Pharmacology

Valproic acid (di-N-propylacetic acid, 2-propylpentanoic acid, 2-propylvaleric acid) is a branched-chain fatty acid sold as the acid itself or as one of its salts, but the common substance in plasma is valproate ion, and there are only minor pharmacokinetic differences between various preparations. Divalproex sodium is a stable coordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. The next generation of valproic acid should possess the following characteristics: broad-spectrum antiepileptic activity, better potency than current generation of valproic acid, lack of teratogenicity and hepatotoxicity, and a favorable pharmacokinetic profile compared with conventional valproic acid, including a low potential for drug interactions.

Pharmacodynamics. Initially, it was believed that valproic acid acts through the GABA system because it inhibits the major GABA-degrading enzyme GABA-transaminase. However, concentrations of valproic acid that are therapeutically effective do not inhibit GABA-transaminase. There is evidence that the antiepileptic effect of valproic acid may be mediated via multiple mechanisms, which include the inhibition of excitatory amino acids (glutamate, aspartate, etc.) and the reduction of the excitability of neuronal membranes through its influence on sodium and potassium channels. Valproic acid has been demonstrated to reduce the number and frequency of spike-wave discharges seen on EEG in patients with absence seizures.

Pharmacokinetics. Valproic acid is rapidly absorbed within one to two hours following oral intake, but this absorption is prolonged in cases of slow-release formulations. Plasma half-life is about 10 hours in adults and is four times this value in neonates. Concomitant treatment with other enzyme-inducing antiepileptic drugs reduces the half-life of valproic acid, but valproic acid does not have enzyme-inducing potential by itself. Within the therapeutic range, valproic acid is highly protein-bound, with 10% as a free fraction. Valproic acid is extensively metabolized in the liver. The therapeutic range of valproic acid is 50 to 100 µg/mL, but no correlation has been proven of plasma concentrations of the drug with seizure control, even though the dose and its plasma concentrations are highly correlated. Dosage of valproic acid is guided by the clinical response, and therapeutic drug monitoring is done only in special situations.

A population-based pharmacokinetic-pharmacodynamic model has been developed to determine the optimal concentration of valproic acid according to the clinical characteristics of each patient (26). This model showed that age, seizure locus, the sodium channel neuronal type I alpha subunit rs3812718 polymorphism and coadministration of carbamazepine, clonazepam, phenytoin, or topiramate are associated with an over 50% reduction in the seizure frequency. This model may be useful for determining the optimal therapeutic concentration of valproic acid for each patient according to the principles of personalized medicine.

Pharmacogenetics. A patients CYP2C9 status may account for predisposition to adverse reactions. Knowledge of pediatric patients' CYP2C9 status enables adjustment of valproic acid dosing by predicting the patients ability to metabolize the drug and, thus, avoid dose-related adverse effects (06). UGT2B7 G211T and C161T polymorphisms can alter the pharmacokinetics in epilepsy patients treated with valproic acid, requiring adjustment of its dose to ensure therapeutic effect (36). A meta-analysis of the influence of UGT1A6 genetic polymorphisms on valproic acid pharmacokinetics has shown that concentration-to-dose ratio are significantly lower for UGT1A6 homozygous variants 541A>G and 552A>C than for the wild type (17).

Clinical trials

Various clinical trials to evaluate the efficacy of valproic acid in partial and generalized seizures were conducted prior to 1995. Early noncomparative trials involving 1393 patients (adults as well as children) demonstrated the value of valproic acid in epileptic patients. Efficacy in partial seizures ranged from 42% to 58%. In subsequent comparative trials such as add-on therapy, valproic acid was shown to be as efficacious as carbamazepine or phenytoin for the control of partial seizures. Add-on valproic acid is effective in the treatment of complex partial seizures.

Valproic acid has been shown to be effective for significantly reducing the frequency of migraine headaches in several clinical trials. For prophylaxis of migraine, the dose is 250 mg twice daily and can be increased up to 1000 mg per day. Intravenous administration of valproate sodium rapidly relieves ongoing intractable migraine headache without causing side effects.

Indications

Valproic acid is indicated as monotherapy or adjunct therapy in simple and complex absence seizures and as adjunct therapy in patients with multiple seizure types, including absence seizures.

Extended-release valproic acid is indicated for prophylaxis of migraine headaches in adults. There is no evidence that it is useful in the acute treatment of migraine headaches.

Divalproex sodium extended-release tablets are approved for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features.

Off-label uses

Contraindications

Valproic acid may be contraindicated in patients with hepatic disease or considerable hepatic dysfunction and patients with known hypersensitivity to valproic acid.

Precautions. Because thrombocytopenia is common in neurologic intensive care unit patients, and several clinical and laboratory factors are associated with it, careful use of valproic acid should be considered in patients with these risk factors (16).

Goals and duration of treatment

The aim of therapy is to control seizures. Therapy is continued for as long as seizure control is required.

In one study, resistance to valproic acid was the most important prognostic factor for refractory seizures in genetic generalized epilepsy (GGE), with a specificity of 100% to identify patients with drug resistance (11). The data in this study suggest that the term "drug resistant GGE" must not be used unless these patients are adequately treated with valproic acid, and the data support resistance to valproic acid as a new clinical biomarker for drug-resistant GGE.

Dosing

Initial dose is 15 mg/kg per day, and it is increased weekly by 5 to 15 mg/kg until seizure control is achieved. The maximum recommended dose is 60 mg/kg per day. The FDA has approved Depakote ER, a once-daily dosage that will simplify the use of the drug and will be available in both the 250 and 500 mg tablets. A continuous-infusion protocol enables rapid intravenous loading of valproic acid in pediatric patients while minimizing adverse events and achieving concentrations in the upper region of the therapeutic range.

