An Open-Label Study to Evaluate the Pharmacokinetics of Intranasal Esketamine and Its Effects on the Pharmacokinetics of Orally-Administered Midazolam and Bupropion in Healthy Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 71
- 主要终点
- Maximum Plasma Concentration (Cmax)
研究概览
简要总结
The primary purpose of this study is to evaluate the induction potential of repeated administration of intranasal esketamine on cytochrome P450 (CYP) 3A4 and CYP2B6 activity in healthy participants using orally administered midazolam and bupropion as probes, respectively and to evaluate the pharmacokinetics of esketamine after a single dose and repeated administration.
详细描述
This is a parallel group, single-center, repeat-dose, fixed-sequence, open-label (all people know the identity of the intervention), study. The effects of repeated administration of intranasal esketamine on the pharmacokinetics of midazolam and bupropion will be evaluated in Cohort 1 and Cohort 2, respectively. Participants in Cohort 1 will receive a single oral dose of midazolam in the morning of Day 1 and Day 17. Participants in Cohort 2 will receive a single oral dose of bupropion in the morning of Day 1 and Day 19. In Cohort 1 and 2 participants will self-administer 5 doses of intranasal esketamine over a 15-day period. The duration of study, from the Screening Phase through Follow-up, is up to 51 days and 54 days for Cohort 1 and Cohort 2, respectively. Blood samples for participants in Cohort 1 will be collected for up to 24 hours after dosing on Days 1 and 17 (midazolam) and for up to 24 hours on Days 2 and 16 (esketamine); For participants in Cohort 2, blood and urine samples for assessment of bupropion pharmacokinetics will be collected for up to 72 hours after dosing on Day 1 and Day 19. Participants' safety will be monitored throughout the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
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
- •Be a man or woman of non-Asian origin 18 to 55 years of age, inclusive
- •Signed an informed consent document indicating they understand the purpose of and procedures required for the study and are willing to participate in the study
- •A woman of child-bearing potential, must have a negative serum β-human chorionic gonadotropin (hCG) pregnancy test at Screening and a negative urine pregnancy test on Day -1 of the treatment period. Women using contraceptives must agree to use an additional birth control method during the study and for 1 month after receiving the last dose of study drug
- •A man who is sexually active with a woman of childbearing potential and has not had a vasectomy, must agree to use an adequate contraception method as deemed appropriate by the investigator (eg, vasectomy, double-barrier, partner using effective contraception) and to not donate sperm during the study and for 3 months after receiving the last dose of study drug
- •Comfortable with self-administration of intranasal medication and able to follow instructions provided
排除标准
- •Clinically significant abnormal values for hematology, clinical chemistry (particularly potassium or magnesium levels below the normal laboratory range), or urinalysis at Screening or at admission to the study center (Day -1) as deemed appropriate by the investigator
- •Clinically significant abnormal physical examination, vital signs, or 12 lead electrocardiogram (ECG) at Screening or at admission to the study center (Day -1) as deemed appropriate by the investigator
- •Use of any prescription or non-prescription medication (including vitamins and herbal supplements), except for paracetamol, contraceptives, and hormonal replacement therapy, within 14 days before the first dose of the study drug is scheduled until completion of the study
- •Has used nasal tobacco powder ("snuff") regularly within the past year.
- •Has a nasal piercing
研究组 & 干预措施
Cohort 1
Participants will receive single oral dose of midazolam 6 milligram (mg) on Day 1 and 17. Participants will self-administer esketamine intranasally thrice per day on morning of Day 2, 5, 9, 12 and 16 (84 mg).
干预措施: Midazolam (Drug)
Cohort 1
Participants will receive single oral dose of midazolam 6 milligram (mg) on Day 1 and 17. Participants will self-administer esketamine intranasally thrice per day on morning of Day 2, 5, 9, 12 and 16 (84 mg).
干预措施: Esketamine (Drug)
Cohort 2
Participants will receive single oral dose of bupropion 150 mg on Day 1 and 19. Participants will self-administer esketamine intranasally thrice per day on morning of Day 4, 7, 11, 14 and 18 (84 mg).
干预措施: Esketamine (Drug)
Cohort 2
Participants will receive single oral dose of bupropion 150 mg on Day 1 and 19. Participants will self-administer esketamine intranasally thrice per day on morning of Day 4, 7, 11, 14 and 18 (84 mg).
干预措施: Bupropion (Drug)
结局指标
主要结局
Maximum Plasma Concentration (Cmax)
时间窗: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
The Cmax is the maximum plasma concentration.
Time to reach maximum concentration (tmax)
时间窗: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
Time to reach the maximum observed plasma concentration.
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity])
时间窗: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z), wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time; and C(last) is the last observed quantifiable concentration; and lambda(z) is elimination rate constant.
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-last])
时间窗: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
The AUC (0-last) is the area under the plasma concentration-time curve from time zero to last quantifiable time, calculated as the sum of AUC(last) and C(last)/lambda(z), wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time; and C(last) is the last observed quantifiable concentration; and lambda(z) is elimination rate constant.
Terminal Half-Life(t[1/2])
时间窗: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
Terminal half-life (t\[(1/2\]) is defined as 0.693/Lambda(z).
Area Under the Plasma Concentration-Time Curve From Time Zero to 12 hours (AUC [0-12])
时间窗: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
The AUC (0-12) is the area under the plasma concentration-time curve from time zero to 12 hours, calculated as the sum of AUC(last) and C(last)/lambda(z), wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time; and C(last) is the last observed quantifiable concentration; and lambda(z) is elimination rate constant.
Cmax metabolite to parent ratio (MPR Cmax)
时间窗: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
Cmax metabolite to parent ratio, and corrected for molecular weight if necessary.
AUC(last) metabolite to parent ratio (MPR AUC[last])
时间窗: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
AUC(last) metabolite to parent ratio, and corrected for molecular weight if necessary.
AUC (infinity) metabolite to parent ratio (MPR AUC [infinity])
时间窗: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
AUC (infinity) metabolite to parent ratio, and corrected for molecular weight if necessary.
Amount of Drug excreted in Urine (Ae)
时间窗: up to Day 17 for Cohort 1; up to Day 19 for Cohort 2
Total amount excreted into the urine, calculated as the sum of all Ae(t1-t2) intervals.
Percentage of Drug dose excreted into urine
时间窗: up to Day 19 for Cohort 2
Total amount excreted into the urine, expressed as a percentage of the administered dose, calculated as (Ae/dose)\*100, and corrected for molecular weight if necessary.
Renal clearance
时间窗: up to Day 19 for Cohort 2
Renal clearance calculated as Ae/AUC (infinity).
Formation Clearance
时间窗: up to Day 19 for Cohort 2
Formation clearance of drug, calculated as Ae of hydroxybupropion/AUC(infinity) of bupropion, and corrected for molecular weight if necessary.
Ae metabolite to parent ratio (MPR Ae)
时间窗: up to Day 19 for Cohort 2
Ae metabolite to parent ratio, and corrected for molecular weight if necessary.
次要结局
- Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)(Baseline up to Day 51 for Cohort 1; Baseline up to Day 54 Cohort 2)