NEUROCRITICAL CARE PHARMACY Valproic Acid Therapeutic Drug Monitoring: Freedom from Total Serum Concentrations By David Hensler, PharmD and Kimberly Levasseur-Franklin, PharmD, BCPS Valproic acid is a broad-spectrum Discordance between total and free serum valproic acid levels has anticonvulsant drug with a narrow therapeutic been reported previously. Hospitalized patients may be at greatest index. Therapeutic drug monitoring is risk for elevated free serum valproic acid levels, particularly in the recommended for patients receiving valproic setting of hypoalbuminemia, which occurs frequently in critically acid to optimize anticonvulsant effi cacy and ill patients. Valproic acid free fractions exceeding 50% may be minimize adverse effects. Interpretation of observed in these patient populations, limiting the usefulness of total serum valproic acid levels in the critically total serum valproic acid levels. ill population may be complicated by the drug’s complex protein binding characteristics. The relationship between total and free serum valproic acid David Hensler, concentrations is variable and heavily dependent upon protein PharmD Serum valproic acid is highly protein bound, binding. While total serum valproic acid levels have traditionally with reported free fractions typically ranging been used for valproic acid therapeutic drug monitoring, free from 5 to 10%. Valproic acid displays variable serum valproic acid levels may better predict pharmacologic protein binding, however, with higher free effects. Measurement of free serum valproic acid levels should fractions anticipated in patients with advanced be considered in critically ill patients with serum albumin age, renal impairment, or hypoalbuminemia. concentrations less than 3.5 g/dL. Serum albumin concentrations less than 3.5 g/dL predict discordance between free and This practice is particularly relevant for patients with total valproic acid levels, with free fractions subtherapeutic total valproic acid levels, despite aggressive valproic increasing linearly with the severity of acid dosing (i.e. >60 mg/kg/day). When possible, measurement hypoalbuminemia. of free serum valproic acid levels should be considered to help Kimberly guide dosing in these critically ill patient populations. Utilizing Levasseur- Higher free fractions are also typically free valproic acid levels in this patient population may help better Franklin, anticipated when total valproic acid levels guide clinicians as to when continued valproic acid dose titration PharmD, BCPS exceed 75 µg/mL. Co-administration of other is worthwhile versus adding another antiepileptic to accomplish highly protein bound drugs (e.g. phenytoin) the specifi ed treatment goal. may displace valproic acid from albumin binding sites and further complicate valproic acid therapeutic drug monitoring. For further reading on discordance between total and free serum valproic acid levels, please see “Comparison of free fraction Total serum valproic acid levels are routinely monitored in clinical serum valproic acid concentrations between inpatients and practice, while free valproic acid is responsible for the drug’s outpatients” by H. Gibbs and colleagues (Am J Health-Syst Pharm pharmacologic effects. Total serum valproic acid concentrations 2015;72:121-126). of 50-100 µg/mL have been associated with anticonvulsant effi cacy and patient tolerance. Though not widely utilized, free serum David Hensler, PharmD is a PGY2 critical care pharmacy resident at valproic acid concentrations of 5-15 µg/mL have been targeted in Midwestern University. Kimberly Levasseur-Franklin, PharmD is a clinical practice. critical care pharmacist in the Neuro ICU at Northwestern Memorial Hospital in Chicago and a member of the NCS Pharmacy Committee. They are invited guest writers for Currents. 25
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