Free Valproic Acid Concentrations and Clinical Outcome

Significant inter-individual variations can be observed in the Fu of phenytoin, carba-mazepine, and valproic acid, especially in the presence of uremia and liver disease. Drug-drug interactions can also lead to elevated free drug concentration. When binding is changed, the total concentration no longer reflects the pharmacologically active free drug in the plasma. Measuring free drug concentrations for antiepileptic drugs eliminates a potential source of interpretative errors in therapeutic drug monitoring using traditional total drug concentrations (37). Usually, total drug concentrations (free + protein bound) are measured in the laboratory because it is technically easier than free drug monitoring, but changes in the extent of protein binding for highly protein-bound drugs are clinically significant (38). For example, if the binding of a drug changes from 98 to 96%, the total drug concentration is unaltered, but the concentration of Fu is doubled (39).

Valproic acid (therapeutic range of 50-100 ^g/mL) is extensively bound to serum proteins, mainly albumin (40). Fluctuations in protein binding occur within the therapeutic range because of the saturable binding phenomenon leading to variations of the Fu from 10 to 50% (41). Moreover, unbound valproic acid concentration may also vary during one dosing interval in patients already stabilized on valproic acid (42), and several studies have reported problems associated with predicting a therapeutic response of valproic acid from total serum concentrations (43,44).

Gidal et al. reported a case where markedly elevated plasma-free valproic acid in a hypoalbuminemic patient contributed to neurotoxicity. The total valproic acid concentration was 103 ^g/mL, but the free valproic acid concentration was 26.8 ^g/mL. This unexpected elevation was due to a low albumin level (3.3 gm/dL) of the patient (45). Haroldson et al. reported a case demonstrating the importance of monitoring free valproic acid in a heart transplant recipient with hypoalbuminemia. When the valproic acid dose was adjusted based on the free valproic acid concentration rather than total valproic acid concentration, the patient improved and was eventually discharged from the hospital (46). Lenn and Robertson demonstrated that the concentration of free valproic acid has clinical significance in management of seizure as well as avoiding undesirable side effects. The authors recommended using free valproic acid concentration for routine patient management (47). Diurnal fluctuations in free and total plasma concentrations of valproic acid at steady state have been reported (48,49). Ahmad et al. reported that total valproic acid concentrations show higher interindividual variation and tend to underestimate the effect of poor compliance, but the use of free valproic acid concentration offers an advantage in therapeutic drug monitoring (50). Although unbound valproic acid concentration mirrors CSF valproic acid concentration, Rapeport et al. (51) reported a lack of dc correlation between free levels and pharmacological effects. Valproic acid is strongly protein bound and is considered not to be removable by extracorporeal means. In the case of severe overdose with valproic acid where free concentration is high because of disproportionate protein binding, extracorporeal means such as hemodialysis and hemoperfusion can be used (52).

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