A Phase I, 2-Part, Open-Label Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Multiple Doses of Risdiplam and the Effect of Risdiplam on the Pharmacokinetics of Midazolam Following Oral Administration in Healthy Participants
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 35
- 试验地点
- 1
- 主要终点
- Part 2: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of Midazolam Alone and in Combination With Risdiplam
研究概览
简要总结
This will be a Phase I, 2-part, open-label, non-randomized study to investigate the safety, tolerability, and pharmacokinetics (PK) of a multiple-dosing regimen of risdiplam (Part 1) and the effect of risdiplam on the PK of midazolam (Part 2) following oral administration in healthy adult male and female participants.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Healthy participants as defined by the Investigator
- •A body mass index (BMI) of 18.0 to 32.0 kg/m2
- •Use of adequate contraception methods during the treatment period and until 4 months after last study drug administration. Males must refrain from donating sperm during this same period
- •Willingness and ability to complete all aspects of the study
排除标准
- •Concomitant disease or condition that could interfere with, or treatment of which might interfere with, the conduct of the study
- •History or evidence of any medical condition potentially altering the absorption, metabolism, or elimination of drugs
- •Surgical history of the GI tract affecting gastric motility or altering the GI tract
- •History or presence of clinically significant ECG abnormalities or cardiovascular disease
- •History of malignancy in the past 5 years
- •Positive result on human immunodeficiency virus (HIV)-1, HIV-2, hepatitis B virus, or hepatitis C virus
- •Donation of blood or blood products for transfusion
- •Participation in an investigational drug medicinal product or medical device study within 90 days prior to Screening
- •Any clinically significant history of hypersensitivity or allergic reactions
- •History of hypersensitivity to midazolam or any other benzodiazepine or its formulation ingredients
- •For Part 2 participants:
- •History of acute angle glaucoma
研究组 & 干预措施
Part 1
Participants will receive a dose of 5 milligram (mg) risdiplam once daily (QD) for 14 consecutive days
干预措施: Risdiplam (Drug)
Part 2
All study participants will receive a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day QD treatment period with risdiplam will begin. The precise dose will be based on the results of Part 1, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam)
干预措施: Risdiplam (Drug)
Part 2
All study participants will receive a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day QD treatment period with risdiplam will begin. The precise dose will be based on the results of Part 1, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam)
干预措施: Midazolam (Drug)
结局指标
主要结局
Part 2: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of Midazolam Alone and in Combination With Risdiplam
时间窗: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD. Blood samples for pharmacokinetic (PK) analysis were taken at defined timepoints on Day 1 for midazolam administered alone and on Day 15 for midazolam administered in combination with risdiplam.
Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of Midazolam Alone and in Combination With Risdiplam
时间窗: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD. Blood samples for PK analysis were taken at defined timepoints on Day 1 for midazolam administered alone and on Day 15 for midazolam administered in combination with risdiplam.
Part 2: Maximum Observed Plasma Concentration (Cmax) of Midazolam Alone and in Combination With Risdiplam
时间窗: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD. Blood samples for PK analysis were taken at defined timepoints on Day 1 for midazolam administered alone and on Day 15 for midazolam administered in combination with risdiplam.
Part 2: AUCinf of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and in Combination With Risdiplam
时间窗: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD. Blood samples for PK analysis were taken at defined timepoints on Day 1 for midazolam administered alone and on Day 15 for midazolam administered in combination with risdiplam.
Part 2: AUClast of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and in Combination With Risdiplam
时间窗: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD. Blood samples for PK analysis were taken at defined timepoints on Day 1 for midazolam administered alone and on Day 15 for midazolam administered in combination with risdiplam.
Part 2: Cmax of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and in Combination With Risdiplam
时间窗: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD. Blood samples for PK analysis were taken at defined timepoints on Day 1 for midazolam administered alone and on Day 15 for midazolam administered in combination with risdiplam.
次要结局
- Part 1: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses(Day 1: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose; Day 2 to Day 13: Predose; Day 14: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 96, and 144 hours postdose)
- Part 2: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses(Day 3: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose; Day 4 to Day 15: Predose; Day 16: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 96, and 144 hours postdose)
- Part 1 and Part 2: Percentage of Participants With Adverse Events After Administration of Multiple Doses of Risdiplam(Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination)
- Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to the End of the Dosing Interval (AUCtau) of Risdiplam and Its Metabolite (M1) Following Multiple Oral Doses(Day 1: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose; Day 2 to Day 13: Predose; Day 14: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 96, and 144 hours postdose)
- Part 1: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses(Day 1: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose; Day 2 to Day 13: Predose; Day 14: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 96, and 144 hours postdose)
- Part 2: AUCtau of Risdiplam and M1 Risdiplam Following Multiple Oral Doses(Day 3: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose; Day 4 to Day 15: Predose; Day 16: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 96, and 144 hours postdose)
- Part 2: Percentage of Participants With Adverse Events After Midazolam Administration Alone and in Combination With Risdiplam(Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination)
- Part 2: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses(Day 3: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose; Day 4 to Day 15: Predose; Day 16: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 96, and 144 hours postdose)