A Bioequivalence Study of Two Formulations Lamotrigine 100 mg Tablets and Lamictal 100 mg Tablets in Healthy Adult Volunteers Under Fasting Conditions

Study Overview
=================
Brief Summary
-----------------
This is an open-labeled, randomized, crossover, two-period, single-center, comparative study, where each participant will be randomly assigned to the reference (Lamictal, 100 mg tablets) or the test (Lamotrigine, 100 mg tablets) formulation in each period of study (sequences Test-Reference (TR) or Reference-Test (RT)), in order to evaluate if both formulations are bioequivalent

Detailed Description
-----------------
The objective of this study is to establish if two formulations of lamotrigine are bioequivalent. Also monitoring, registration and evaluation of adverse events that can be performed. The test formulation is Lamotrigine, Tablets 100 mg (Pharmtechnology LLC, Belarus). The reference formulation is Lamictal®, Tablets 100 mg (GlaxoSmithKlein Trading CJSC, Russia). 28 healthy adult volunteers of both genders, with age ranging from 18 to 45 years old, will be divided into two cohorts with equal number of subjects (14). Each participant in a cohort will receive single tablet (100 mg of lamotrigine) of the test or the reference products with 200 ml of water after an overnight fast of at least 10 hours. Participants will fast 4 hours after administration of the study drugs. Next meals will be after 6, 9 and 12 hours after administration of formulations. Standardized meals will be provided in each study period. Water will not be accessible to the participants 1 hour prior to administration of the study drugs and 2 hours after administration of the study drugs in each period. In each period blood samples will be collected during 30 minutes before dosing and 0.5, 1.00, 1.5, 1.75, 2.00, 2.25, 2.5, 2.75, 3.00, 3.5, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 24.00, 36.00, 48.00, 72.00, 96.00, 120.00 hours after dosing (total number: 23). The washout period will be 21 days. At the bio-analytical stage, a validated High Performance Liquid Chromatography with tandem Mass Spectrometry detection (HPLC/MS) method will be used to determine plasma concentrations of lamotrigine. ANOVA will be performed on log transformed pharmacokinetic parameters Cmax, Area Under the pharmacokinetic Curve from the beginning of the study till the time of the last measured concentration (AUC0-t) and 90% confidence interval will be constructed for the ratio of geometric means of the test and the reference products, obtained from the log-transformed data. Bioequivalence will be concluded if the ratio estimate as well as its 90% confidence interval for lamotrigine falls within the acceptable range of 80.00% to 125.00% for Cmax and AUC0-t

Official Title
-----------------
Single-Dose Open-label Randomized Crossover, in Two Periods and in Two Sequences, Single-Center Comparative Bioequivalence Study of Two Formulations Lamotrigine, 100 mg Tablets (Pharmtechnology LLC, Republic of Belarus), and Lamictal®, 100 mg Tablets (GlaxoSmithKline Trading Closed Joint-Stock Company (CJSC), Russia), in Healthy Volunteers Under Fasting Conditions

