Evaluation of Free Valproate Concentration in Critically Ill Patients

Abstract

Protein binding of valproate is variable in ICU patients, and the total valproate concentration does not predict the free valproate concentration, even when correcting for albumin. We sought to quantify valproate free concentration among ICU patients, identify risk factors associated with an increasing free valproate concentration, and evaluate the association between free valproate concentration with potential adverse drug effect. DESIGN:Retrospective multicenter cohort study. SETTING: Two academic medical centers.PATIENTS: Patients greater than or equal to 18 years of age with concomitant free and total valproate concentrations collected in the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS:Two-hundred fifty-six patients were included in the study, with a median age of 56 years (42-70) and 65% of patients were male. The median total valproate concentration was 53 µg/mL (38-70 µg/mL), the free valproate concentration was 12 µg/mL (7-20 µg/mL), and the free fraction was 23.6% (17.0-33.9%). Therapeutic discordance between the free and total valproate concentration occurred in 70% of patients. On multivariable analysis, increased free valproate concentration was associated with higher total valproate concentration (per 5 µg/mL increase, increase 1.72 µg/mL, 95% CI, 1.48-1.96) and lower serum albumin (per 1 g/dL decrease, increase 4.60 µg/mL, 95% CI, 2.71-6.49). There was no association between free valproate concentration and adverse effects. CONCLUSIONS:The valproate total and free concentration was discordant in the majority of patients (70%). Increased valproate free concentration was associated with hypoalbuminemia and total valproate concentration. Clinical decisions based on total valproate concentration may be incorrect for many ICU patients. Prospective, controlled studies are needed to confirm these findings and their clinical relevance.

Clinical Consequences of Occult Free Valproate Toxicity in Critically Ill Adult Patients: A Multicenter Retrospective Cohort Study

“…Rates of occult toxicity in hospitalized patients vary from 29.7% to 87%; the high rate of 84% occult toxicity in our population may reflect a higher severity of illness, as many prior cohorts reported a mixed population of non-ICU and critically ill adults. 4,5,13–16 Additionally, our cohort had an overall low serum albumin (median 2.8 g/dL) and a high use of interacting medications (29% with propofol and 22% with aspirin exposure). This may reflect a selection bias in which free valproate concentrations were more likely to be measured in patients with these determinants, but our pattern of occult toxicities is consistent with previous reports, further enforcing our findings.…”

Derivation and Validation of a New Equation for Estimating Free Valproate Concentration in Critically Ill Adult Patients

“…More than 40 years ago, this assumption was called into question for valproate (8) and was recently shown to not be true among ICU patients (9,10). Total VPAC are discordant with measured free VPAC in 70-87% of ICU patients (9,10). The limited availability of free VPAC assays has spurred the development of care equation-based models to predict free VPAC (13)(14)(15)(16)(17).…”

“…Therapeutic drug monitoring of total drug concentrations assumes that they consistently reflect the biologically active free concentrations (i.e., that free fraction is normal and constant such that the concentrations are therapeutically concordant). More than 40 years ago, this assumption was called into question for valproate ( 8 ) and was recently shown to not be true among ICU patients ( 9 , 10 ). Total VPAC are discordant with measured free VPAC in 70–87% of ICU patients ( 9 , 10 ).…”

“…Monitoring of these values was not protocolized during the study period. Data regarding administration of concomitant medications previously associated with valproate displacement from albumin binding sites were collected including aspirin, ibuprofen, ketorolac, clevidipine, propofol, and IV fat emulsion ( 9 , 10 ). Medications were considered concomitant if they were administered during the 24 hours preceding free VPAC sample collection.…”

“…ICU patients and others at risk for altered protein binding have consistently shown much higher free fractions ranging from 15% to 89% (9). The resultant therapeutic discordance may lead to erroneous dose adjustments when guided by total VPAC alone (9)(10)(11). Free VPAC monitoring is warranted in these patients given significant interindividual variability to prevent dose-related toxicities associated with increased free VPAC (6)(7)(8).…”