High unbound fraction of valproic acid in a hypoalbuminemic critically ill patient on renal replacement therapy.

OBJECTIVE: To describe a hypoalbuminemic critically ill patient with subtherapeutic total valproic acid serum concentrations but unbound valproic acid concentrations within normal limits. CASE SUMMARY: During an intensive care unit admission, a 61-year-old woman with urosepsis and multiorgan dysfunction syndrome developed tonic-clonic seizures with respiratory failure, and tracheal intubation was performed. An intravenous loading dose of valproic acid 1500 mg (25 mg/kg) was administered and therapy was continued with valproic acid 750 mg (12.5 mg/kg) twice daily. Because of progressive renal failure, continuous venovenous hemofiltration was started on day 3 of valproic acid therapy. On day 7 of valproic acid therapy, routine testing of serum valproic acid trough concentration returned as undetectable. Subsequent determinations of trough serum concentrations of total valproic acid showed values below the therapeutic range. Data from a full pharmacokinetic curve (multiple blood samples during a dosing interval) showed that the free fraction of valproic acid was >60%. Although total valproic acid concentrations were still low, the unbound concentrations were considered therapeutic. Serum albumin was 1.2 g/dL on the multiple sampling day. DISCUSSION: The patient's hypoalbuminemia probably explains the remarkably high free fraction of valproic acid. Our hypothesis is that the low albumin level was associated with high plasma clearance of valproic acid, leading to extremely low total drug concentrations. To our knowledge, this high percentage of free valproic acid has not been previously described. CONCLUSIONS: Health-care professionals should be aware of the need of early determination of both total and free fraction valproic acid serum concentrations in hypoalbuminemic critically ill patients. Increasing the dose of valproic acid purely based on total valproic acid serum concentrations in this patient population should be avoided.