Healthy
Conditions
Brief summary
This study is designed to evaluate the relative bioavailability, or the degree and rate at which the drug is absorbed by the body of two cenobamate formulations (200 mg Oral Suspension and a 200 mg Oral Tablet) and to assess the effect of food on the oral bioavailability of the 200 mg Oral Suspension. This study will also look at the safety and tolerability of the oral suspension and the oral tablet under both fasted and fed conditions.
Detailed description
This study is an open-label, randomized, single-dose, single-center, three-period, six-sequence, balanced crossover study in healthy male and female subjects to assess the relative bioavailability of 200 mg of cenobamate given as an oral tablet or oral suspension and to evaluate the effect of food on the bioavailability of a 200 mg dose of cenobamate given as an oral suspension in fasting and fed conditions. The study consists of a 28-day screening period, followed by single dose administration of cenobamate (tablet or suspension) on Day 1, Day 22, and Day 43, an assessment period of 62 days and a follow-up visit on Day 69. All subjects will be confined to the clinical site from Day -1 (the day before period 1 dosing) until the morning of Day 4, Day 20 (the day of the last PK sampling for period 1) until the morning of Day 25, and Day 41 (the day of the last PK sampling for period 2) until the morning of Day 46. Outpatient visits will be performed regularly until the 456-hour PK sampling for each period. The follow-up visit will occur on Day 69 (±1 day).
Interventions
DRUGCenobamate 200Mg Tab Fasted
Cenobamate (YKP3089) is a small molecule approved in the United States (US) for the treatment of partial onset seizures (POS) in adult patients.
DRUGCenobamate Oral Suspension Fed
Cenobamate (YKP3089) is a small molecule approved in the United States (US) for the treatment of partial onset seizures (POS) in adult patients.
DRUGCenobomate Oral Suspension Fasted
Cenobamate (YKP3089) is a small molecule approved in the United States (US) for the treatment of partial onset seizures (POS) in adult patients.
Sponsors
SK Life Science, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
• This study is an open-label, randomized, single-dose, single-center, three-period, six-sequence, balanced crossover study in healthy male and female subjects to assess the relative bioavailability of 200 mg of cenobamate given as an oral tablet or oral suspension and to evaluate the effect of food on the bioavailability of a 200 mg dose of cenobamate given as an oral suspension in fasting and fed conditions
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male or female subjects of 18 to 50 years of age (inclusive), at the time of screening 2. Able to read, understand, sign, and date a written informed consent form (ICF) before study participation at screening 3. Agree to use effective methods of contraception as described in Section 12.1.7.8 and Section 12.1.7.9. 4. Body mass index (BMI) between 18.5 and 30.0 kg/m2 (inclusive) at screening 5. Judged to be in good health on the basis of medical history, physical examination, and routine laboratory measurements (i.e., without clinically relevant pathology) 6. Electrocardiogram (ECG) (12-lead), arterial blood pressure, and heart rate within the normal range of the study center or considered not clinically significant by the Investigator. 7. Able to understand and comply with protocol requirements and instructions and likely to complete the study as planned 8. Females of non-childbearing potential (18 to 50 years of age (inclusive)), who have undergone a sterilization procedure at least 6 months prior to dosing with official documentation (e.g., bilateral tubal ligation or bilateral salpingectomy or hysterectomy), or be postmenopausal with amenorrhea for at least 1 year prior to dosing and follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal status as per Principal Investigator's judgment
Exclusion criteria
1. Clinically relevant abnormal medical history, abnormal findings on physical examination, vital signs, ECG, or laboratory tests at Screening that the Investigator judges as likely to interfere with the objectives of the trial or the safety of the volunteer 2. Smokers (subjects who have smoked within 6 months at screening) 3. History of any drug related hypersensitivity reactions as well as severe hypersensitivity reactions (like angioedema) or DRESS as evaluated by the Investigator 4. