A Phase 1, Single-Center, Repeat-Dose, Open-Label, Fixed-Sequence Drug-Drug Interaction Study of ZX008 in Healthy Male Or Female Study Participants 18 To 55 Years Of Age
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 22
- 试验地点
- 2
- 主要终点
- Maximum concentration (Cmax) of midazolam administered alone
研究概览
简要总结
The purpose of the study is to assess the single-dose pharmacokinetics (PK) of 3 probe drugs (midazolam, bupropion, and metformin) before and after repeat doses of ZX008
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 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
- •Participant must be 18 to 55 years of age inclusive at the time of signing the informed consent form (ICF)
- •Body weight of at least 50 kg and body mass index within the range 18 to 32 kg/m^2 (inclusive)
- •Male or female
- •Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
排除标准
- •Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) above 1.1x upper limit of normal (ULN)
- •Bilirubin >ULN (isolated bilirubin <1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
- •Participant has clinically significant current or past history of cardiovascular or cerebrovascular disease, such as valvular heart disease, and/or pulmonary hypertension. Participants with any history of stroke or myocardial infarction are excluded.
- •Clinically significant history or presence of electrocardiogram (ECG) or echocardiogram (ECHO) findings as judged by the investigator or designee at the Screening Visit and Check-in, including each criterion listed below:
- •Abnormal sinus rhythm (heart rate outside of 40bpm and 100bpm)
- •QTcF (QT interval corrected using Fridericia's formula) interval >450 msec for male participants or >470 msec for female participants (QTcF is the QT interval corrected for heart rate according to Fridericia's formula, it can be either machine read or manually overread)
- •QRS interval >120 msec, confirmed by manual over read
- •PR interval >220 msec
- •Greater than trace aortic valve regurgitation
- •Greater than trace mitral valve regurgitation
- •Possible signs of pulmonary arterial hypertension (PAH) with abnormal pulmonary artery systolic pressure (PASP) or PASP >35 mmHg
- •Evidence of left ventricular dysfunction (systolic or diastolic)
- •Clinically significant structural cardiac abnormality, including, but not limited to, mitral valve prolapse, atrial or ventricular septal defects, and patent ductus arteriosus with reversal of shunt (right to left shunt). Note: Patent foramen ovale or a bicuspid aortic valve is not considered exclusionary
- •Clinically significant abnormal blood pressure (as determined by the investigator)
- •Participant has a current or past history of glaucoma
- •Participant has used hepatic enzyme-inducing drugs (eg, glucocorticoids, phenobarbital, isoniazid, phenytoin, rifampicin) within 30 days before the first administration of the cocktail of 3 probe drugs (metformin, midazolam, bupropion) and through the day of discharge from the site
- •Participant has used other prescription drugs, including vaccinations, over-the-counter medications, herbal/traditional medicines, or dietary supplements within 14 days before the first administration of the cocktail of probe drugs (excluding medicines for external use), with the exception of acetaminophen (up to 2 g/day)
- •Consent to genotyping is required for participation in the study. Poor metabolizers of CYP (cytochrome P450) 3A4 or CYP2B6 based on genotyping and as categorized by the testing laboratory will be excluded from the study
- •Positive test for alcohol and/or prohibited concomitant drugs (including cotinine) at Screening Visit and on Day -1
- •Participant has donated blood or plasma or has experienced blood loss ≥500 mL within 90 days, ≥200 mL within 30 days, or has donated any blood or plasma within 14 days before first administration of study treatments
- •Any consumption of food products with a known Drug-drug interaction (DDI) impact (eg, grapefruit, grapefruit juice, Seville oranges, or products containing them) for at least 1 week before Day 1 and through day of discharge from the site
- •Consumption of more than 600 mg of caffeine/day (1 cup of coffee contains approximately 100 mg of caffeine, 1 cup of tea approximately 30 mg, and 1 glass of cola approximately 20 mg) within 30 days before Day 1 and through day of discharge from the site
- •Participant is a current smoker or has used nicotine-containing products (eg, tobacco, patches, gum, vapes, or e-cigarettes) within 35 days before Day 1 and through day of discharge from the site
研究组 & 干预措施
Treatment Arm
Study participants will receive a single dose of the cocktail of probe drugs at pre-specified timepoints followed by a wash out period. The same study participants will then receive repeated oral doses of fenfluramine HCl (ZX008) and a single dose of the cocktail of probe drugs at pre-specified time points during this Treatment Period.
干预措施: midazolam (Drug)
Treatment Arm
Study participants will receive a single dose of the cocktail of probe drugs at pre-specified timepoints followed by a wash out period. The same study participants will then receive repeated oral doses of fenfluramine HCl (ZX008) and a single dose of the cocktail of probe drugs at pre-specified time points during this Treatment Period.
