Bioequivalence Study of Sodium Valproate and Valproic Acid Tablets

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.

Bioequivalence means the absence of greater-than-allowable difference between the systemic bioavailability of a test product and that of an innovator product. The United States Food and Drug Administration (US FDA) has defined bioequivalence as 'the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study'. The FDA considers two products bioequivalent if the 90% confidence interval of the relative mean plasma concentration (Cmax), area under the serum drug concentration versus time curve from zero time to 24 hours (AUC0-24) and area under the serum drug concentration versus time curve from zero time to infinity (AUC0-∞) of the test to innovator product is within 80% to 125%. For narrow therapeutic index drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions, this difference in blood concentrations or drug exposure might not be unacceptable and a narrow limit for bioequivalence is proposed.

Bioequivalence is the important tool to characterize the therapeutic efficacy of the drug product. The objective of the bioequivalence study is to provide assurance of switchability between various formulations in the interest of clinical safety. Switchability actually demands that, within the same patient, the drug concentration of the test formulation remain within the same therapeutic window achieved by the innovator formulation.

The main objective of this study is to investigate the bioequivalence of sodium valproate and valproic acid extended release tablets (VALPROT 500XR), manufactured by Asian Pharmaceuticals Pvt. Ltd. with an innovation brand having the same composition, following a single, oral dose administered.

This is an open-label, randomized, two-way crossover study comprising sixteen healthy volunteers between 18 and 60 years of age. Potential subjects will be recruited via local advertisement. Dropouts will be replaced if the number of evaluable subjects drops below 16.

Subjects meeting set inclusion criteria will be enrolled in the study after obtaining informed written consent. Complete physical examination will be carried out at the time of initial screening and also within 24 hours after each dose whenever required. Laboratory tests including liver function and renal function tests will be carried out at the time of initial screening, prior to the administration of each dose. If any person has abnormal liver function (abnormal level of liver enzymes) and/or abnormal renal function (abnormal creatinine and urea level), he/she will be withdrawn from the study.

On the first study day, volunteers will be grouped randomly into two groups. One group will be given test formulation and other will be given reference formulation. Exactly 15 minutes before the first dose, 3 ml blood sample will be collected and later at 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, 60 and 72 hours after drug administration.

After giving a washout period of 7 days, on the second study day, volunteers will exchange the formulations.

Blood sample will be collected in vacutainer tubes with no anticoagulant. It will be allowed to clot at room temperature for 20 minutes. Then blood sample will be centrifuged at 3000 rpm for 15 minutes. Serum will be transferred into a separate serum container and will be promptly frozen at -20 degree Celsius until assay. Plasma samples will be analyzed using a validated bioanalytical method in the analytical laboratory of Kathmandu University. The single-dose pharmacokinetic parameters that will be evaluated include Cmax, AUC0-24, AUC0-∞, and the elimination half-life (t1/2).