Conditions
-----------------
Healthy Adults

Intervention / Treatment
-----------------
* Drug: Lamotrigine
* Drug: Lamictal


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy caucasian men or women aged between 18 to 45 years Subjects having no clinically significant medical history and no clinically significant abnormalities in general physical examination, laboratory assessments and imaging studies Body mass index 18.5-30 kg/m² with body mass >45 kg and ≤100 kg Non-breastfeeding women Non-pregnant women (negative pregnancy test) If subject is a female and is of childbearing potential, she should be practicing an acceptable non-hormonal method of birth control for the duration of the study(the entire time from the moment of signing the informed consent form and within 14 days after the completion of the study), such as a combination of male condom and diaphragm with spermicide If subject is a male and has a female partner of childbearing potential, he should be practicing an acceptable method of birth control for the duration of the study(the entire time from the moment of signing the informed consent form and within 14 days after the completion of the study), such as a double barrier method of birth control or sexual continence during the whole study and within 14 days after its' completion Subjects are able to understand the requirements of the study, to sign a written informed consent, and also to accept all the restrictions imposed during the course of the study, and to agree to return for the required investigations Exclusion Criteria: Subjects with a known history of allergic disorders Hypersensitivity to lamotrigine or to any of the excipients of the test and the reference product Lactase deficiency, lactose intolerance, glucose-galactose malabsorption Subjects with a known history of drug intolerance Dehydration due to diarrhea, vomiting, or another cause in the last 24 hours before the beginning of the first period of the study Subjects with history of psychiatric disorders History of convulsions, epilepsy and any other neurological disorders Adherence to any low sodium diet for 2 weeks before starting research, or adherence to a special diet (for example, vegetarian, vegan, with restriction of the use of salt) or lifestyle (work at night, extreme physical exertion) Use of gestagen-containing injectable hormonal contraceptives, implants, intrauterine hormonal therapeutic systems within 6 months prior to start of the study Female subjects of child bearingpotential having unprotected intercourse with an unsterilized sexual partner within 30 days prior to start of the study Consumption of xanthine-containing foods and drinks (tea, coffee, coca-cola, chocolate), alcohol, products containing poppy within 72 hours prior to start of the first period of the study Consumption of citrus fruits (including grapefruit and grapefruit juice) and cranberries (including cranberry juice and other cranberry drinks) within 14 days prior to start of the study Acute and chronic cardiovascular, respiratory, gastrointestinal diseases, neuroendocrine disorders, renal and/or hepatic impairment, blood system disorders Other conditions which, according to the researcher's judgment, may affect absorption, distribution, biotransformation and elimination of any formulation or increase risks of deterioration of volunteer's condition Surgical interventions on the gastrointestinal tract with the exception of appendectomy Acute infectious diseases less than 4 weeks prior to the start of the study ECG abnormalities Sitting systolic blood pressure < 100 mm Hg or > 130 mm Hg and/or sitting diastolic blood pressure < 70 mm Hg or > 90 mm Hg Heart rate <60 or >90 beats per minute at screening check-in Use of liver enzyme inducers and inhibitors, in particular isoenzyme CYP3A4 (inducers: omeprazole, cimetidine, products containing the extract of Hypericum perforatum, barbiturates, carbamazepine, phenytoin, glucocorticoids; inhibitors: antiviral drugs, clarithromycin, ciprofloxacin, gestodene etc.) within 2 months prior to the start of the study Use of any systemic drugs within 14 days prior to the start of the study Use of Over-The-Counter (OTC) drugs, including herbs and nutritional supplements within 7 days prior to the First Dosing Date (including vitamins and natural food additives, phyto supplements,herbal preparations such as, cat's claw, angelica officinalis, oenothera, feverfew, garlic, ginger, ginkgo, red clover, horse chestnut, green tea, ginseng) Donation of plasma or blood (450 ml or more) within 2 months prior to the start of the study Intake of more than 10 units alcohol per week (1 unit of alcohol is equivalent to ½ liter of beer, 200 ml dry wine or 50 ml of spirits) or history of alcoholism, drug addiction, drug abuse Smoking more than 10 cigarettes per day Participation in other clinical trials of medicines within 3 months prior to the start of the study Positive test for syphilis, hepatitis B, hepatitis C or HIV Positive pregnancy test (for female subjects with child bearing potential) Breast-feeding In the case of using of oral hormonal contraceptives, they should be withdrawn 2 months prior to the start of the study Positive test for alcohol in exhaled air Positive urinary screen test for the content of narcotic and potent substances during screening and at each arrival at the research stage Volunteers who don't intend to comply with the study protocol and/or not credible therein and who are, at the discretion of the Principal Investigator, unable to understand and assess the information about the study, expected risks and possible discomfort in the process of signing written informed consent The values of standard laboratory and instrumental parameters that go beyond the reference values of the local clinical laboratory

