Valpros/Valpros i-IV Mechanism of Action

Pharmacologic Category: Anticonvulsant/antiepileptic.
Pharmacology: Pharmacodynamics: Valpros: Sodium valproate and valproic acid are antiepileptic drugs (AEDs). The mechanism by which valproate exerts its antiepileptic effects is not known. However, its anticonvulsant effect may be related, at least in part, to increased brain concentrations of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA).
Valpros i-IV: The mechanism by which sodium valproate exerts its effects is not known. However, its anticonvulsant effect may be related, at least in part, to increased brain concentrations of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA). This effect of sodium valproate on the GABA neurotransmitter is also believed to possibly contribute to its antimanic properties.
Pharmacokinetics: Valpros: The controlled release formulation of sodium valproate + valproic acid reduces the possibility of fluctuations in plasma concentrations compared with conventional formulations.
Sodium valproate and valproic acid circulate in the plasma as the valproate ion and trough valproic acid plasma levels are used to monitor both.
After oral administration, sodium valproate is rapidly converted to valproic acid and valproic acid dissociates to the valproate ion in the gastrointestinal tract.
Absorption of valproate is rapid and complete. Peak plasma concentrations are achieved between 2 to 8 hours.
In healthy human subjects under fasting conditions, the mean C_max of valproic acid (21.29 µg/mL) was achieved 5.08 hours (t_max) after oral administration of a single dose of 500 mg controlled release tablet containing sodium valproate and valproic acid. The AUC_(0-t) was 233.12 µg.hr/mL and the AUC_(0-∞) was 241.42 µg.hr/mL.
The relationship between dose and total valproic acid concentration is nonlinear; concentration does not increase proportionally with dose because of saturable protein binding. The pharmacokinetics of unbound drug are linear.
Valproate is rapidly distributed; distribution appears to be restricted to plasma and rapidly exchangeable extracellular water. The volume of distribution is 0.2 L/kg body weight.
Valproate has been detected in the cerebrospinal fluid (CSF) (about 10% of plasma concentrations), saliva (about 1% of plasma concentrations), and milk (about 1 to 10% of plasma concentrations). The drug crosses the placenta.
Plasma protein binding of valproate is concentration dependent; the free fraction of the drug increases from 10% at a concentration of 40 mcg/mL to 18.5% at a concentration of 130 mcg/mL. Protein binding is between 80 to 95%.
Valproate is metabolized principally in the liver by beta (over 40%) and omega oxidation (up to 15 to 20%). The metabolites are excreted in urine; 30 to 50% of an administered dose is excreted as glucuronide conjugates. Less than 3% of an administered dose is excreted in urine unchanged. The major metabolite in urine is 2-propyl-3-ketopentanoic acid; minor urinary metabolites are 2-propylglutaric acid, 2-propyl-5-hydroxypentanoic acid, 2-propyl-3-hydroxypentanoic acid, and 2-propyl-4-hydroxypentanoic acid. Small amounts of drug are also excreted in feces and in expired air.
Valproate is eliminated by first-order kinetics. Mean plasma clearance of total or free valproic acid is 0.56 m² or 4.6 L/hr per 1.73 m², respectively. Plasma elimination half-life (t_1/2) was 4.95 hours.
Valpros i-IV: Equivalent doses of intravenous (IV) valproate and oral valproate products are expected to result in equivalent peak and trough plasma concentrations and total systemic exposure to the valproate ion when the IV valproate is administered as a 60 minute infusion. Although the rate of valproate ion absorption may vary with the specific formulation, any such differences should be of minor clinical importance under steady-state conditions achieved with chronic therapy for seizure disorders.
Distribution of sodium valproate is rapid and most likely restricted to the circulation and rapidly exchangeable extracellular water. Cerebrospinal fluid and breast milk levels were found to be 5 to 15% and about 1 to 10% of plasma levels, respectively. 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).
The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear.
Sodium valproate is metabolized almost entirely in 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 the urine.
Sodium valproate is almost completely metabolized prior to excretion. Plasma half-life is variable but generally appears to be 8 to 12 hours (range: 3.84 to 15.77 hours). It may be shorter in patients receiving other anticonvulsants or in children and patients receiving the medicine for long periods.
Special Population: Hepatic Impairment (see Contraindications and Warnings): Liver disease impairs the capacity to eliminate valproate. A study showed that the clearance of free valproate was decreased by 50% in patients with cirrhosis and by 16% in patients with acute hepatitis, compared with healthy subjects. In this 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. Thus, 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.
Renal Impairment: In patients with renal failure (creatinine clearance <10 mL/min), a slight reduction (27%) in the unbound clearance of valproate has been reported. However, hemodialysis typically reduces valproate concentrations by about 20%. 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.
Pediatric: Children between 3 months and 10 years old have 50% higher clearance of the drug expressed by weight (i.e., mL/min per kg) than adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Infants <2 months old have a markedly decreased ability to eliminate valproate compared with older children and adults. This may be due to reduced clearance (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).
Geriatrics: The capacity of elderly patients (68 to 89 years old) to eliminate valproate has been shown to be reduced compared with younger adults (22 to 26 years old). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in this age group.