Valproate Protein Binding Is Highly Variable in ICU Patients and Not Predicted by Total Serum Concentrations: A Case Series and Literature Review

Abstract

Protein binding of valproate was highly inconsistent in this cohort of ICU patients, and total valproate concentrations did not predict free concentrations, even when correcting for albumin. Additional research to define best practice for dosing and monitoring valproate and the relationship between free valproate concentrations and clinical or adverse effects in ICU patients is needed.

Repurposing Valproate, Enteral Clonidine, and Phenobarbital for Comfort in Adult ICU Patients: A Literature Review with Practical Considerations

“…Valproate is highly bound to albumin (generally more than 90%) in a concentration‐dependent manner. The free fraction of valproate may be elevated in the setting of hypoalbuminemia, uremia, drugs known to displace it from albumin (e.g., aspirin, ibuprofen, propofol, clevidipine, and intravenous fat emulsion), and at the upper end of its reference range due to albumin binding site saturation . Table summarizes valproate's pharmacokinetic properties.…”

“…Free serum concentrations, which represent the amount of drug available for effectiveness, toxicity, and metabolism, should be considered in patients at risk for altered protein binding. Free serum valproate concentration has been associated with neurotoxicity, hyperammonemia, and thrombocytopenia . A study of 15 adult ICU patients found the median free fraction of valproate (percentage of drug not bound to albumin) was 48% (range 15–89%), and no patient had an expected valproate free fraction of 5–10% .…”

“…This is important because total serum concentration can be misleading and result in inappropriate dose escalations and potential harm. A reference range for free serum concentration has yet to be defined, but most reports used 5–13 mg/L …”

“…The free fraction of valproate may be elevated in the setting of hypoalbuminemia, uremia, drugs known to displace it from albumin (e.g., aspirin, ibuprofen, propofol, clevidipine, and intravenous fat emulsion), and at the upper end of its reference range due to albumin binding site saturation. 13 Table 1 summarizes valproate's pharmacokinetic properties. Table 2 outlines data describing the use of valproate for behavioral control in the ICU.…”

“…13 A study of 15 adult ICU patients found the median free fraction of valproate (percentage of drug not bound to albumin) was 48% (range 15-89%), and no patient had an expected valproate free fraction of 5-10%. 13 This is important because total serum concentration can be misleading and result in inappropriate dose escalations and potential harm. A reference range for free serum concentration has yet to be defined, but most reports used 5-13 mg/L.…”