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Pharmacology: Mechanism of Action: Valproic Acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).
Pharmacodynamics: ER tablet: The relationship between plasma concentration and clinical response is not well-documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate may not provide a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases.
Epilepsy: The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations.
Mania: In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 85 and 125 mcg/mL.
Syrup: Valproic acid is a carboxylic acid. It dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its antiepileptic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).
Pharmacokinetics: ER tablet: Valproic acid and its salts are rapidly absorbed from the gastrointestinal tract; the rate, but not the extent, of absorption is delayed if given with or after food. Valproic acid is extensively metabolised in the liver, a large part by glucuronidation and the rest by a variety of complex pathways. It does not appear to enhance its own metabolism, but metabolism may be enhanced by other drugs which include hepatic microsomal enzymes. Valproic acid is extremely bound to plasma proteins. The extent of protein binding is concentration dependent and is stated to be about 90 to 95% at total concentrations of 50 micrograms/mL, falling to about 80 to 85% at 100 micrograms/mL. Reported half lives for valproic acid have ranged from about 5 to 20 hours; the shorter half-lives have generally been recorded in epileptic patients receiving multiple drug therapy. The target range of total plasma valproic acid is usually quoted as being 40 to 100 micrograms/mL (280 to 700 micromoles/litre) but routine monitoring of plasma concentrations are not generally considered to be of use as an aid to assessing control. Valproic acid crosses the placental barrier and small amounts are distributed into breastmilk.
Syrup: Absorption: Valproic acid is rapidly and almost completely absorbed from the gastrointestinal tract. While the absorption rate from gastrointestinal tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected.
Total daily systemic bioavailability (extend absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are insequential from a practical clinical standpoint.
Co-administration of oral valproate products with food and substitution among the various divalproex sodium and valproic acid formulations should cause no clinical problems in the management of patients with epilepsy (see Dosage & Administration). Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution: Protein binding: The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin and tolbutamide) (see Interactions).
CNS distribution: Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration).
Metabolism: Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine. The relationship between dose and total valproate concentration is nonlinear, concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drugs are linear.
Excretion: Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special populations: Neonates: Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding).
Geriatric: The capacity of elderly patients to eliminate valproate has been shown to be reduced compared to younger adults. Intrinsic clearance is reduced by 39%; the free fraction of valproate is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly (see Dosage & Administration).
Pediatric: Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.
Gender: There are no differences in the body surface area adjusted unbound clearance between males and females.
Ethnicity: The effects of race on the kinetics of valproate have not been studied.
Renal impairment: A slight reduction (27%) in the clearance of unbound valproate has been reported in patients with renal failure (creatinine clearancesee10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading.
Hepatic impairment (See Contraindications and Hepatotoxicity under Precautions): Liver disease impairs the capacity to eliminate valproate. The clearance of free valproate was decreased by 50% in patients with cirrhosis and by 16% in patients with acute hepatitis. The half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal.
Plasma level and clinical effect: The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species.
Epilepsy: The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations.
