Valproic Acid: A Reappraisal of its Pharmacological Properties and Clinical Efficacy in Epilepsy

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Abstract

Synopsis

Valproic acid is a branched-chained fatty acid, structurally unrelated to any other antiepileptic drug. Since publication of the original review in the Journal in 1977, several clinical trials have documented its efficacy and safety in adults and children for the treatment of generalised seizures (absence, tonic-clonic, myoclonic), partial seizures (simple, complex, secondarily generalised) and compound/combination seizures (including those refractory to treatment with other antiepileptic drugs). Valproic acid monotherapy has demonstrated efficacy equivalent to that of carbamazepine, phenytoin, and phenobarbital in the treatment of both generalised and partial seizures and ethosuximide in the treatment of absence seizures.

Synopsis

Adverse effects associated with the drug are primarily gastrointestinal (nausea, vomiting, dyspepsia) in nature, although the use of enteric-coated formulations has reduced the incidence of abdominal discomfort. Weight gain, tremor and transient hair loss are commonly reported. Importantly, valproic acid has minimal neurological adverse effects (sedation, ataxia, impairment of cognitive function) compared with other antiepileptic drugs, a finding that may be of particular relevance in many patients with epilepsy. The incidence of rare, fatal liver failure has been greatly reduced by identifying and avoiding administration of valproic acid to high risk patient populations. An estimated risk of 1 to 2% for neural tube defects, predominantly spina bifida aperta, with maternal use of valproic acid therapy has been reported. Valproic acid inhibits hepatic drug metabolism and displaces other highly bound drugs from their plasma protein binding sites. Therefore, coadministered drugs which are highly protein bound or hepatically metabolised may require dosage adjustment. Enzyme-inducing antiepileptic drugs may increase valproic acid metabolism and necessitate increasing its dosage.

Synopsis

Thus, comparative trials and extensive clinical experience have demonstrated the efficacy and tolerability of valproic acid and support its role as a valuable and well established first-line treatment for patients with a broad range of seizure types.

Pharmacodynamic Properties

The mechanism of action of valproic acid has yet to be fully elucidated, although much attention has focused on its effect on the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Valproic acid increases synaptosomal GABA concentrations via activation of the major synthetic enzyme, glutamic acid decarboxylase. It has also demonstrated strong inhibition of the catabolic enzymes succinic semialdehyde dehydrogenase and GABA transaminase. Evidence also exists which suggests that valproic acid reduces neurotransmission mediated by the excitatory amino acid gamma-hydroxybutyric acid, which produces absence-like seizures in animals. In addition to its effect on amino acid neurotransmitters, valproic acid appears to possess a direct neuronal membrane depressant effect through its influence on sodium or potassium conductance.

Pharmacodynamic Properties

Valproic acid has anticonvulsant activity in a number of animal models of tonic-clonic, partial and absence seizures, in which seizures were induced by chemical, electrical or sensory stimuli. It is active against generalised (absence, clonic, tonic, tonic-clonic) seizures induced by a variety of chemical convulsants. The drug also prevents quinolinic acid-induced seizures and suppresses behavioural alterations in a rat model of human complex partial seizures.

Pharmacodynamic Properties

Valproic acid reduces the number and duration of spike wave discharges seen on electroen-cephalographic (EEG) tracings in patients with absence seizures and photosensitive epilepsy. Patients free of these seizures show a good correlation between their clinical and EEG responses. This correlation is generally not seen for other seizure types. Valproic acid has minimal effects on psychomotor and cognitive function compared with phenobarbital or phenytoin in healthy volunteers and patients with epilepsy.

Pharmacokinetic Properties

Single-dose pharmacokinetic properties of the various oral formulations of valproic acid have been assessed in healthy adult volunteers and in adults with epilepsy. Peak plasma concentrations following oral administration of valproic acid increased dose-proportionally, ranged from 24.5 mg/L after a 250mg dose to 108 mg/L after a 1000mg dose, and were achieved within 1 to 3 hours for uncoated tablets, 3 to 5 hours for enteric-coated tablets and 5 to 10 hours for controlled-release tablets. The mean bioavailability of oral formulations of valproic acid approaches 100%. Administration with food delays the rate but not extent of absorption. The apparent volume of distribution (Vd) ranges from 0.1 to 0.4 L/kg, suggesting confinement principally to the circulation and extracelluar fluid. The drug is about 90% plasma protein bound, although the unbound fraction increases nonlinearly with total plasma valproic acid concentrations above 80 to 85 mg/L.

