Bioequivalence Study of Sodium Valproate and Valproic Acid Tablets

NCT05641649 | Unknown Phase 4 DMC

• 1 other identifier: BE-001-022
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 2

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.

Conditions

Epilepsy

Keywords

Bioequivalence; Pharmacokinetics; Valproic acid; Sodium valproate

Outcome Measures

Primary Outcomes (1)

• Collected blood samples will be analyzed using a validated bioanalytical method to investigate bioequivalence of test and innovator formulations. If the formulations are found to be bioequivalent these will be considered interchangeable in clinical use.

  For determining bioequivalence of test and innovator formulations, serum drug concentration will be estimated initially. Using this data, other pharmacokinetic parameters will also be estimated like time to peak concentration (tmax), elimination half-life (T1/2), area under the serum drug concentration versus time curve from zero time to 24 hrs (AUC(0-24)), area under the plasma concentration-time curve from zero to infinity (AUC 0-∞), and the elimination half-life (t1/2), using a standard pharmacokinetic software. Test and innovator formulation will be considered bioequivalent if the 90% confidence interval of the ratio of a log-transformed exposure measure (AUC and/or Cmax) falls within the range 80-125%.

  Blood samples will be collected for up to 24 hours of administration of formulations in both study days. Blood sample analysis, determination of pharmacokinetic parameters and statistical analysis to evaluate bioequivalence will take nearly 2 months.

Secondary Outcomes (3)

• Peak plasma concentration (Cmax)

  Blood samples collection up to 24 hours of drug administration

• Area under the plasma concentration-time curve from zero to infinity (AUC 0-∞)

  Blood samples collection up to 24 hours of drug administration

• Area under the plasma concentration-time curve from zero to 24 hours (AUC 0-24)

  Blood samples collection up to 24 hours of drug administration

Study Arms (2)

Test formulation group of volunteers

EXPERIMENTAL

Sixteen healthy subjects aged between 18 and 60 years who satisfy the inclusion/ exclusion criteria will be enrolled in the study. Volunteers will be assigned to take particular formulation by a method of randomization on the first study day. Half of the volunteers falling in the test formulation arm will be given a tablet of test formulation with 200 ml of water in an empty stomach on the first study day. In the second study day, these volunteers will be exchanging the formulations.

Drug: Sodium valproate and valproic acid extended release tablet

Innovator formulation group of volunteers

EXPERIMENTAL

Sixteen healthy subjects aged between 18 and 60 years who satisfy the inclusion/ exclusion criteria will be enrolled. Volunteers will be assigned to take particular formulation by a method of randomization on the first study day. Half of the volunteers falling in the innovator formulation arm will be given a tablet of innovator formulation with 200 ml of water in an empty stomach on the first study day. In the second study day, these volunteers will be exchanging the formulations.

Drug: Sodium valproate and valproic acid extended release tablet

Interventions

Sodium valproate and valproic acid extended release tablet DRUG

Test or innovator tablet formulation of sodium valproate and valproic acid will be administered orally to the volunteers on each study days in fasting condition. Volunteers will be receiving a single tablet of either of the formulations on the study days by a randomization technique so that each of them receives both formulations during the study period.

Also known as: Test drug: VALPROT 500XR, Reference drug: Encorate chrono 500

Innovator formulation group of volunteers; Test formulation group of volunteers

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age: 18 - 60 years.
• Gender: Male / female or both
• Weight: At least 50 kg (110 lbs) and within 15% of Ideal Body Weight (IBW). BMI between 18.0 and 29.9 kg/m², inclusive
• All subjects should be judged normal and healthy during a pre-study medical evaluation (physical examination, including vital signs, laboratory evaluations, 12-lead ECG, hepatitis B, hepatitis C and HIV tests) performed within 14 days of the initial dose of study medication.
• Consent: Demonstrates understanding of the study and willingness to participate as evidenced by voluntary written informed consent (signed and dated) obtained

You may not qualify if:

