, the active unbound (free) portion of VPA can be misrepresented by total VPA serum levels in certain clinical scenarios. Monitoring free VPA serum levels may be warranted when assessing the clinical response to VPA therapy.

Objectives

The aims were to conduct a systematic review to identify a therapeutic range for free VPA serum levels; to explore the correlation of free VPA serum levels with clinical toxicity and therapeutic benefit; and to examine predictors of discordance between free and total VPA levels.

Methods

Medline, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, BIOSIS Previews, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched from the time of database inception to June 20, 2021. Randomized controlled trials and observational studies that evaluated any patient receiving VPA with free VPA level monitoring were included.

Results

Of 189 citations, we identified 27 relevant studies, which included 14 observational studies, two case series, and 11 case reports. Three studies provided a therapeutic range for free VPA levels between 20 and 410 μmol/L. Two studies suggested the occurrence of hyperammonemia and thrombocytopenia at free VPA serum levels above 60 µmol/L and 103.3 µmol/L, respectively. Two studies suggested an upper limit for neurotoxicity at free VPA serum levels of 70 µmol/L and 207.9 µmol/L. Hypoalbuminemia was identified as a predictor of therapeutic discordance.

Conclusions

This review demonstrates a paucity of data informing the clinical utility of free VPA serum levels. Further high-quality trials are needed to validate an optimal therapeutic range for free VPA levels.

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Acknowledgements

The authors would like to thank Ursula Ellis, reference librarian at the University of British Columbia, for their help with the literature search.

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  1. University of British Columbia, Faculty of Pharmaceutical Sciences, Vancouver, BC, Canada

    Kevin Lin & Karen Dahri

  2. Department of Pharmacy, Vancouver General Hospital, Vancouver, BC, Canada

    Vivien F. S. Cao & Karen Dahri

  3. Lower Mainland Pharmacy Services, Vancouver, BC, Canada

    Charles Au

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VC provided the concept for this systematic review. KL and VC performed the literature search and data analysis, and drafted the original manuscript. KD, VC, and CA critically reviewed and edited the manuscript.

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Lin, K., Cao, V.F.S., Au, C. et al. Clinical Pharmacokinetic Monitoring of Free Valproic Acid Levels: A Systematic Review. Clin Pharmacokinet 61, 1345–1363 (2022). https://doi.org/10.1007/s40262-022-01171-w

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