Open-label, Single-center Study in Healthy Subjects to Investigate the Effect of Oral Givinostat on Pharmacokinetics (PK) of Intravenous and Oral Midazolam and Oral Dabigatran Etexilate (PART 1)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 26
- 试验地点
- 1
- 主要终点
- Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug
研究概览
简要总结
Primary objective:
- To assess the potential inhibitory and inducing effect of oral givinostat on the single dose pharmacokinetics (PK) of intravenous or oral midazolam.
- To assess the potential inhibitory and inducing effect of oral givinostat on the single dose PK of oral dabigatran etexilate.
Secondary objective:
To assess the safety and tolerability of concomitant administration of givinostat plus midazolam and dabigatran etexilate.
详细描述
This study was planned as a phase I, open-label, 3-part, fixed-sequence, nonrandomized study in healthy male and female subjects. The study evaluated the givinostat (ITF2357) potential drug-drug interaction (DDI) at level of CYP3A-mediated metabolism and P-glycoprotein (P-gp) transport with intravenous or oral midazolam and with oral dabigatran etexilate.
More precisely, the study aimed at assessing the potential (inhibitory or inducing) effect of givinostat on the PK of midazolam IV, on the PK of oral midazolam and on the PK of dabigatran etexilate.
The study lasted from Day 1 to Day 20. Subjects were confined from Day -1 to Day 20. On Days 6 and 17, single doses of 1 mg midazolam IV and 75 mg dabigatran etexilate, were administered 1 hour after the planned morning time of givinostat administration. On day 1, however, drugs were not administered 1h after gininostat.
On Days 7 and 18, a single oral dose of 2.5 mg midazolam oral solution was administered 1 hour after the planned morning time of givinostat administration.
On day 2, however, the drugs were not administered 1h after gininostat.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
盲法说明
The study was conducted as open label. Blinding procedures were not applicable
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
- 未提供
排除标准
- •At Admission to Treatment Period
- •Any clinically relevant abnormalities on clinical laboratory tests.
- •Positive urine alcohol, drugs-of-abuse or cotinine screen tests.
- •Positive urine pregnancy test.
- •Positive or inconclusive SARS-CoV-2 test prior to admission.
- •Use of prescription or non-prescription medicinal products within the previous 28 days or within 5-half-lives of the medicinal product, whichever is longer.
- •Any reason which, in the opinion of the Investigator, would prevent the subject from participating in the study.
- •For Part 1 subjects:
- •At Screening
- •Known history of hypersensitivity and/or allergic reactions to midazolam, other benzodiazepines, dabigatran etexilate or to any excipient of the formulations.
- •Clinically relevant history of impaired respiratory function, obstructive sleep apnea, myasthenia gravis, respiratory arrest and/or cardiac arrest.
- •History of glaucoma.
- •Presence of respiratory failure.
- •Presence of active clinically significant bleeding.
- •Lesion or condition considered to pose a significant risk factor for major bleeding including, but not limited to: current or recent gastrointestinal ulceration, malignant neoplasms, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.
- •Presence of a medical condition requiring anticoagulant treatment.
- •At Admission to Treatment Period
- •Treatment with anticoagulants within 28 days or 5 drug half-lives, whichever was longer, before admission.
研究组 & 干预措施
Givinostat alone or combo with Midazolam IV and with oral Dabigatran, or combo with oral Midazolam
On Days 1, 6 and 17, single doses of midazolam 1 mg IV and dabigatran etexilate 75 mg were administered 1 hour after the planned (as per Day 4) morning time of givinostat administration. On Days 2, 7 and 18, a single oral dose of midazolam 2.5 mg oral solution was administered 1 hour after the planned (as per Day 4) morning time of givinostat administration. From Day 4 to Day 18, givinostat 50 mg as oral suspension was administered twice a day, in the morning and in the evening. On Day 19, only the morning dose was administered.
干预措施: Givinostat 10 mg/mL (Drug)
Givinostat alone or combo with Midazolam IV and with oral Dabigatran, or combo with oral Midazolam
On Days 1, 6 and 17, single doses of midazolam 1 mg IV and dabigatran etexilate 75 mg were administered 1 hour after the planned (as per Day 4) morning time of givinostat administration. On Days 2, 7 and 18, a single oral dose of midazolam 2.5 mg oral solution was administered 1 hour after the planned (as per Day 4) morning time of givinostat administration. From Day 4 to Day 18, givinostat 50 mg as oral suspension was administered twice a day, in the morning and in the evening. On Day 19, only the morning dose was administered.
干预措施: Midazolam 1mg/ml IV (Drug)
Givinostat alone or combo with Midazolam IV and with oral Dabigatran, or combo with oral Midazolam
On Days 1, 6 and 17, single doses of midazolam 1 mg IV and dabigatran etexilate 75 mg were administered 1 hour after the planned (as per Day 4) morning time of givinostat administration. On Days 2, 7 and 18, a single oral dose of midazolam 2.5 mg oral solution was administered 1 hour after the planned (as per Day 4) morning time of givinostat administration. From Day 4 to Day 18, givinostat 50 mg as oral suspension was administered twice a day, in the morning and in the evening. On Day 19, only the morning dose was administered.
干预措施: Midazolam 2.5 mg oromucosal solution (Drug)
Givinostat alone or combo with Midazolam IV and with oral Dabigatran, or combo with oral Midazolam
On Days 1, 6 and 17, single doses of midazolam 1 mg IV and dabigatran etexilate 75 mg were administered 1 hour after the planned (as per Day 4) morning time of givinostat administration. On Days 2, 7 and 18, a single oral dose of midazolam 2.5 mg oral solution was administered 1 hour after the planned (as per Day 4) morning time of givinostat administration. From Day 4 to Day 18, givinostat 50 mg as oral suspension was administered twice a day, in the morning and in the evening. On Day 19, only the morning dose was administered.