• Social Habits:
• i. Use of any tobacco products within month of the start of the study. ii. Ingestion of any alcoholic, caffeine- or xanthine-containing food or beverage within 48 hours prior to the initial dose of study medication.
• iii. Ingestion of any vitamins or herbal products within 7 days prior to the initial dose of the study medication.
• iv. Any recent, significant change in dietary or exercise habits. v. History of drug and/or alcohol abuse.
• Medications:
• i. Use of any prescription or over-the-counter (OTC) medications within 14 days prior to the initial dose of study medication.
• ii. Use of any medication known to alter hepatic enzyme activity within 28 days prior to the initial dose of study medication.
• Diseases:
• i. History of any significant cardiovascular, hepatic, renal, pulmonary, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic disease.
• ii. Acute illness at the time of either the pre-study medical evaluation or dosing.
• iii. A positive HIV, hepatitis B, or hepatitis C tests.
• Abnormal and clinically significant laboratory test results:
• i. Clinically significant deviation from the Guide to Clinically Relevant Abnormalities.
• ii. Abnormal and clinically relevant ECG tracing.
• Clinical Studies i. Participation in any clinical study (inclusive of final post-study examination) within the 12 weeks before screening visit.

Sponsors & Collaborators

• Kathmandu University: lead
• Asian Pharmaceuticals Pvt. Ltd.: collaborator

Study Sites (2)

Department of Pharmacy, Kathmandu University

Dhulikhel, Bagmati, Nepal

Location

Dhulikhel Hospital, Kathmandu University Teaching Hospital

Dhulikhel, Bagmati, Nepal

Location

Related Publications (7)

• Bialer M. Extended-release formulations for the treatment of epilepsy. CNS Drugs. 2007;21(9):765-74. doi: 10.2165/00023210-200721090-00005.

  PMID: 17696575 BACKGROUND

• Perucca E. Extended-release formulations of antiepileptic drugs: rationale and comparative value. Epilepsy Curr. 2009 Nov-Dec;9(6):153-7. doi: 10.1111/j.1535-7511.2009.01326.x.

  PMID: 19936129 BACKGROUND

• Dutta S, Reed RC, Cavanaugh JH. Absolute bioavailability and absorption characteristics of divalproex sodium extended-release tablets in healthy volunteers. J Clin Pharmacol. 2004 Jul;44(7):737-42. doi: 10.1177/0091270004266782.

  PMID: 15199078 RESULT

• Fujii A, Yasui-Furukori N, Nakagami T, Niioka T, Saito M, Sato Y, Kaneko S. Comparative in vivo bioequivalence and in vitro dissolution of two valproic acid sustained-release formulations. Drug Des Devel Ther. 2009 Feb 6;2:139-44. doi: 10.2147/dddt.s3556.

  PMID: 19920901 RESULT

• Yasui-Furukori N, Saito M, Nakagami T, Niioka T, Sato Y, Fujii A, Kaneko S. Different serum concentrations of steady-state valproic acid in two sustained-release formulations. Psychiatry Clin Neurosci. 2007 Jun;61(3):308-12. doi: 10.1111/j.1440-1819.2007.01656.x.

  PMID: 17472600 RESULT

• Dulac O, Alvarez JC. Bioequivalence of a new sustained-release formulation of sodium valproate, valproate modified-release granules, compared with existing sustained-release formulations after once- or twice-daily administration. Pharmacotherapy. 2005 Jan;25(1):35-41. doi: 10.1592/phco.25.1.35.55626.

  PMID: 15767218 RESULT

• Roberts D, Easter D, O'Bryan-Tear G. Epilim chrono: a multidose, crossover comparison of two formulations of valproate in healthy volunteers. Biopharm Drug Dispos. 1996 Mar;17(2):175-82. doi: 10.1002/(SICI)1099-081X(199603)17:23.0.CO;2-J.

  PMID: 8907724 RESULT

MeSH Terms

Conditions

Epilepsy

Interventions

Valproic Acid

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids

Study Officials

• Rajani Shakya, PhD

  Kathmandu University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: On the first study day, volunteers will be grouped into two. One group will be given test formulation and other will be given innovator formulation. Simple randomization technique will be used for this. Predose blood sample will be collected 15 minutes before drug administration. Later 3 ml blood sample will be collected 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, group of volunteers who have received test formulation on first study day will be given innovator and those who received innovator on the first study day will be given test formulation on the second study day.

Study Record Dates

• First Submitted: November 10, 2022
• First Posted: December 8, 2022
• Study Start: August 6, 2023
• Primary Completion: October 13, 2023
• Study Completion: November 30, 2023
• Last Updated: October 11, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

NE (2)