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with pharmacokinetics of the study drug (except appendectomy and simple hernia repair) 5. Any prescribed or over-the-counter medication taken within 2 weeks prior to start of administration of study drug (Day 1) or within 6 times the elimination half-life of the medication prior to start of study drug intake (whichever is longer). Occasional use of acetaminophen is allowed up until 24 hours before dosing 6. Consumption of herbal medications, dietary supplements and specific fruit products. Subjects should have stopped consumption of herbal medications or dietary supplements (e.g., St. John's Wort, ginkgo biloba, and garlic supplements), and grapefruit or grapefruit juice, or Seville oranges at least 2 weeks before the first dosing day of study drug. Vitamins/mineral supplements are allowed up until 24 hours before dosing 7. History of drug or alcohol abuse or addiction within 2 years before the start of study drug dosing, or a positive test results for alcohol or drugs of abuse, such as amphetamine, barbiturate, benzodiazepine, cocaine, methadone, opiates, oxycodone, phencyclidine, propoxyphene, cannabinoid (THC), MDMA (Ecstasy), methaqualone, and tricyclic antidepressant (TCA) 8. Regular consumption of more than 2 units of alcoholic beverages per day or more than 14 units per week (1 unit of alcohol equals 1 pint \[473 mL\] of beer or lager, 1 glass \[125 mL\] of wine, 25 mL shot of 40% spirit) before screening 9. Consumption of an average of more than 5 servings (8 ounces per serving) per day of coffee, cola, or other caffeinated or methyl xanthine beverages before screening 10. Consumption of any caffeine- or methyl xanthine-containing products (e.g., coffee, tea, chocolate, or soda) or alcoholic beverages within 48 hours prior to Day 1 of each period and until the end of each PK sampling period 11. Participation in a clinical study involving administration of either an investigational or a marketed drug within 2 months or 7 half-lives (whichever is longer) before screening 12. Blood donation or a significant loss of blood within 60 days of the start of study drug dosing or donation of more than 1 unit of plasma within 7 days before screening 13. Positive result at screening for any of the following infectious disease tests: hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), human immunodeficiency virus antigen and antibody (HIV Ag, HIV Ab) 14. Illness within 5 days before the start of study drug dosing (illness is defined as an acute \[serious or non-serious\] condition \[e.g., the flu or the common cold\]) 15. History of any known relevant allergy/hypersensitivity (including allergy to the trial medication or its excipients) 16. Subject who is judged not eligible for study participation by Investigator 17. History of Familial Short QT syndrome.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax | 120, 192, 264, 360, 456, hours post-dose | Maximum observed plasma concentration of cenobamate |
| Tmax | 120, 192, 264, 360, 456 hour post-dose | Time to reach Maximum observed plasma concentration of cenobamate |
| Area Under the Concentration Curve to Last Measurable Concentration | 120, 192, 264, 360, 456 hour post-dose | AUC from the time of dosing to the time of the last measurable concentration of cenobamate |
| Area Under the Concentration Curve From 0 to Infinity | 120, 192, 264, 360, 456 hour post-dose | Area Under the Concentration Curve (AUC) from time 0 extrapolated to infinity |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events | Day 1 to Day 69 | To evaluate the safety and tolerability of each cenobamate formulation administered under either fed (Oral Dose of cenobamate administered at a single 200 mg/20 mL suspension ) or fasted (Both tablet and oral suspension formulations) incidence of treatment-emergent adverse events will be monitored. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sequence 1 Treatment ABC, with 21 day washout periods between each dose.
Treatment A: cenobamate 200 mg oral tablet fasted Treatment B: cenobamate 200 mg/20 mL oral suspension fasted Treatment C: cenobamate 200 mg/20 mL oral suspension fed | 4 |
| Sequence 2 Treatment BCA, with 21 day washout periods between each dose.
Treatment A: cenobamate 200 mg oral tablet fasted Treatment B: cenobamate 200 mg/20 mL oral suspension fasted Treatment C: cenobamate 200 mg/20 mL oral suspension fed | 5 |
| Sequence 3 Treatment CAB, with 21 day washout periods between each dose.
Treatment A: cenobamate 200 mg oral tablet fasted Treatment B: cenobamate 200 mg/20 mL oral suspension fasted Treatment C: cenobamate 200 mg/20 mL oral suspension fed | 5 |
| Sequence 4 Treatment CBA, with 21 day washout periods between each dose.
Treatment A: cenobamate 200 mg oral tablet fasted Treatment B: cenobamate 200 mg/20 mL oral suspension fasted Treatment C: cenobamate 200 mg/20 mL oral suspension fed | 4 |
| Sequence 5 Treatment ACB, with 21 day washout periods between each dose.
Treatment A: cenobamate 200 mg oral tablet fasted Treatment B: cenobamate 200 mg/20 mL oral suspension fasted Treatment C: cenobamate 200 mg/20 mL oral suspension fed | 6 |
| Sequence 6 Treatment BAC, with 21 day washout periods between each dose.
