A precision approach to therapeutic drug monitoring of valproate to evaluate markers of toxicity

Abstract Objective Treatment with valproic acid (VPA) is associated with risk of liver toxicity. The aim of this study was to use a precision approach to investigate pharmacokinetic variability of both total and unbound serum concentrations of VPA and perform complementary biochemical analyses to evaluate possible markers of toxicity in a clinical setting. Methods Therapeutic drug monitoring (TDM) data (2018–2022) including total and free unbound serum concentrations of VPA, measurements of concomitantly used antiseizure medications, and biochemical analyses of ammonia and liver enzymes were used. Results We included 704 measurements from 288 patients (131/157 female/male, median age = 25 years, range = 0–74). Median VPA dose was 1050 mg/day (range = 150–3900); total and unbound VPA concentrations were 430 μmol·L −1 (range = 57–866) and 44 μmol·L −1 (range = 15–125), respectively. Extensive pharmacokinetic intraindividual variability of VPA was observed with long‐term TDM, the coefficient of variability being 21% (range = 6%–55%) in those with five or more measurements ( n = 31). Comedication was noted in 85%, where lamotrigine, clobazam, or levetiracetam were most common. Enzyme inducers/inhibitors and age affected the concentration/dose ratio of both total and unbound VPA. There was a significant linear correlation between total exposure of VPA ( n = 379; r 2 = .014, p < .05) and ammonia levels but the correlation was not significant with unbound VPA ( n = 189; r 2 = .0045). Supplementary clinical data were studied in 16 patients with high ammonia levels (>85 μmol·L −1 ), and 14 of 16 had signs of toxicity. Serum alanine aminotransferase (ALT) was not correlated with total/unbound VPA concentrations, and no one had a greater than threefold increase in ALT as a sign of toxicity. Significance Combined use of TDM including total and unbound VPA serum concentrations and biochemical analyses of ammonia and liver enzymes are useful as tailored precision monitoring to aid clinical decision‐making in patients with suspected symptoms of toxicity.