The Bioequivalence Study of Lamotrigine Dispersible/Chewable Tablets 5mg×5 Compared With Lamotrigine Compressed Tablet 25mg in Chinese Healthy Male Subjects

Study Overview
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Brief Summary
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This is a single dose, open-label, randomized, two-period crossover study to demonstrate the bioequivalence of lamotrigine dispersible/chewable tablets (5mg×5) and lamotrigine compressed tablets (25mg) in healthy Chinese male subjects in fasting conditions. The safety, tolerability and pharmacokinetic profile of lamotrigine dispersible/chewable tablets will also be assessed.

Detailed Description
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This is a single dose, open-label, randomized, two-period crossover study to demonstrate the bioequivalence of lamotrigine dispersible/chewable tablets (5mg×5) and lamotrigine compressed tablets (25mg) in healthy Chinese male subjects in fasting conditions. 24 healthy Chinese male subjects will be enrolled to provide data from at least 22 evaluable subjects . In Period 1, subjects will be randomized in equal numbers to be dosed with either lamotrigine dispersible/chewable 5mg×5 tablets or lamotrigine compressed tablet 25mg×1. Following a washout of at least 14 days, subjects will be crossed over in Period 2 to receive the treatment that they did not receive in Period 1. Pharmacokinetic blood samples will be collected over 168 hours post dose. Venous blood (2 ml each) is taken immediately before dosing (pre-dose) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post dose to determine the lamotrigine concentration in serum. Drug concentration in serum at different time points will be determined for each subject with a validated bioanalytical method using LC/MS/MS method. The main pharmacokinetic parameters such as Cmax, tmax, AUC(0-inf), AUC(0-t), t1/2, λz, CL/F and Vd/F are calculated for subjects using non-compartment analysis method. Physical examination, electrocardiogram and clinical laboratory tests are conducted at screening and 168 hours after administration of each dose; vital signs are measured at scheduled time; adverse events are recorded throughout the study. Clinically relevant safety measurement values are tabulated to evaluate the safety and tolerability of lamotrigine dispersible/chewable tablet. Safety evaluation lasts up to 168 hours after the second oral administration.

Official Title
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A Single-Dose, Open-Label, Randomized, Two-Period Crossover Study to Demonstrate the Bioequivalence of Lamotrigine Dispersible/Chewable Tablets (5mg×5) and Lamotrigine Compressed Tablet (25mg) in Healthy Chinese Male Subjects.