干预措施: Dabigatran etexilate 75 mg oral hard capsules (Drug)
结局指标
主要结局
Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug
时间窗: In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
Maximum observed plasma concentration (Cmax) of midazolam and 1-hydroxymidazolam following Administration of Midazolam IV Alone (Day 1) and Co-Administration of Midazolam IV and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect) and following Administration of Oral Midazolam Alone (Day 2) and Co-Administration of Oral Midazolam and Givinostat (Day 7 - Potential Inhibitory Effect, and Day 18 - Potential Inducing Effect). 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations.
Cmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
时间窗: In the turn of 72 hours after administration of dabigatran on day 1,6,17
Maximum observed plasma concentration (Cmax) of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected in K2-EDTA collection tubes at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations.
Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug
时间窗: In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
tmax =Time of occurrence of Cmax. 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations.
Tmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
时间窗: In the turn of 72 hours after administration of dabigatran on day 1,6,17
The time of occurrence of maximum observed concentration (tmax) of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations.
t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
时间窗: In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
T1/2 is the Apparent terminal elimination half-life, calculated as ln(2)/λz. t1/2 of midazolam and 1-hydroxymidazolam following Administration of Midazolam IV Alone (Day 1) and Co-Administration of Midazolam IV and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect) and following Administration of Oral Midazolam Alone (Day 2) and Co-Administration of Oral Midazolam and Givinostat (Day 7 - Potential Inhibitory Effect, and Day 18 - Potential Inducing Effect). 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations.
t1/2 for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
时间窗: In the turn of 72 hours after administration of dabigatran on day 1,6,17
Apparent terminal elimination half-life, calculated as ln(2)/λz. The t1/2 of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations.
AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
时间窗: In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
AUC0-t =area under the curve from time zero to last sampling time with quantifiable concentrations. AUC0-t of midazolam and 1-hydroxymidazolam following Administration of Midazolam IV Alone (Day 1) and Co-Administration of Midazolam IV and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect) and following Oral Midazolam Alone (Day 2) and Co-Administration of Oral Midazolam and Givinostat (Day 7 - Potential Inhibitory Effect, and Day 18 - Potential Inducing Effect). 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations.
AUC0-t for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
时间窗: In the turn of 72 hours after administration of dabigatran on day 1,6,17
AUC0-t =area under the curve from time zero to last sampling time with quantifiable concentrations. AUC0-t of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations.
AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
时间窗: In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
AUC0-inf=Total AUC extrapolated to infinity, calculated as AUC0-t + Clast/λz, where Clast is the last measurable concentration and λz is the apparent terminal elimination rate constant. 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations.
AUC0-inf for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
时间窗: In the turn of 72 hours after administration of dabigatran on day 1,6,17
AUC0-inf = Total AUC extrapolated to infinity, calculated as AUC0-t + Clast/λz, where Clast is the last measurable concentration and λz is the apparent terminal elimination rate constant. AUC0-inf of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations.
%AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
时间窗: In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
Area under the curve or AUC is a pharmacokinetic statistic used to describe the total exposure to a drug. More specifically, it is the time-averaged concentration of drug circulating in the body fluid analyzed (normally plasma, blood or serum). Standard calculation of AUC involves using non-compartmental techniques to calculate the AUC from time 0 to the last measurable concentration. This is called AUC0-t and represents the observed exposure to a drug. The total AUC or AUC0-∞ is the area under the curve from time 0 extrapolated to infinite time. %AUCextrap = Percentage of AUC0-∞ due to extrapolation from the time of the last measurable concentration (tlast) to infinity, i.e., residual area, calculated as 100 ∙(AUC0-∞ - AUC0-t) / AUC0-∞.
%AUC0extrap (%) for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
时间窗: In the turn of 72 hours after administration of dabigatran on day 1,6,17
Area under the curve (AUC) is a pharmacokinetic statistic used to describe the total exposure to a drug. More specifically, it is the time-averaged concentration of drug circulating in the body fluid analyzed. The total AUC (AUC0-∞) is the area under the curve from time 0 extrapolated to infinite time. * AUC0extrap = Percentage of AUC0-∞ due to extrapolation from the time of the last measurable concentration (tlast) to infinity, i.e., residual area, calculated as 100 ∙(AUC0-∞ - AUC0-t) / AUC0-∞. * AUC0extrap of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatra
λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
时间窗: In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
Apparent first order elimination rate constant associated with the terminal (log-linear) portion of the concentration versus time curve. The parameter is estimated by linear least square regression analysis using the last three (or more) non-zero concentrations. 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations.
λz of Dabigatran (Total and Free), Following Single Doses of Givinostat
时间窗: In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
Apparent first order elimination rate constant associated with the terminal (log-linear) portion of the concentration versus time curve. The parameter is estimated by linear least square regression analysis using the last three (or more) non-zero concentrations. Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations.
次要结局
- Number of Adverse Events by Severity (Mild, Moderate, Severe)(Throughout the study and 10-14 days after the EoS (follow-up visit), i.e. up to date 30-34)
- Incidence of Patients With at Least One Adverse Events by Severity (Mild, Moderate, Severe)(During the study and 10-14 days after the EoS (follow-up visit), i.e. up to day 30-34)