Variable Free and Total Valproic Acid Concentrations in Sole- and Multi-Drug Therapy

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Abstract
Summary: Total and free valproic acid (VPA) serum concentrations differ between patients on sole therapy (SOLE Group) and those taking multiple drugs (MULTI Group). We found significantly higher total and free VPA levels and free fractions in 25 SOLE patients than in 29 MULTI patients, both at morning predose (minimum) and postdose (maximum) testing. Results in SOLE versus MULTI patients were, respectively, as follows: total minimum 70.5 vs. 50.2 μg/ml (p > 0.01); total maximum 106.8 vs. 89.5 μg/ml (p > 0.05); free minimum 9.8 vs. 4.4 μg/ml (p > 0.001); free maximum 18.9 vs. 12.0 μg/ml (p > 0.01). The wide variation in total and free levels suggests the need to monitor VPA levels carefully. Not only does use of other drugs influence VPA kinetics, but the time since last dose also affects levels. Nonlinear binding causes large increases in free levels as total VPA concentration rises. We monitor free and total VPA at minimum and maximum along with evaluation of side effects and seizures for better interpretation of dosage requirements.