Conditions
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Epilepsy

Intervention / Treatment
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* Drug: Lamotrigine Dispersible/Chewable tablets 5mg*5
* Drug: Lamotrigine Compressed tablet 25mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male non-smoker, based on medical history and physical examination. 18-40 years old, inclusive. Body weight >50 kg, and result of BMI is between 18.0 and 24.0 kg/m2, inclusive. Capable of returning to study site for follow-up according to the requirement of protocol and willing to comply with the policy, procedure and restriction of the study. Capable of reading and understanding the information listed in the consent form. Signing the informed consent prior to any study related procedure. Results of laboratory tests within the range of reference normal range, or slight abnormality which judged as not clinically significant by investigator. AST, ALT, alkaline phosphatase and total bilirubin =<1.5 x ULN ((total bilirubin >1.5 x ULN alone is acceptable if direct bilirubin <35% of total bilirubin). Normal blood pressure (systolic blood pressure 90-140 mmHg, diastolic blood pressure < 90mmHg) and pulse rate (60-100/min). No clinically significant abnormality on 12-lead ECG. Corrected QT interval < 450 ms; or corrected QT interval < 480 ms for subjects with bundle-branch block. Male subjects with female partners of child-bearing potential must agree to use contraceptive method after first dose of study treatment and until two weeks after the completion of the study. Exclusion Criteria: Current or chronic history of cardiovascular, respiratory, gastrointestinal, endocrine, hepatic, hematological, psychical or nervous system diseases, use of drug that can change the absorption, metabolism or elimination of study drug, or result in danger or other drugs or diseases that interfere with the interpretation of study data. Personal or familial history of hypersensitivity to lamotrigine or drug with similar chemical composition. Participation in other clinical trial within 30 days prior to enrollment in the study. Use of prescription or non-prescription drugs, including monoamine oxidase inhibitor or herbal drug within 14 days prior to the screening; excluding use of lubricating oil or contraceptive barrier device containing spermicidal agents, and other contraception device. History of abnormality of liver function, abnormal hepatic or biliary system, or positive hepatitis B surface antigen (HBsAg), or positive hepatitis C surface antibody (HCAb) or ALT ≥ 2x upper limit of normal (ULN). Having Gilbert syndrome. Positive serum HIV antibody. Alcohol abuser, defined as alcohol consumption exceeding 3 units/day or 21 units/week. A unit equal to about 240 ml beer, 25 ml spirits or 125 ml wine. Positive drug monitoring at screening. Evidence for obviously active disease of hematological system, or obvious blood loss within 3 months. Blood donation 3 months prior to study. Current or past history of nervous-psychiatric disorder, as assessed by Columbia Suicide Severity Rating Scale-baseline evaluation or in the opinion of investigator that the subject is at risk of suicide or with history of suicide behavior/attempt. Unsuitable for participating in the study according to the law. Unsuitable for participating in the study in the opinion the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lamotrigine (Lamictal) D/C 5mg*5, Crossover<br>Single dose of lamotrigine dispersible/chewable (D/C)5mg*5 tablets at Day1 and Single dose of Lamotrigine Compressed 25mg*1 tablet at Day15 | Drug: Lamotrigine Dispersible/Chewable tablets 5mg*5<br>* Single dose of lamotrigine dispersible/chewable 5mg*5 tablets at Day1 and Single dose of Lamotrigine Compressed 25mg*1 tablet at Day15<br>* Other names: Lamictal;Drug: Lamotrigine Compressed tablet 25mg<br>* Single dose of lamotrigine compressed 25mg*1 tablet at Day1 and Single dose of lamotrigine dispersible/chewable 5mg*5 tablets at Day15<br>* Other names: Lamictal;|
| Experimental: Lamotrigine (Lamictal) Compressed 25mg, Crossover<br>Single dose of lamotrigine compressed 25mg*1 tablet at Day1 and Single dose of lamotrigine dispersible/chewable 5mg*5 tablets at Day15 | Drug: Lamotrigine Dispersible/Chewable tablets 5mg*5<br>* Single dose of lamotrigine dispersible/chewable 5mg*5 tablets at Day1 and Single dose of Lamotrigine Compressed 25mg*1 tablet at Day15<br>* Other names: Lamictal;Drug: Lamotrigine Compressed tablet 25mg<br>* Single dose of lamotrigine compressed 25mg*1 tablet at Day1 and Single dose of lamotrigine dispersible/chewable 5mg*5 tablets at Day15<br>* Other names: Lamictal;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration-time curve from time zero to infinity [AUC(0-inf)], including bioequivalence evaluation | AUC(0-inf) is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC(0-inf) is defined as area under the concentration vs. time curve from zero to infinity. | pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168 hours post-dose | 
| Area under the concentration-time curve up to the last time point at which the concentration is above the lower limit of quantification [AUC(0-t)], including bioequivalence evaluation | AUC(0-t) is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC(0-t) is defined as AUC from time 0 to the last data point above the Lower Limit of Quantification. | pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168 hours post-dose | 
| The observed maximum serum drug concentration (Cmax), including bioequivalence evaluation | Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. | pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to reach Cmax (tmax) |  | pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168 hours post-dose | 
| Elimination half-time (t½) |  | pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168 hours post-dose | 
| Elimination rate constant, linear regression according to linear serum drug concentration-time curve |  | pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168 hours post-dose |