Pharmacokinetic Properties

Valproic acid undergoes biotransformation via 5 main metabolic pathways. The majority of an administered dose is excreted as metabolites in their free form or as glucuronide conjugates. Plasma clearance of valproic acid ranges from 0.4 to 0.6 L/h in healthy volunteers and is independent of hepatic blood flow. Increased clearance is observed in patients with epilepsy receiving concurrent hepatic enzyme-inducing antiepileptic drugs. Valproic acid has a low hepatic extraction ratio and only unbound drug is cleared. The elimination half-life (t1/2β) of valproic acid ranges from 9 to 16 hours, with patients receiving concomitant hepatic enzyme-inducing antiepileptic drugs exhibiting half-life values in the lower end of this range.

Pharmacokinetic Properties

In neonates, t1/2β, Vd and the percentage of unbound valproic acid are increased compared with values in infants or children. Mean t1/2β values vary considerably, ranging from 30 to 60 hours in untreated neonates born to epileptic mothers, to 17 to 40 hours in treated neonates. Compared with adults, higher plasma clearance and lower t1/2β values are observed in children aged 2 to 10 years. Valproic acid clearance decreases with increasing paediatric age, with children aged ≥10 years having pharmacokinetic parameters similar to those reported in adults. Unbound plasma valproic acid concentrations are 67% higher in elderly patients due to reduced clearance and a reduction in drug binding to plasma proteins. A reduction in clearance of unbound drug is also observed in patients with alcoholic cirrhosis. Plasma protein binding of valproic acid appears to be reduced in patients with renal impairment or insulin-dependent diabetes mellitus.

Pharmacokinetic Properties

Although a therapeutic range of 40 to 100 mg/L has been suggested, the clinical efficacy of valproic acid may not be clearly correlated with the total plasma drug concentration. In addition, several factors confound interpretation of the relationship between plasma drug concentration and clinical efficacy. These include a relatively short half-life, diurnal variations in absorption and clearance, nonlinear protein binding and large diurnal fluctuations of free fatty acids which displace valproic acid from plasma protein binding sites. Higher plasma valproic acid concentrations are generally needed to achieve seizure control in patients with partial seizures than in those with generalised seizures.

Clinical Efficacy

Results from early, noncomparative studies demonstrated the efficacy of valproic acid in a total of 1393 patients (808 adults and 585 children) from trials of polytherapy (valproic acid as add-on therapy), conversion therapy (patients converted from other antiepileptic drugs to valproic acid due to lack of efficacy or adverse effects) and valproic acid monotherapy in previously untreated patients. Efficacy rates (≥75% seizure reduction from baseline) for valproic acid (20 to 40 mg/kg/day for 6 months to 5 years) ranged from 24 to 86% for a variety of seizure types. In this analysis, valproic acid was particularly effective in the treatment of generalised seizure types (absence, myoclonic and tonic-clonic), with efficacy rates of 67 to 86%. Valproic acid was also effective in the treatment of partial seizure types (simple, complex, secondarily generalised), with efficacy rates ranging from 42 to 58%.

Clinical Efficacy

Although there are very few placebo-controlled or comparative trials of add-on design, valproic acid has significantly reduced the incidence of tonic-clonic, absence and partial seizures compared with placebo. It demonstrated similar efficacy to ethosuximide in the treatment of absence seizures and clonazepam in the treatment of generalised and partial seizures. In subsequent comparative trials of monotherapy, valproic acid demonstrated efficacy comparable efficacy with that of carbamazepine, phenytoin and phenobarbital in the treatment of tonic-clonic and partial seizures, and with ethosuximide in the treatment of absence seizures. The drug has also demonstrated some evidence of efficacy in the treatment of infantile spasms (West Syndrome), Lennox-Gastaut syndrome, febrile seizures and status epilepticus.

