What is the significance of a valproic acid (Valproate) trough level of 359 micromoles per liter in a 72-year-old female patient weighing 44 kilograms?

From the Guidelines

The valproic acid trough level of 359 μmol/L in this 72-year-old, 44 kg female is elevated and requires dose adjustment to minimize the risk of toxicity and adverse effects, particularly given the potential for valproate to cause weight gain, polycystic ovaries, and hyperandrogenism, as noted in studies such as 1. I recommend reducing the current valproic acid dose by approximately 25-30% and rechecking the level in 5-7 days after reaching steady state. Some key points to consider in the management of this patient include:

• Monitoring the patient closely for signs of toxicity including drowsiness, confusion, tremor, nausea, vomiting, and ataxia.
• Recognizing that elderly patients and those with lower body weight often require lower doses due to decreased drug clearance and reduced volume of distribution.
• Being aware that age-related changes in hepatic metabolism and renal function can lead to drug accumulation, and the patient's small body size further increases the risk of toxicity.
• Considering the potential for valproate to cause endocrine disorders, as suggested by studies such as 1, which found associations between valproate use and menstrual irregularities, polycystic ovaries, and hyperandrogenism in women with epilepsy. While this level is elevated, it's not in the severely toxic range (typically >700 μmol/L) that would require immediate discontinuation. However, if the patient is showing any signs of toxicity, consider temporarily holding doses until symptoms improve. When adjusting the dose, maintain consistent dosing intervals to avoid fluctuations in serum levels. It's also important to note that the use of valproic acid has been associated with complications such as thrombocytopenia and hepatotoxicity, as mentioned in 1.

From the FDA Drug Label

The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 μg/mL in females Therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 μg/mL The therapeutic range is commonly considered to be 50 to 100 μg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations

The valproic acid trough level of 359 μm/L (or 359 μg/mL, assuming 1 μm/L = 1 μg/mL) is above the usually accepted therapeutic range of 50 to 100 μg/mL. Additionally, it is above the threshold of 110 μg/mL, where the probability of thrombocytopenia increases significantly in females. Therefore, this level is considered toxic and may increase the risk of adverse reactions, including thrombocytopenia 2 2.

From the Research

Valproic Acid Trough Level

• The valproic acid trough level of 359 um/L in a 72-year-old female, weighing 44kg, is within the therapeutic range, but the potential for hepatotoxicity and other adverse effects should be considered 3, 4.
• The incidence of liver damage induced by valproic acid is 0.01%, and severe hepatotoxicity is rare but can be fatal 3.
• The risk of hepatotoxicity may be enhanced by conditions such as starvation, inborn errors of metabolism, additional neurological disease, and concomitant administration of enzyme-inducing drugs 4.

Monitoring and Interpretation

• The timing of blood sample collection for valproic acid concentration is important, and trough sampling is easily achieved just before a morning daily dose 5.
• For once-daily evening dosing, a blood sample collected 12 to 15 hours later may give a plasma valproic acid concentration value that is 18% to 25% higher than the trough value 5.
• Waiting longer, such as 18 to 21 hours, may result in concentration values that are merely 3% to 13% higher than trough values, which may provide acceptable information for monitoring purposes 5.

Adverse Effects and Interactions

• Hyperammonemic encephalopathy with normal liver function is an uncommon serious adverse effect of valproate therapy, and alteration in sensorium is a presenting clinical feature 6.
• The risk factors for hyperammonemic encephalopathy include high initial dose, long-term valproate therapy, and concomitant administration of other medications such as topiramate 6.
• Valproic acid treatment may affect liver function tests, plasma free carnitine, and lipid peroxidation in childhood epilepsies, and further studies are needed to understand its mechanism 7.