Value of therapeutic drug level monitoring and unbound (free) levels

SummaryTherapeutic drug monitoring (TDM) has declined with newer anti-epileptic drugs (AEDs) having no therapeutic window. Use of unbound (free) fraction has almost completely disappeared. The case reported highlights its importance and offers sound reason for its retention.A 66-year-old Caucasian man with known epilepsy was admitted with vomiting, ataxia and nystagmus presumably due to AED toxicity. Medications included valproate (VPA) 1 g bd; phenytoin (PHT) 200 mg tds; carbamazepine (CBZ) 400 mg mane, 200 mg midi, 400 mg nocte; levetiracetam (LEV) 250 mg bd. Initial AED-TDM revealed total serum levels of CBZ: 27 μmol/L; PHT: 37 μmol/L; VPA 499 μmol/L, therapeutic or subtherapeutic. Free levels were subsequently measured demonstrating CBZ: 8.2 μmol/L; PHT: 5 μmol/L; VPA 93 μmol/L. Consequently, VPA was initially omitted and dosage reduced with cessation of toxicity. AED regimen was greatly simplified and remained efficacious.This case highlights the value of TDM with polypharmacy and suggested AED toxicity. Total AED levels failed to identify the cause, which the unbound, free fraction identified. While total PHT was borderline subtherapeutic (37 μmol/L; range: 40–80) the free level was therapeutic (5 μmol/L; range: 4–8) and while VPA was therapeutic (VPA 499 μmol/L; range: 300–750) the free level was supratherapeutic (93 μmol/L; range: 30–75). Acknowledgement of discordance between total and free levels for highly protein-bound AED is highlighted.