Special considerations

Pregnancy. Valproic acid is excreted in breast milk, and caution should be exercised when valproic acid is administered to a nursing woman. Maternal exposure to valproic acid during the first trimester of pregnancy significantly increased the risk of major malformations (15). Tests for the detection of neural tube defects and other congenital malformations should be carried out as a part of routine prenatal care. In utero exposure to valproate, as compared with other commonly used antiepileptic drugs, is associated with an increased risk of impaired cognitive function at three years of age (24). Valproic acid exposure in rats leads to autistic-like behavior in their offspring, including social and communication deficits, but this animal model of autism, although valid, has limitations in translation to a clinical setting (30).

In 2014, the European Medicine Agency (EMA) recommended that valproate not be used to treat epilepsy or bipolar disorder or for prevention of migraine in girls and women who are pregnant or who can become pregnant unless other treatments are ineffective or not tolerated. The European Medicine Agencys data show that children exposed to valproate in the womb are at an approximately 11% risk for malformations at birth such as neural tube defects and cleft palate compared with a 2% to 3% risk among children in the general population. EMA further recommends that women for whom valproate is the only option should use effective contraception.

Pediatrics. Children under the age of 2 years and those with congenital metabolic disorders or mental retardation are more susceptible to hepatotoxicity. Valproic acid was well tolerated in clinical trials of pediatric patients.

Geriatric. Pharmacokinetics of valproic acid in the elderly do not differ significantly from those in younger adults. However, there may be reduced drug clearance due to lower plasma protein binding and drug metabolizing capacity in the elderly that requires a slightly lower dose than in younger adults. Dose adjustments are based on clinical response rather than on total plasma drug concentrations.

Anesthesia. There are no special precautions for anesthesia in patients on valproic acid therapy.

Interactions

Valproic acid potentiates the effect of CNS depressants, which bind extensively to serum proteins and result in alterations of valproic acid serum concentrations. Plasma concentrations of valproic acid are known to decrease during the concomitant administration of carbapenem antibiotics, which are used for the treatment of drug-resistant infections (27). Interaction with carbapenem antibiotics aggravate epileptic seizures in 48% of the patients, and renal disease as well as enzyme-inducing antiepileptic drugs that include valproic acid are risk factors that contribute to the severity of reduced serum valproic acid level (14). Valproic acid enhances metabolism of clozapine, predominantly effecting the degradation of norclozapine and requiring therapeutic drug monitoring (13). Interactions with other antiepileptic drugs are described in the Physicians Desk Reference.

Adverse effects

The most frequently reported adverse reactions are gastrointestinal disturbances (nausea, vomiting), transient hair loss, and neurologic disorders (tremor, somnolence, dizziness, headache). Endocrine and metabolic dysfunctions such as hyperandrogenism, menstrual disorders, polycystic ovary syndrome, hyperinsulinism, changes in sex hormones, abnormalities in pubertal development, and impaired skeletal growth have been reported as adverse effects of long-term valproic acid therapy. The most important adverse effect is hepatic failure, which is more likely to occur in infants under the age of two years. Patients on long-term (over two years) treatment with valproic acid should be monitored carefully as 25.3% of them develop isolated hyperammonemia (31).

Adverse effects on the nervous system. Valproic acid-induced dementia is well known. Several other adverse effects on the nervous system have been reported, but it is difficult to sort them out when valproic acid is used in conjunction with other antiepileptic drugs. Rare cases of altered consciousness with cerebral atrophy have been reported but improvement usually occurs with reversal of cerebral atrophy after discontinuation of valproic acid. Hyperammonemic encephalopathy is a rare but serious adverse reaction to valproic acid and monitoring of serum ammonia levels are recommended (37). However, several cases of valproic acid-induced encephalopathy have been reported with increased seizure frequency and with or without hyperammonemia. A patient who developed encephalopathy during valproic acid therapy without hyperammonemia or hepatic impairment recovered following discontinuation of the drug (29). Valproic acid can occasionally aggravate absence seizure in patients with absence epilepsy.

Valproic acid has histone deacetylaserelated and neurotoxic effects, but other mechanisms are also being studied. Valproic acid can induce neuronal cell death through a calpain-dependent apoptotic pathway (05).

Pancreatitis. Pancreatitis is recognized as an adverse event in patients receiving various valproic acid preparations. The serum lipase level is more sensitive than the serum amylase level and should be obtained when pancreatitis is suspected. Rechallenge with valproic acid is dangerous and should be avoided. Based on the review of published literature on this topic, the FDA has recommended the following black box warning:

For details, see the Physicians Desk Reference.

Metabolic side effects of valproic acid therapy. These include an increase in glucose-stimulated pancreatic insulin secretion, which might be followed by an increase in body weight and obesity. Long-term valproic acid use can increase bone resorption in adult epileptic patients and lead to a decreased bone mineral density. Controlled clinical trials are required to determine whether treatment with bisphosphonates or calcitonin might be of benefit in preventing osteoclastic bone resorption and consequent hypercalcemia in valproic acid-treated patients. Weight gain has also been reported as a sequel of valproic acid therapy (35).

Treatment of toxic effects. Carnitine supplementation may be useful for treating valproic acid-induced toxicity by limiting cytosolic omega-oxidation and the production of toxic metabolites that are involved in liver toxicity and ammonia accumulation (21).