Treatment A: cenobamate 200 mg oral tablet fasted Treatment B: cenobamate 200 mg/20 mL oral suspension fasted Treatment C: cenobamate 200 mg/20 mL oral suspension fed | 4 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Positive urine drug screen test | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 1 | 2 | 0 |
Baseline characteristics
| Characteristic | Sequence 3 | Sequence 4 | Sequence 1 | Total | Sequence 5 | Sequence 2 | Sequence 6 |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 30.6 years STANDARD_DEVIATION 12.92 | 29.5 years STANDARD_DEVIATION 8.74 | 28.0 years STANDARD_DEVIATION 4.32 | 30.6 years STANDARD_DEVIATION 8.83 | 28.5 years STANDARD_DEVIATION 8.17 | 35.6 years STANDARD_DEVIATION 11.67 | 31.0 years STANDARD_DEVIATION 5.48 |
| Body Mass Index (BMI) | 23.76 kg/m2 STANDARD_DEVIATION 2.919 | 25.15 kg/m2 STANDARD_DEVIATION 3.36 | 24.30 kg/m2 STANDARD_DEVIATION 1.128 | 24.56 kg/m2 STANDARD_DEVIATION 2.726 | 24.47 kg/m2 STANDARD_DEVIATION 3.133 | 24.38 kg/m2 STANDARD_DEVIATION 3.047 | 25.58 kg/m2 STANDARD_DEVIATION 3.336 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 7 Participants | 1 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 3 Participants | 3 Participants | 21 Participants | 5 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 180.72 cm STANDARD_DEVIATION 5.404 | 182.00 cm STANDARD_DEVIATION 0.469 | 174.93 cm STANDARD_DEVIATION 9.016 | 176.05 cm STANDARD_DEVIATION 9.371 | 172.13 cm STANDARD_DEVIATION 11.965 | 173.36 cm STANDARD_DEVIATION 8.993 | 174.60 cm STANDARD_DEVIATION 13.879 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 3 Participants | 4 Participants | 23 Participants | 6 Participants | 2 Participants | 3 Participants |
| Region of Enrollment United States | 5 participants | 4 participants | 4 participants | 28 participants | 6 participants | 5 participants | 4 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants | 5 Participants | 1 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 3 Participants | 23 Participants | 5 Participants | 4 Participants | 3 Participants |
| Weight | 77.52 kg STANDARD_DEVIATION 9.785 | 83.38 kg STANDARD_DEVIATION 10.779 | 74.45 kg STANDARD_DEVIATION 6.982 | 76.24 kg STANDARD_DEVIATION 10.795 | 72.93 kg STANDARD_DEVIATION 13.896 | 73.30 kg STANDARD_DEVIATION 10.458 | 77.93 kg STANDARD_DEVIATION 13.178 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 24 | 0 / 25 |
| other Total, other adverse events | 8 / 25 | 8 / 24 | 7 / 25 |
| serious Total, serious adverse events | 0 / 25 | 0 / 24 | 0 / 25 |
Outcome results
Primary
Area Under the Concentration Curve From 0 to Infinity
Area Under the Concentration Curve (AUC) from time 0 extrapolated to infinity
Time frame: 120, 192, 264, 360, 456 hour post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A | Area Under the Concentration Curve From 0 to Infinity | 308.0 (μg•h/mL) |
| Treatment B | Area Under the Concentration Curve From 0 to Infinity | 309.5 (μg•h/mL) |
| Treatment C | Area Under the Concentration Curve From 0 to Infinity | 296.0 (μg•h/mL) |
Primary
Area Under the Concentration Curve to Last Measurable Concentration
AUC from the time of dosing to the time of the last measurable concentration of cenobamate
Time frame: 120, 192, 264, 360, 456 hour post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A | Area Under the Concentration Curve to Last Measurable Concentration | 304.0 (μg•h/mL) |
| Treatment B | Area Under the Concentration Curve to Last Measurable Concentration | 302.5 (μg•h/mL) |
| Treatment C | Area Under the Concentration Curve to Last Measurable Concentration | 277.0 (μg•h/mL) |
Primary
Cmax
Maximum observed plasma concentration of cenobamate
Time frame: 120, 192, 264, 360, 456, hours post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A | Cmax | 4.880 (μg/mL) |
| Treatment B | Cmax | 4.680 (μg/mL) |
| Treatment C | Cmax | 3.860 (μg/mL) |
Primary
Tmax
Time to reach Maximum observed plasma concentration of cenobamate
Time frame: 120, 192, 264, 360, 456 hour post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A | Tmax | 3.000 (h) |
| Treatment B | Tmax | 0.750 (h) |
| Treatment C | Tmax | 5.000 (h) |
Secondary
Number of Participants With Treatment-Emergent Adverse Events
To evaluate the safety and tolerability of each cenobamate formulation administered under either fed (Oral Dose of cenobamate administered at a single 200 mg/20 mL suspension ) or fasted (Both tablet and oral suspension formulations) incidence of treatment-emergent adverse events will be monitored.
Time frame: Day 1 to Day 69
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment A | Number of Participants With Treatment-Emergent Adverse Events | 8 Participants |
| Treatment B | Number of Participants With Treatment-Emergent Adverse Events | 8 Participants |
| Treatment C | Number of Participants With Treatment-Emergent Adverse Events | 7 Participants |