Healthy
Conditions
Keywords
Bioequivalence, Lamotrigine Extended Release, Generic, Pharmacokinetic
Brief summary
The objective of this study is to determine bioequivalence between two different formulations of lamotrigine extended release tablets (one reference product and one generic product) in a healthy adult population, following a single oral dose under fed conditions.
Detailed description
This is a single center, randomized, open-label, single dose, two treatment, four-period, two-sequence, fully replicated crossover design in the fed state. The study will include two treatments: * Treatment-A: One dose of Lamotrigine extended-release tablet (Test) administered in the morning after a 10-hour overnight fast and 30 minutes after the start of a high-fat, high-calorie breakfast. * Treatment-B: One dose of Lamictal XR extended-release tablet (Reference) administered in the morning after a 10 hour overnight fast and 30 minutes after the start of a high-fat, high-calorie breakfast. A total of 30 healthy subjects will be dosed to ensure that at least 24 subjects will complete the 4-period replicate design. For each treatment period, subjects will be confined from the day prior to dosing until approximately 48 hours post-dose. Subjects will return to the clinical site for the remaining blood samples. There will be a minimum 14-day washout between doses. Subject participation from the Screening Visit to the Follow-Up Visit will be approximately 71 days.
Interventions
DRUGLamotrigine Extended Release
Lamotrigine Extended Release (generic) and Lamictal XR (brand).
Sponsors
Vince & Associates Clinical Research, Inc.
Algorithme Pharma Inc
Food and Drug Administration (FDA)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male or female subjects ≥18 to ≤50 years of age 2. Subject is willing and able to provide informed consent 3. Body mass index (BMI) greater than or equal to 18.00 kg/m2 and below 30.00 kg/m2 at screening 4. Body weight greater than or equal to 50 kg at screening 5. Subject is a non-smoker and has not used any nicotine containing products within 6 months prior to screening 6. Subjects who are considered generally healthy upon completion of medical history, physical examination, vital signs, screening laboratory results and screening ECG in the opinion of the Investigator 7. Subjects who are willing and able to comply with the visit schedule, laboratory tests, pharmacokinetic sampling schedule and other study procedures 8. Subjects who are willing and able to maintain their eligibility throughout the study. 9. A female study subject must meet one of the following criteria: * If of childbearing potential - agrees to use one of the accepted contraceptive regimens from at least 30 days prior to the first administration of the study medication, during the study, and for at least 30 days after the last dose of the study medication. An acceptable method of contraception includes one of the following: * Abstinence from heterosexual intercourse * Progestogen-containing hormonal contraceptives (birth control pills, injectable/implant/insertable hormonal birth control products, transdermal patch) * Intrauterine device (without hormones) * Condom with spermicide * If a female of non-childbearing potential - should be surgically sterile (i.e. has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or in a menopausal state (at least 1 year without menses), as confirmed by FSH levels (post menopausal must be confirmed by the subject having a serum follicle stimulating hormone greater than 40mIU/ml at screening). Females of non-childbearing potential must present a proof of partial or total hysterectomy; if such proof is not available, the female will be considered to be of childbearing potential. 10. A male study subject must agree to use one of the accepted contraceptive regimens during the study and for at least 90 days after the last dose of the study medication; * Abstinence from heterosexual intercourse * Female partner with hormonal contraceptives (birth control pills, injectable/implant/insertable hormonal birth control products, transdermal patch) * Female partner with intrauterine device (with or without hormones) * Female partner with condom with spermicide used by male study subject * Female partner of non-childbearing potential * Male sterilization with absence of sperm in the post vasectomy ejaculate 11. A male study subject must agree not to donate sperm during the study and for at least 90 days after the last dose of the study medication
Exclusion criteria
