Divalproex Sodium Extended-Release (Page 11 of 14)
12.3 Pharmacokinetics
The absolute bioavailability of divalproex sodium extended-release tablets administered as a single dose after a meal was approximately 90% relative to intravenous infusion.
When given in equal total daily doses, the bioavailability of divalproex sodium extended-release tablets are less than that of divalproex sodium tablets. In five multiple-dose studies in healthy subjects (N=82) and in subjects with epilepsy (N=86), when administered under fasting and nonfasting conditions, divalproex sodium extended-release tablets given once daily produced an average bioavailability of 89% relative to an equal total daily dose of divalproex sodium tablets given BID, TID, or QID. The median time to maximum plasma valproate concentrations (Cmax ) after divalproex sodium extended-release tablets administration ranged from 4 to 17 hours. After multiple once-daily dosing of divalproex sodium extended-release tablets, the peak-to-trough fluctuation in plasma valproate concentrations was 10-20% lower than that of regular divalproex sodium tablets given BID, TID, or QID.
Conversion from Divalproex Sodium Tablets to Divalproex Sodium Extended-Release Tablets
When divalproex sodium extended-release tablets are given in doses 8 to 20% higher than the total daily dose of divalproex sodium tablets, the two formulations are bioequivalent. In two randomized, crossover studies, multiple daily doses of divalproex sodium tablets were compared to 8 to 20% higher once-daily doses of divalproex sodium extended-release tablets. In these two studies, divalproex sodium extended-release tablets and divalproex sodium tablets regimens were equivalent with respect to area under the curve (AUC; a measure of the extent of bioavailability). Additionally, valproate Cmax was lower, and Cmin was either higher or not different, for divalproex sodium extended-release tablets relative to divalproex sodium tablets regimens (see Table 9).
| Table 9. Bioavailability of Divalproex Sodium Extended-ReleaseTablets Relative to Divalproex Sodium Tablets When Divalproex Sodium Extended-Release Tablets Dose is 8 to 20% Higher | ||||
| Study Population | Regimens | Relative Bioavailability | ||
| Divalproex sodium extended-release tablets vs. Divalproex sodium tablets | AUC24 | Cmax | Cmin | |
| Healthy Volunteers (N=35) | 1000 & 1500 mgDivalproex sodium extended-release tablets vs.875 & 1250 mg Divalproex sodium tablets | 1.059 | 0.882 | 1.173 |
| Patients with epilepsy on concomitant enzyme-inducing antiepilepsy drugs (N = 64) | 1000 to 5000 mgDivalproex sodium extended-release tablets vs.875 to 4250 mgDivalproex sodium tablets | 1.008 | 0.899 | 1.022 |
Concomitant antiepilepsy drugs (topiramate, phenobarbital, carbamazepine, phenytoin, and lamotrigine were evaluated) that induce the cytochrome P450 isozyme system did not significantly alter valproate bioavailability when converting between divalproex sodium tablets and divalproex sodium extended-release tablets.
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].
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration).
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 drug are linear.
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.
The valproate pharmacokinetic profile following administration of divalproex sodium extended-release tablets was characterized in a multiple-dose, non-fasting, open label, multi-center study in children and adolescents. Divalproex sodium extended-release tablets once daily doses ranged from 250-1750 mg. Once daily administration of divalproex sodium extended-release tablets in pediatric patients (10-17 years) produced plasma VPA concentration-time profiles similar to those that have been observed in adults.
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). 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 (2.4)].
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).
The effects of race on the kinetics of valproate have not been studied.
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)].
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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