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

Abstract

Therapeutic 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) 1g bd; phenytoin (PHT) 200mg tds; carbamazepine (CBZ) 400mg mane, 200mg midi, 400mg nocte; levetiracetam (LEV) 250mg bd. Initial AED-TDM revealed total serum levels of CBZ: 27micromol/L; PHT: 37micromol/L; VPA 499micromol/L, therapeutic or subtherapeutic. Free levels were subsequently measured demonstrating CBZ: 8.2micromol/L; PHT: 5micromol/L; VPA 93micromol/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 (37micromol/L; range: 40-80) the free level was therapeutic (5micromol/L; range: 4-8) and while VPA was therapeutic (VPA 499micromol/L; range: 300-750) the free level was supratherapeutic (93micromol/L; range: 30-75). Acknowledgement of discordance between total and free levels for highly protein-bound AED is highlighted.