Therapeutic drug monitoring of phenytoin and valproic acid in critically ill patients at Windhoek Central Hospital, Namibia

Background: Phenytoin and valproic acid, anticonvulsants, have a low therapeutic index and are highly plasma protein bound, mainly to albumin. Hypoalbuminaemia is common in critically ill patients and increases the unbound drug concentration. Thus, monitoring unbound rather than total plasma drug concentrations is recommended to optimise the dosing of these drugs. Objective: This retrospective study determined unbound plasma concentrations of phenytoin and valproic as a more accurate value of drug levels than total plasma drug concentrations. Methods: Total plasma concentrations were retrieved for 56 Intensive Care Unit patients for phenytoin and 93 for valproic acid. Total drug concentrations were converted to unbound concentrations using a serum albumin-based normalising equation. Results: Total phenytoin plasma concentration was below (41.1% of patients), within (46.4%) or above (12.5%) the therapeutic range (10 mu g/mL - 20 mu g/mL). However, the predicted unbound plasma concentration of phenytoin was above the therapeutic range (1 mu g/mL - 2 mu g/mL) in the majority of patients (57.1%). For valproic acid, the total plasma concentration of most patients (87.1%) was below the therapeutic range (50 mu g/mL - 100 mu g/mL); among remaining patients (12.9%), it was within the therapeutic range. In the majority of patients (91.4%), the predicted unbound plasma concentration of valproic acid was between 2.5 mu g/mL and 20 mu g/mL. Conclusion: The usefulness of monitoring the total phenytoin or valproic acid levels for dose optimisation is limited as it is an inaccurate indicator of a patient's drug therapeutic state. Thus, the unbound plasma drug concentrations should be quantified experimentally or predicted in resource-limited settings.

Automated summary

This retrospective study found that monitoring unbound plasma concentrations of phenytoin and valproic acid may provide a more accurate assessment of drug levels compared to total plasma drug concentrations. The majority of patients had unbound plasma concentrations of phenytoin or valproic acid outside the therapeutic range, highlighting the limitations of using total drug concentrations for dose optimization.