A Randomized, Double-blind, Placebo-controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TS-161 Administered Orally to Healthy Male and Female Participants
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 70
- 试验地点
- 1
- 主要终点
- TS-161 Plasma Pharmacokinetic Profile - Tmax
研究概览
简要总结
This is a Phase 1, first-in-human study involving single and multiple oral doses of TS-161 in healthy male and female participants. The safety, tolerability, pharmacokinetics and pharmacodynamics of TS-161 will be evaluated.
The study includes 3 parts; Part A (single ascending dose: Cohorts 1 to 5) , Part B (single dose, cerebrospinal fluid [CSF] collection: Cohort 6), and Part C (multiple ascending dose: Cohorts 7 to 9). Participants will be assigned to one of the 9 Cohorts.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy adult male and female participants between 18 and 55 years of age, inclusive
- •Body weight ≥ 45 kg
- •Body Mass Index (BMI) 18 - 30 kg/m^2, inclusive
排除标准
- •Significant history or presence of medical disorders or condition capable of significantly affecting the absorption, metabolism, or elimination of drugs
- •History or presence of psychiatric or neurologic disease or condition
- •History of seizures
- •Abnormal EEG observed at screening
- •Abnormal blood pressure
- •Breast cancer within the past 10 years, or any other malignancies within the past 5 years
- •Clinically significant abnormal results in electrocardiogram, blood and urine test
- •History or presence of liver disease
- •Participants using medication or supplements within 14 days prior to dosing
- •Use of N-methyl-D-aspartate (NMDA) receptor modulators (example: dextromethorphan, ketamine, amantadine, memantine) within 90 days of screening
- •Loss of blood or blood products in excess of 450 mL within 60 days prior to screening
- •Used any investigational drug within 60 days prior to screening
- •Recent history of alcohol or drug abuse
- •Any participant who currently uses or has used tobacco products or nicotine-containing products (cigarettes, pipes, e-cigarettes, nicotine patches, etc.) for one month or more prior to screening
- •Exclusion Criteria for Part B only:
- •Significant abnormalities in lumbar spine
- •History of clinically significant back pain, back pathology, and/or back injury
- •History of migraines, and/or frequent, severe headaches
- •History or presence of significant active bleeding or coagulation disorder or use of non-steroidal anti-inflammatory drugs or other drugs that affect coagulation or platelet function within 14 days prior to lumbar catheter insertion
- •Allergy to lidocaine (Xylocaine®) or related drugs
- •History of adverse reaction to lumbar puncture or epidural procedure
研究组 & 干预措施
Part A: Cohort 1: TS-161 15 mg
Single dose of TS-161 15 mg or placebo in a fasted condition.
干预措施: TS-161 Placebo (Drug)
Part C: Cohort 7: TS-161 TBD
Daily doses of TS-161 or placebo for 10 days in a fed condition. The dose level will be determined based on the results from the preceding cohorts.
干预措施: TS-161 Placebo (Drug)
Part A: Cohort 1: TS-161 15 mg
Single dose of TS-161 15 mg or placebo in a fasted condition.
干预措施: TS-161 (Drug)
Part A: Cohort 2: TS-161 50 mg
Single dose of TS-161 50 mg or placebo which will be dosed first in a fasted condition, and then in a fed condition, with a washout period in between 2 dosing. Although planned, all subsequent dose levels after Cohort 1 will be determined based on the results from the preceding cohorts.
干预措施: TS-161 (Drug)
Part A: Cohort 2: TS-161 50 mg
Single dose of TS-161 50 mg or placebo which will be dosed first in a fasted condition, and then in a fed condition, with a washout period in between 2 dosing. Although planned, all subsequent dose levels after Cohort 1 will be determined based on the results from the preceding cohorts.
干预措施: TS-161 Placebo (Drug)
Part A: Cohort 3: TS-161 100 mg
Single dose of TS-161 100 mg or placebo in a fasted condition. Although planned, all subsequent dose levels after Cohort 1 will be determined based on the results from the preceding cohorts.
干预措施: TS-161 (Drug)
Part A: Cohort 3: TS-161 100 mg
Single dose of TS-161 100 mg or placebo in a fasted condition. Although planned, all subsequent dose levels after Cohort 1 will be determined based on the results from the preceding cohorts.
干预措施: TS-161 Placebo (Drug)
Part A: Cohort 4: TS-161 200 mg
Single dose of TS-161 200 mg or placebo in a fasted condition. Although planned, all subsequent dose levels after Cohort 1 will be determined based on the results from the preceding cohorts.
干预措施: TS-161 (Drug)
Part C: Cohort 8: TS-161 TBD
Daily doses of TS-161 or placebo for 10 days in a fed condition. The dose level will be determined based on the results from the preceding cohorts.
干预措施: TS-161 (Drug)
Part A: Cohort 4: TS-161 200 mg
Single dose of TS-161 200 mg or placebo in a fasted condition. Although planned, all subsequent dose levels after Cohort 1 will be determined based on the results from the preceding cohorts.
干预措施: TS-161 Placebo (Drug)
Part A: Cohort 5: TS-161 400 mg
Single dose of TS-161 400 mg or placebo in a fasted condition. Although planned, all subsequent dose levels after Cohort 1 will be determined based on the results from the preceding cohorts.
干预措施: TS-161 (Drug)
Part A: Cohort 5: TS-161 400 mg
Single dose of TS-161 400 mg or placebo in a fasted condition. Although planned, all subsequent dose levels after Cohort 1 will be determined based on the results from the preceding cohorts.
