Background Therapeutic drug monitoring (TDM) of total valproic acid (TVPA) concentrations is challenging because of its variable pharmacokinetics. In our department The authors normalise the total VPA (NTVPA) according to serum albumin (Hermida et al). The accepted serum concentration range is 50-150 mg/L. Higher concentrations could be useful in complicated seizures such as status epilepticus (SE).

Purpose The aim of this study was to evaluate the safety of high NTVPA levels.

Materials and methods Retrospective observational study in patients treated with VPA included in TDM program with a minimum of two NTVPA levels over 150 mg/L separated by at least 7 days.

Parameters recorded: sex, age, ward admitted to, indication for VPA, dose administered, concomitant antiepileptic therapy, TVPA, albumin, efficacy variables (seizures, electroencephalogram (EEG)) and adverse effects.

Results 24 patients were included (13 men) with 140 TVPA analyses (5.8 analyses/patient (2-13)). Mean age was 61.9 years (29-86). 16 patients were admitted to intensive care units. Patients were followed for a mean of 31.4 days (7-156). Mean VPA dose was 27.6 mg/kg/day. 14 (58.3%) were treated for SE. 6 patients died. Mean TVPA and NTVPA (mg/L) were 65.6 (31.6-140) and 214.7 (151-377) respectively and a mean albuminaemia was 25 g/L. Median NTVPA was 203.5 mg/L and the 75th percentile was 245.2 mg/L.

Most of the patients (n=13) received combined treatment with one or more of the following antiepileptic drugs: phenytoin, levetiracetam, oxcarbazepine, carbamazepine, clonazepam, phenobarbital and lacosamide.

2 patients had clinical seizures despite high levels of NTVPA, both confirmed by EEG. Side effects due to VPA were: diarrhoea (n=1) and sedation (n=2). However, 15 patients were pharmacologically sedated. 7 patients had alanine-aminotransferase levels over twofold the normal range (>1.4 ukat/L) and 12 patients had platelet count <135x10E9/L.

Conclusions Expanded therapeutic range NTVPA levels may be a safe option to treat complicated seizures. In the light of our results, The authors suggest 245 mg/L as an upper level of the therapeutic range of NTVPA.