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

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 mu mol/L. Two studies suggested the occurrence of hyperammonemia and thrombocytopenia at free VPA serum levels above 60 mu mol/L and 103.3 mu mol/L, respectively. Two studies suggested an upper limit for neurotoxicity at free VPA serum levels of 70 mu mol/L and 207.9 mu mol/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.