1. Females who are pregnant or are breastfeeding 2. Females who are using any estrogen-containing hormonal contraceptives 3. History of known clinically significant drug allergies or reactions to lamotrigine, or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs in the opinion of the Investigator 4. Clinically significant history or evidence of gastrointestinal, hepatic, renal, endocrine, pulmonary, neurological, psychiatric, cardiovascular, hematologic, dermatologic, immunologic disease or any other condition known to interfere with the absorption, distribution, metabolism or distribution of drugs that in the opinion of the Investigator would jeopardize the safety of the subject or impact validity of study results 5. Presence of observed abnormality (evidenced from physical examination, ECG, vital signs, or laboratory evaluation) that would be clinically significant in the opinion of the Investigator 6. History of regular alcohol consumption exceeding 7 drinks per week for females and 14 drinks per week for males within 6 months of screening 7. Has current or recent history (within the past year) of alcohol or drug abuse or dependence 8. Any clinically significant illness in the previous 30 days prior to screening 9. Use of any enzyme-modifying drugs, including strong inhibitors of CYP enzymes (such as cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem, and HIV antivirals) and strong inducers of CYP enzymes (such as barbiturates, carbamazepine, glucocorticoids, phenytoin, rifampin, St John's Wort) in the previous 30 days prior to screening 10. Known presence of rare hereditary problems of galactose and /or lactose intolerance or glucose-galactose malabsorption 11. Unusual dietary habits (e.g., vegan, Atkins), dietary restrictions, and/or food allergies. 12. Any planned surgery from the screening visit until the end of the study 13. Positive urine screen for alcohol, cotinine and/or drugs of abuse at screening and at each admission of each treatment period 14. Positive test results for HIV-1/HIV-2 Antibodies, Hepatitis B surface Antigen (HBsAg) or Hepatitis C Antibody (HCVAb) 15. Albumin values less than 4 g/dL at screening 16. Triglyceride values greater than 200 mg/dL at screening 17. Treatment with any investigational drug 30 days prior to screening 18. Participation in other clinical studies within 30 days prior to screening 19. Blood donation (excluding plasma donation) of approximately 500 mL within 56 days prior to screening 20. Subject is unlikely to comply with the study protocol or, in the opinion of the Investigator, would not be a suitable candidate for participation in the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Lamotrigine Concentration vs. Time Curve From Sample Time Point 0 Hour to Sample Time Point 144 Hour. | 144 hours | Pre-dose, and post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours Lamotrigine and Lamictal have the same active ingredient Lamotrigine. |
| AUC 0-Inf | 144 hours | Area Under the Lamotrigine Concentrations vs. time curve from sample time point 0 hour to sample time point 144hours plus extrapolation to infinity of the terminal concentration slope. This describes the total exposure to Lamotrigine. Sampling times include: Pre-dose, and post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours. Lamotrigine and Lamictal have the same active ingredient. |
| Cmax | 2 to 144 hours | The maximum concentration of the Lamotrigine achieved in specified time frame for each treatment. Sampling times include: post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours. Lamotrigine and Lamictal have the same active ingredient. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Tmax | 2 to 144 hours | Time from 0 concentration sample point to the Cmax sample point. Sampling times include: post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours. |
| λZ | 2 to 144 hours | Apparent elimination rate constant, estimated by linear regression of the terminal linear portion of the log concentration versus time curve. Sampling times include: post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours. |
| Thalf | 2 to 144 hours | It is the terminal elimination half-life, calculated as ln(2)/λZ. Sampling times include: post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants 30 participants
Completed subjects received two rounds of Lamictal and Lamotrigine. | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 32 years |
| BMI | 26.05 kg/m^2 STANDARD_DEVIATION 2.54 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 30 |
| other Total, other adverse events | 9 / 30 | 11 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 |
Outcome results
Primary
Area Under the Lamotrigine Concentration vs. Time Curve From Sample Time Point 0 Hour to Sample Time Point 144 Hour.
Pre-dose, and post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours Lamotrigine and Lamictal have the same active ingredient Lamotrigine.