干预措施: metformin (Drug)
Treatment Arm
Study participants will receive a single dose of the cocktail of probe drugs at pre-specified timepoints followed by a wash out period. The same study participants will then receive repeated oral doses of fenfluramine HCl (ZX008) and a single dose of the cocktail of probe drugs at pre-specified time points during this Treatment Period.
干预措施: fenfluramine HCl (Drug)
Treatment Arm
Study participants will receive a single dose of the cocktail of probe drugs at pre-specified timepoints followed by a wash out period. The same study participants will then receive repeated oral doses of fenfluramine HCl (ZX008) and a single dose of the cocktail of probe drugs at pre-specified time points during this Treatment Period.
干预措施: bupropion (Drug)
结局指标
主要结局
Maximum concentration (Cmax) of midazolam administered alone
时间窗: Plasma samples will be collected starting from Day 1 at predose and at multiple specified time points (up to 96 hours) postdose
Cmax=Maximum concentration.
Maximum concentration (Cmax) of metformin administered alone
时间窗: Plasma samples will be collected starting from Day 1 at predose and at multiple specified time points (up to 96 hours) postdose
Cmax=Maximum concentration.
Maximum concentration (Cmax) of bupropion administered alone
时间窗: Plasma samples will be collected starting from Day 1 at predose and at multiple specified time points (up to 96 hours) postdose
Cmax=Maximum concentration.
Area under the curve from 0 to infinity (AUC) of midazolam administered alone
时间窗: Plasma samples will be collected starting from Day 1 at predose and at multiple time points (up to 96 hours) postdose
AUC=Area under the curve from 0 to infinity.
Area under the curve from 0 to infinity (AUC) of metformin administered alone
时间窗: Plasma samples will be collected starting from Day 1 at predose and at multiple time points (up to 96 hours) postdose
AUC=Area under the curve from 0 to infinity.
Area under the curve from 0 to infinity (AUC) of bupropion administered alone
时间窗: Plasma samples will be collected starting from Day 1 at predose and at multiple time points (up to 96 hours) postdose
AUC=Area under the curve from 0 to infinity.
Area under the curve from 0 to the time of the last quantifiable concentration AUC(0-t) of midazolam administered alone
时间窗: Plasma samples will be collected starting from Day 1 at predose and at multiple time points (up to 96 hours) postdose
AUC(0-t)=Area under the curve from 0 to the time of the last quantifiable concentration.
Area under the curve from 0 to the time of the last quantifiable concentration AUC(0-t) of metformin administered alone
时间窗: Plasma samples will be collected starting from Day 1 at predose and at multiple time points (up to 96 hours) postdose
AUC(0-t)=Area under the curve from 0 to the time of the last quantifiable concentration.
Area under the curve from 0 to the time of the last quantifiable concentration AUC(0-t) of bupropion administered alone
时间窗: Plasma samples will be collected starting from Day 1 at predose and at multiple time points (up to 96 hours) postdose
AUC(0-t)=Area under the curve from 0 to the time of the last quantifiable concentration.
Maximum concentration (Cmax) of midazolam after ZX008 administration
时间窗: Plasma samples will be collected starting from Day 22 at predose and at multiple specified time points (up to 96 hours) postdose of midazolam
Cmax=Maximum concentration.
Maximum concentration (Cmax) of metformin after ZX008 administration
时间窗: Plasma samples will be collected starting from Day 22 at predose and at multiple specified time points (up to 96 hours) postdose of metformin
Cmax=Maximum concentration.
Maximum concentration (Cmax) of bupropion after ZX008 administration
时间窗: Plasma samples will be collected starting from Day 22 at predose and at multiple specified time points (up to 96 hours) postdose of bupropion
Cmax=Maximum concentration.
Area under the curve from 0 to infinity (AUC) of midazolam after ZX008 administration
时间窗: Plasma samples will be collected starting from Day 22 at predose and at multiple time points (up to 96 hours) postdose of midazolam
AUC=Area under the curve from 0 to infinity.
Area under the curve from 0 to infinity (AUC) of metformin after ZX008 administration
时间窗: Plasma samples will be collected starting from Day 22 at predose and at multiple time points (up to 96 hours) postdose of metformin
AUC=Area under the curve from 0 to infinity.
Area under the curve from 0 to infinity (AUC) of bupropion after ZX008 administration
时间窗: Plasma samples will be collected starting from Day 22 at predose and at multiple time points (up to 96 hours) postdose of bupropion
AUC=Area under the curve from 0 to infinity.
Area under the curve from 0 to the time of the last quantifiable concentration AUC(0-t) of the cocktail of midazolam after ZX008 administration
时间窗: Plasma samples will be collected starting from Day 22 at predose and at multiple time points (up to 96 hours) postdose of midazolam
AUC(0-t)=Area under the curve from 0 to the time of the last quantifiable concentration.