干预措施: TS-161 Placebo (Drug)
Part B: Cohort 6: TS-161 TBD
Single dose of TS-161 in a fasted condition. The dose level will be determined based on the results from the preceding cohorts.
干预措施: TS-161 (Drug)
Part C: Cohort 7: TS-161 TBD
Daily doses of TS-161 or placebo for 10 days in a fed condition. The dose level will be determined based on the results from the preceding cohorts.
干预措施: TS-161 (Drug)
Part C: Cohort 8: TS-161 TBD
Daily doses of TS-161 or placebo for 10 days in a fed condition. The dose level will be determined based on the results from the preceding cohorts.
干预措施: TS-161 Placebo (Drug)
Part C: Cohort 9: TS-161 TBD
Daily doses of TS-161 or placebo for 10 days in a fed condition. The dose level will be determined based on the results from the preceding cohorts.
干预措施: TS-161 (Drug)
Part C: Cohort 9: TS-161 TBD
Daily doses of TS-161 or placebo for 10 days in a fed condition. The dose level will be determined based on the results from the preceding cohorts.
干预措施: TS-161 Placebo (Drug)
结局指标
主要结局
TS-161 Plasma Pharmacokinetic Profile - Tmax
时间窗: Parts A and B: Day 1 predose and at multiple time points (up to 48 hours) postdose; Part C: Day 1 predose and at multiple time points (up to 12 hours) postdose, Day 2 to Day 9 predose, Day 10 predose and at multiple time points (up to 48 hours) postdose
Time to maximum plasma concentration
Incidence and severity of Adverse Events
时间窗: Parts A and B: Day 1 to Day 8; Part C: Day 1 to Day 17
TS-161 Plasma Pharmacokinetic Profile - Cmax
时间窗: Parts A and B: Day 1 predose and at multiple time points (up to 48 hours) postdose; Part C: Day 1 predose and at multiple time points (up to 12 hours) postdose, Day 2 to Day 9 predose, Day 10 predose and at multiple time points (up to 48 hours) postdose
Maximum plasma concentration
TS-161 Plasma Pharmacokinetic Profile - AUC(0-tau)
时间窗: Part C: Day 1 predose and at multiple time points (up to 12 hours) postdose, Day 2 to Day 9 predose, Day 10 predose and at multiple time points (up to 48 hours) postdose
Area under the plasma concentration versus time curve over a dosing interval
TS-161 Plasma Pharmacokinetic Profile - T1/2
时间窗: Parts A and B: Day 1 predose and at multiple time points (up to 48 hours) postdose; Part C: Day 1 predose and at multiple time points (up to 12 hours) postdose, Day 2 to Day 9 predose, Day 10 predose and at multiple time points (up to 48 hours) postdose
Apparent terminal elimination half-life
TS-161 Plasma Pharmacokinetic Profile - AUC(0-last)
时间窗: Parts A and B: Day 1 predose and at multiple time points (up to 48 hours) postdose
Area under the plasma concentration versus time curve from time zero to last measurable concentration
TS-161 Plasma Pharmacokinetic Profile - Vd,z/F
时间窗: Parts A and B: Day 1 predose and at multiple time points (up to 48 hours) postdose; Part C: Day 1 predose and at multiple time points (up to 12 hours) postdose, Day 2 to Day 9 predose, Day 10 predose and at multiple time points (up to 48 hours) postdose
Apparent volume of distribution following oral administration
TS-161 Urine Pharmacokinetic Profile - Fe%
时间窗: Part A: Day 1 predose and pooled for multiple intervals (up to 48 hours) postdose; Part C: Day 1 predose and pooled for multiple intervals (up to 48 hours after last dose) postdose
Percent of dose excreted in urine
TS-161 Urine Pharmacokinetic Profile - CLr
时间窗: Part A: Day 1 predose and pooled for multiple intervals (up to 48 hours) postdose; Part C: Day 1 predose and pooled for multiple intervals (up to 48 hours after last dose) postdose
Renal Clearance
TS-161 Plasma Pharmacokinetic Profile - CL/F
时间窗: Parts A and B: Day 1 predose and at multiple time points (up to 48 hours) postdose; Part C: Day 1 predose and at multiple time points (up to 12 hours) postdose, Day 2 to Day 9 predose, Day 10 predose and at multiple time points (up to 48 hours) postdose
Apparent clearance following oral administration
TS-161 Urine Pharmacokinetic Profile - Ae
时间窗: Part A: Day 1 predose and pooled for multiple intervals (up to 48 hours) postdose; Part C: Day 1 predose and pooled for multiple intervals (up to 48 hours after last dose) postdose
Amount excreted in urine
次要结局
- TS-161 CSF Pharmacokinetic Profile - Tmax(Part B: Day 1 predose and at multiple time points (up to 24 hours) postdose)
- TS-161 CSF Pharmacokinetic Profile - Cmax(Part B: Day 1 predose and at multiple time points (up to 24 hours) postdose)
- TS-161 CSF Pharmacokinetic Profile - AUC(0-last)(Part B: Day 1 predose and at multiple time points (up to 24 hours) postdose)
- TS-161 CSF Pharmacokinetic Profile - T1/2(Part B: Day 1 predose and at multiple time points (up to 24 hours) postdose)
- Changes from baseline in relative and absolute powers of the delta, theta, alpha, beta and gamma bands using quantitative electroencephalogram (qEEG) compared to placebo(Part A: predose and at multiple time points (up to 8 hours) postdose)