Time frame: 144 hours
Population: Fully replicated crossover study (all completed subjects received two rounds of Lamictal and Lamotrigine). Completed participants contributed two data points for each treatment, however, some subjects provided one or partial data point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Generic Lamotrigine Extended Release Tablet | Area Under the Lamotrigine Concentration vs. Time Curve From Sample Time Point 0 Hour to Sample Time Point 144 Hour. | 119966.6 h*ng/mL | Standard Deviation 32391 |
| Brand Lamictal XR Tablet | Area Under the Lamotrigine Concentration vs. Time Curve From Sample Time Point 0 Hour to Sample Time Point 144 Hour. | 121969.5 h*ng/mL | Standard Deviation 33663.6 |
Comparison: 90% confidence interval of the geometric mean ratio of test/reference90% CI: [0.9598, 1.0134]
Primary
AUC 0-Inf
Area Under the Lamotrigine Concentrations vs. time curve from sample time point 0 hour to sample time point 144hours plus extrapolation to infinity of the terminal concentration slope. This describes the total exposure to Lamotrigine. Sampling times include: Pre-dose, and post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours. Lamotrigine and Lamictal have the same active ingredient.
Time frame: 144 hours
Population: Fully replicated crossover design (all completed subjects received two rounds of Lamictal and Lamotrigine). Completed participants contributed two data points for each treatment, however, some subjects provided one or partial data point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Generic Lamotrigine Extended Release Tablet | AUC 0-Inf | 128824.9 h*ng/mL | Standard Deviation 39291.6 |
| Brand Lamictal XR Tablet | AUC 0-Inf | 134410.3 h*ng/mL | Standard Deviation 47446.8 |
90% CI: [0.9484, 1.0095]
Primary
Cmax
The maximum concentration of the Lamotrigine achieved in specified time frame for each treatment. Sampling times include: post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours. Lamotrigine and Lamictal have the same active ingredient.
Time frame: 2 to 144 hours
Population: Fully replicated crossover design (all completed subjects received two rounds of Lamictal and Lamotrigine). Completed participants contributed two data points for each treatment, however, some subjects provided one or partial data point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Generic Lamotrigine Extended Release Tablet | Cmax | 2338.9 ng/mL | Standard Deviation 353.2 |
| Brand Lamictal XR Tablet | Cmax | 2244.6 ng/mL | Standard Deviation 341.2 |
90% CI: [1.0079, 1.0877]
Other Pre-specified
Thalf
It is the terminal elimination half-life, calculated as ln(2)/λZ. Sampling times include: post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours.
Time frame: 2 to 144 hours
Population: Fully replicated crossover design (all completed subjects received two rounds of Lamictal and Lamotrigine). Completed participants contributed two data points for each treatment, however, some subjects provided one or partial data point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Generic Lamotrigine Extended Release Tablet | Thalf | 34.77 hours | Standard Deviation 10.57 |
| Brand Lamictal XR Tablet | Thalf | 34.56 hours | Standard Deviation 11.34 |
Other Pre-specified
Tmax
Time from 0 concentration sample point to the Cmax sample point. Sampling times include: post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours.
Time frame: 2 to 144 hours
Population: Fully replicate crossover design (all completed subjects received two rounds of Lamictal and Lamotrigine). Completed participants contributed two data points for each treatment, however, some subjects provided one or partial data point.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Generic Lamotrigine Extended Release Tablet | Tmax | 10 hours |
| Brand Lamictal XR Tablet | Tmax | 22 hours |
Other Pre-specified
λZ
Apparent elimination rate constant, estimated by linear regression of the terminal linear portion of the log concentration versus time curve. Sampling times include: post-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36, 48, 72, 96, 120, 144 hours.
Time frame: 2 to 144 hours
Population: Fully replicated crossover design (all completed subjects received two rounds of Lamictal and Lamotrigine). Completed participants contributed two data points for each treatment, however, some subjects provided one or partial data point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Generic Lamotrigine Extended Release Tablet | λZ | 0.0218 per hour | Standard Deviation 0.0067 |
| Brand Lamictal XR Tablet | λZ | 0.0221 per hour | Standard Deviation 0.0067 |