Tolerability

The most common adverse effects associated with valproic acid are mild to moderate in severity, with gastrointestinal disturbances (nausea, vomiting, dyspepsia), weight gain, neurological effects (tremor, fatigue, somnolence, dizziness, headache) and transient hair loss being the most frequently reported. Compared with other antiepileptic drugs, dermatological (skin rash, hirsutism) and neurological adverse effects occur less frequently with valproic acid. Elevated liver function tests, hyperammonaemia and thrombocytopenia have been reported, but are generally not clinically significant. Rare valproic acid-induced fatal hepatotoxicity occurs more frequently in patients ≤ 2 years old receiving polytherapy and generally manifests within 6 months of therapy initiation. Increased incidence of congenital abnormalities (including facial dysmorphia, neural tube defects and multiple malformations) has been demonstrated in offspring born to both treated and untreated mothers with epilepsy. An estimated risk of 1 to 2% for neural tube defects, predominately spina bifida aperta, is reported for infants born to women treated with valproic acid during pregnancy.

Drug Interactions

Concomitant administration of valproic acid can affect the plasma concentrations of other drugs by displacement from plasma proteins and/or inhibition of hepatic metabolism. Clinically relevant increases in plasma concentrations of phenobarbital, unbound phenytoin, carbamazepine-10,11-epoxide, ethosuximide, lamotrigine, felbamate and diazepam have been reported. Hepatic enzyme-inducing drugs such as phenytoin, carbamazepine and phenobarbital can significantly reduce steady-state plasma valproic acid concentrations. When used in combination with drugs known to induce hepatic enzyme activity, or when known hepatic enzyme-inducing drugs are discontinued, the dosage of valproic acid may need adjustment. The efficacy of oral contraceptives is not compromised by concomitant use of valproic acid.

Dosage and Administration

The recommended initial dosage of valproic acid in the US is 15 mg/kg/day, increasing at 1-week intervals by 5 to 10 mg/kg/day (maximum 60 mg/kg/day) as necessary until seizures are controlled or adverse effects preclude further increases. In the UK and Europe, the initial adult monotherapy dosage is 600mg daily, increasing by 200mg at 3-day intervals until seizure control is achieved (maximum dosage 2500 mg/day). The starting dosage for children weighing > 20kg is 400 mg/day with spaced intervals until seizure control is achieved (usually within the range of 20 to 30 mg/kg/day). In children weighing < 20kg, a dosage of 20 mg/kg/day is recommended and, in severe cases, may be increased with concurrent plasma valproic acid concentration monitoring. In children requiring dosages above 40 mg/kg/day, clinical chemistry and haematological parameters should be monitored. Enteric-coated and controlled-release preparations are usually administered once or twice daily, although uncoated preparations may need to be given in 3 or 4 divided doses to minimise variations in plasma drug concentrations. Gastrointestinal irritation may be minimised by administration with or after food, or by slowly increasing the dosage from an initial low level. The intravenous formulation may be used in patients with epilepsy for whom oral therapy is temporarily not possible. Therapeutic plasma valproic acid concentrations for most patients will range from 40 to 100 mg/L.

Dosage and Administration

Due to the presence of drug interactions with other antiepileptic medications, the dosage of carbamazepine, phenobarbital, phenytoin and felbamate may need to be reduced when valproic acid is added to the treatment regimen. The initial and maintenance dosage of lamotrigine should be reduced by 50% upon addition to existing valproic acid therapy. When hepatic enzyme-inducing drugs such as phenobarbital, carbamazepine or phenytoin are added to the treatment regimen, the dosage of valproic acid may need to be increased. Treatment with valproic acid is contraindicated in patients with hepatic disease or significant hepatic dysfunction. The benefits of antiepileptic therapy during pregnancy must be evaluated against the possible risks of neural tube defects and patients should be informed of these as well as the need for screening. Patients receiving valproic acid should be monitored for platelet count and coagulation parameters prior to planned surgery.

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