Valproate Sodium (Page 10 of 12)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Valproate sodium exists as the valproate ion in the blood. 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).

12.2 Pharmacodynamics

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.

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.

Equivalent doses of valproate sodium and divalproex sodium yield equivalent plasma levels of the valproate ion [see Clinical Pharmacology (12.3)].

12.3 Pharmacokinetics

Bioavailability

Equivalent doses of intravenous (IV) valproate and oral valproate products are expected to result in equivalent Cmax , Cmin , and total systemic exposure to the valproate ion when the IV valproate is administered as a 60 minute infusion. However, the rate of valproate ion absorption may vary with the formulation used. These differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy.

Administration of divalproex sodium tablets and IV valproate (given as a one hour infusion), 250 mg every 6 hours for 4 days to 18 healthy male volunteers resulted in equivalent AUC, Cmax , Cmin at steady state, as well as after the first dose. The Tmax after IV valproate sodium occurs at the end of the one hour infusion, while the Tmax after oral dosing with divalproex sodium occurs at approximately 4 hours. Because the kinetics of unbound valproate are linear, bioequivalence between valproate sodium and divalproex sodium up to the maximum recommended dose of 60 mg/kg/day can be assumed. The AUC and Cmax resulting from administration of IV valproate 500 mg as a single one hour infusion and a single 500 mg dose of divalproex sodium syrup to 17 healthy male volunteers were also equivalent.

Patients maintained on valproic acid doses of 750 mg to 4,250 mg daily (given in divided doses every 6 hours) as oral divalproex sodium alone (n = 24) or with another stabilized antiepileptic drug [carbamazepine (n = 15), phenytoin (n = 11), or phenobarbital (n = 1)], showed comparable plasma levels for valproic acid when switching from oral divalproex sodium to IV valproate (1-hour infusion).

Eleven healthy volunteers were given single infusions of 1,000 mg IV valproate over 5, 10, 30, and 60 minutes in a 4‑period crossover study. Total valproate concentrations were measured; unbound concentrations were not measured. After the 5 minute infusions (mean rate of 2.8 mg/kg/min), mean Cmax was 145 ± 32 mcg/mL, while after the 60 minute infusions, mean Cmax was 115 ± 8 mcg/mL. Ninety to 120 minutes after infusion initiation, total valproate concentrations were similar for all 4 rates of infusion. Because protein binding is nonlinear at higher total valproate concentrations, the corresponding increase in unbound Cmax at faster infusion rates will be greater.

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 Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions of valproate with other drugs].

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 to 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 to 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 drug are linear.

Elimination

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 terminal half-life for valproate monotherapy after an intravenous infusion of 1,000 mg was 16 ± 3 hours.

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

Effect of Age

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). For example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months.

Children

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.

Elderly

The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26 years).

Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and Administration (2.2)].

Effect of Sex

There are no differences in the body surface area adjusted unbound clearance between males and females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2 , respectively).

Effect of Race

The effects of race on the kinetics of valproate have not been studied.

Effect of Disease

Liver Disease

Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, 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 [see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)].

Renal Disease

A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 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.

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