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Sequence Test-Reference (TR)<br>14 participants (total number of enrolled volunteers - 28) assigned to sequence TR will receive a single 100 mg dose of the test product Lamotrigine (1 x 100 mg tablet) marked as T in period 1 and a single 100 mg dose of the reference product Lamictal (1 x 100 mg tablet) marked as R in period 2. These treatments will be administered orally with 200 ml of water at ambient temperature, in the morning, following a 10-hour overnight fast. The tablet must be swallowed whole and must not be chewed or broken. | Drug: Lamotrigine<br>* Lamotrigine, 100 mg Tablets, manufactured by Pharmtechnology LLC, Belarus<br>* Other names: the test product;Drug: Lamictal<br>* Lamictal®, 100 mg Tablets, marketed by GlaxoSmithKline Trading CJSC, Russia<br>* Other names: the reference product;|
| Other: Sequence Reference-Test (RT)<br>14 participants (total number of enrolled volunteers - 28) assigned to sequence RT will receive a single 100 mg dose of the reference product Lamictal (1 x 100 mg tablet) marked as R in period 1 and a single 100 mg dose of the test product Lamotrigine (1 x 100 mg tablet) marked as T in period 2. These treatments will be administered orally with 200 ml of water at ambient temperature, in the morning, following a 10-hour overnight fast. The tablet must be swallowed whole and must not be chewed or broken. | Drug: Lamotrigine<br>* Lamotrigine, 100 mg Tablets, manufactured by Pharmtechnology LLC, Belarus<br>* Other names: the test product;Drug: Lamictal<br>* Lamictal®, 100 mg Tablets, marketed by GlaxoSmithKline Trading CJSC, Russia<br>* Other names: the reference product;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of lamotrigine for the test and the reference products | Maximum concentration in plasma among observed concentrations at pre-specified time points | Time points: 0,00 (within 30 minutes before dosing) and 0.5, 1.00, 1.5, 1.75, 2.00, 2.25, 2.5, 2.75.3.00, 3.5, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 24.00, 36.00, 48.00, 72.00, 96.00, 120.00 hours after dosing | 
| AUC0-t of lamotrigine for the test and the reference products | Area under the plasma concentration versus time curve from time 0 to the last measured concentration | Time points: 0,00 (within 30 minutes before dosing) and 0.5, 1.00, 1.5, 1.75, 2.00, 2.25, 2.5, 2.75.3.00, 3.5, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 24.00, 36.00, 48.00, 72.00, 96.00, 120.00 hours after dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-∞ of lamotrigine for the test and the reference products | Area under the plasma concentration versus time curve from time 0 to infinite time | Time points: 0,00 (within 30 minutes before dosing) and 0.5, 1.00, 1.5, 1.75, 2.00, 2.25, 2.5, 2.75.3.00, 3.5, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 24.00, 36.00, 48.00, 72.00, 96.00, 120.00 hours after dosing | 
| Tmax of lamotrigine for the test and the reference products | Time to maximum measured plasma concentration | Time points: 0,00 (within 30 minutes before dosing) and 0.5, 1.00, 1.5, 1.75, 2.00, 2.25, 2.5, 2.75.3.00, 3.5, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 24.00, 36.00, 48.00, 72.00, 96.00, 120.00 hours after dosing | 
| T1/2 of lamotrigine for the test and the reference products | Elimination or terminal half-life | Time points: 0,00 (within 30 minutes before dosing) and 0.5, 1.00, 1.5, 1.75, 2.00, 2.25, 2.5, 2.75.3.00, 3.5, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 24.00, 36.00, 48.00, 72.00, 96.00, 120.00 hours after dosing | 
| Kel of lamotrigine for the test and the reference products | Elimination rate constant | Time points: 0,00 (within 30 minutes before dosing) and 0.5, 1.00, 1.5, 1.75, 2.00, 2.25, 2.5, 2.75.3.00, 3.5, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 24.00, 36.00, 48.00, 72.00, 96.00, 120.00 hours after dosing | 
| AUCresid% of lamotrigine for the test and the reference products | Residual area under the pharmacokinetic curve from the time of the last measured concentration to infinity time | Time points: 0,00 (within 30 minutes before dosing) and 0.5, 1.00, 1.5, 1.75, 2.00, 2.25, 2.5, 2.75.3.00, 3.5, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 24.00, 36.00, 48.00, 72.00, 96.00, 120.00 hours after dosing | 
| Number of treatment-related adverse events (AE) for the test and the reference products as assessed by guidance predefined in the protocol | An AE is defined as any untoward medical occurrence in a subject administered the test or the reference product and which does not necessarily have a causal relationship with the treatment. | Up to 27 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Bioequivalence, Lamotrigine