Bioequivalence Study of Sodium Valproate and Valproic Acid Tablets
brief summary
Bioavailability is the extent and rate to which the active drug ingredient or active moiety from the drug product is absorbed and becomes available at the site of drug action. Bioavailability of an active substance delivered from a pharmaceutical product should be known and reproducible. In the past, several therapeutic misadventures related to differences in bioavailability affirm to the necessity of testing the performance of dosage forms in delivering the active substance to the systemic circulation and thereby to the site of action. If there is no clinically significant difference in the bioavailability of two medicines they are considered to be bioequivalent. The bioavailability and bioequivalence studies of various drug candidates have been routine regulatory requirements in many countries for licensing of the drug product. Department of Drug Administration, Ministry of health and Population has encouraged Nepalese Pharmaceutical Industries legally to submit pharmacokinetic data where possible for licensing purpose for certain drug candidates and their dosage forms. The comparative in-vivo bioequivalence study is necessary for those products which have low therapeutic index, low bioavailability, non-linear kinetics, poor dissolution profile, variable bioavailability and/or bioequivalence. Department of Drug Administration necessitated bioequivalence and bioavailability study for the modified release dosage form of those drug molecules whose blood steady state concentration is of great importance, e.g. sodium valproate, valproic acid, carbamazepine, antibiotics etc. Considering the need to confirm safety and effectiveness of the medications and also for the regulatory requirement, this study to assess the bioequivalence of sodium valproate and valproic acid extended release tablet manufactured by a Nepalese pharmaceutical company, Asian Pharmaceuticals Pvt. Ltd., with an innovator formulation is being carried out in healthy human volunteers.
detailed description
Successful therapeutic management of patients with epilepsy requires selection of an appropriate antiepileptic regimen, optimal dosing and patient compliance. Valproate is primarily used to treat epilepsy and bipolar disorder. Valproate exists in two main molecular variants; sodium valproate and valproic acid. These molecules have been widely used in the last decade and is now considered as relatively safe and effective anticonvulsant agents. These drug molecules were registered in Department of Drug administration of Nepal long time back.
The mechanism of action of valproate is not clear. There are three proposed mechanism of action: 1) It increases the brain γ-aminobutyric acid (GABA), 2) It potentiates the postsynaptic response to GABA, and 3) It exerts a direct membrane effect.
Valproate can be administrated by intravenous, oral and rectal routes. Among them, the oral route is mostly and widely used. Valproate is highly bound (90%) to human plasma albumin at therapeutic concentrations. This property tends to keep most of the drug within the vascular compartment. The clearance of valproate is independent of liver blood flow but is highly dependent on the free fraction. It has been recognized that the blood levels-dose relationship for valproate is highly variable among patients. Valproate is eliminated almost exclusively by hepatic metabolism (\>96% of administered dose).
Sodium valproate and valproic acid are the critical dose medicines. Critical dose medicines are those medicines for which relatively small variations in plasma concentrations may cause significant adverse effects or loss of efficacy. Stable serum levels of valproic acid without marked peak-to-trough fluctuations, reduced frequency of dosing, and the possibility of dosing flexibility will improve cure rate, patient compliance, satisfaction and, ultimately, quality of life. Valproic acid is available in different dosage forms for parenteral and oral use. All available oral formulations are almost completely bioavailable, but they differ in dissolution characteristics and absorption rates. Extended-release formulations can be very helpful in achieving above mentioned objectives and avoiding consequences due to differences in dissolution characteristics.
"VALPROT 500XR" is the extended release formulation of sodium valproate and valproic acid manufactured in Nepal by Asian Pharmaceuticals Pvt. Ltd. Due to presence of several brands of these molecules in the market, there is possibility of brand substitution in patients. If the newer brand has different pharmacokinetic property and bioavailability than the conventional ones then this can lead to several problems like loss of seizure control, seizure related injury, accidents etc. So, it is prudent to ensure that the values for pharmacokinetic parameters of existing formulations and the newly designed formulation are comparable with each other. Yet there is no information available on pharmacokinetic profile of this new extended release formulation. Therefore, there is a strong need of a bioequivalence study to make comparison of pharmacokinetic profile of "VALPROT 500XR" and the marketed innovator brand to prove them interchangeable.
official title
Bioequivalence Study of Sodium Valproate and Valproic Acid Extended Release Tablets in Healthy Human Volunteers