Area under the curve from 0 to the time of the last quantifiable concentration AUC(0-t) of metformin after ZX008 administration
时间窗: Plasma samples will be collected starting from Day 22 at predose and at multiple time points (up to 96 hours) postdose of metformin
AUC(0-t)=Area under the curve from 0 to the time of the last quantifiable concentration.
Area under the curve from 0 to the time of the last quantifiable concentration AUC(0-t) of bupropion after ZX008 administration
时间窗: Plasma samples will be collected starting from Day 22 at predose and at multiple time points (up to 96 hours) postdose of bupropion
AUC(0-t)=Area under the curve from 0 to the time of the last quantifiable concentration.
Maximum Concentration (Cmax) of Midazolam Alone and in Combination With ZX008 at Steady State
时间窗: Day 1 (Treatment Period 1) and Day 22 (Treatment Period 2): Predose, 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10,12, 24, 36, 48, 72, and 96 hours Postdose
Cmax is the maximum observed plasma concentration of Midazolam alone and in combination with ZX008 at steady state.
Maximum Concentration (Cmax) of Metformin Alone and in Combination With ZX008 at Steady State
时间窗: Day 1 (Treatment Period 1) and Day 22 (Treatment Period 2): Predose, 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10,12, 24, 36, 48, 72, and 96 hours Postdose
Cmax is the maximum observed plasma concentration of Metformin alone and in combination with ZX008 at steady state.
Maximum Concentration (Cmax) of Bupropion Alone and in Combination With ZX008 at Steady State
时间窗: Day 1 (Treatment Period 1) and Day 22 (Treatment Period 2): Predose, 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10,12, 24, 36, 48, 72, and 96 hours Postdose
Cmax is the maximum observed plasma concentration of Bupropion alone and in combination with ZX008 at steady state.
Area Under the Curve From 0 to Infinity (AUC) of Midazolam Alone and in Combination With ZX008 at Steady State
时间窗: Day 1 (Treatment Period 1) and Day 22 (Treatment Period 2): Predose, 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10,12, 24, 36, 48, 72, and 96 hours Postdose
AUC is area under the plasma concentration-time curve from time 0 to infinity of Midazolam alone and in combination with ZX008 at steady state.
Area Under the Curve From 0 to Infinity (AUC) of Metformin Alone and in Combination With ZX008 at Steady State
时间窗: Day 1 (Treatment Period 1) and Day 22 (Treatment Period 2): Predose, 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10,12, 24, 36, 48, 72, and 96 hours Postdose
AUC is area under the plasma concentration-time curve from time 0 to infinity of Metformin alone and in combination with ZX008 at steady state.
Area Under the Curve From 0 to Infinity (AUC) of Bupropion Alone and in Combination With ZX008 at Steady State
时间窗: Day 1 (Treatment Period 1) and Day 22 (Treatment Period 2): Predose, 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10,12, 24, 36, 48, 72, and 96 hours Postdose
AUC is area under the plasma concentration-time curve from time 0 to infinity of Bupropion alone and in combination with ZX008 at steady state.
Area Under the Curve From 0 to the Time of the Last Quantifiable Concentration AUC(0-t) of Midazolam Alone and in Combination With ZX008 at Steady State
时间窗: Day 1 (Treatment Period 1) and Day 22 (Treatment Period 2): Predose, 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10,12, 24, 36, 48, 72, and 96 hours Postdose
AUC(0-t) is area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration of Midazolam alone and in combination with ZX008 at steady state.
Area Under the Curve From 0 to the Time of the Last Quantifiable Concentration AUC(0-t) of Metformin Alone and in Combination With ZX008 at Steady State
时间窗: Day 1 (Treatment Period 1) and Day 22 (Treatment Period 2): Predose, 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10,12, 24, 36, 48, 72, and 96 hours Postdose
AUC(0-t) is area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration of Metformin alone and in combination with ZX008 at steady state.
Area Under the Curve From 0 to the Time of the Last Quantifiable Concentration AUC(0-t) of Bupropion Alone and in Combination With ZX008 at Steady State
时间窗: Day 1 (Treatment Period 1) and Day 22 (Treatment Period 2): Predose, 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10,12, 24, 36, 48, 72, and 96 hours Postdose
AUC(0-t) is area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration of Bupropion alone and in combination with ZX008 at steady state.
次要结局
- Percentage of study participants with treatment-emergent adverse events (TEAEs)(From Baseline (Day 1) to the end of Safety Follow-Up (up to 116 days))
- Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)(From Baseline (Day 1) to the End of Safety Follow-Up (up to 116 days))