An Open-Label Study Evaluating the Effect of Food on the Pharmacokinetics of Palovarotene and the Effect of Palovarotene on the Pharmacokinetics of the CYP3A4 Substrate Midazolam in Two Cohorts of Healthy Adult Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 48
- 试验地点
- 1
- 主要终点
- Minimum observed plasma concentration at steady state, taken as the lowest plasma concentration during dosing interval for DDI cohort
研究概览
简要总结
Study to evaluate the effect of food and the effect of swallowing capsule whole versus sprinkling on apple sauce on the pharmacokinetics (PK)/bioavailability of palovarotene, and evaluate the effect of palovarotene on the PK of the CYP3A4 substrate midazolam.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 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
- •Generally healthy male or female aged 18 to 55 years, inclusive; body mass index (BMI) of 18 to 30 kg/m2 and a body weight of >50 kg; resting pulse of >45 bpm and <100 bpm; systolic and diastolic blood pressure of <140/90 mmHg
排除标准
- •a history or current evidence of a clinically significant or uncontrolled disease, disease or condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs
- •exposure to synthetic oral retinoids or creams containing retinoids in the past 30 days prior to the signature of the informed consent.
- •history or presence of silent infections, including positive tests for human immunodeficiency virus type 1 (HIV-1), human immunodeficiency virus type 2 (HIV-2), hepatitis B virus (HBV), or hepatitis C virus (HCV)
- •history of allergy or hypersensitivity to retinoids, gelatin, or lactose
- •For the DDI component only, the subject had a history of allergy or hypersensitivity to benzodiazepines, midazolam, cherries, or midazolam formulation excipients
研究组 & 干预措施
PK Cohort 1
Subjects received three single oral doses of palovarotene on Days 1, 6, and 11, separated by 5-day washout periods.
Sequence A-B-C: Subjects received a single oral dose of palovarotene whole capsule under fasting conditions (at least a 10-hour overnight fast); followed by a single oral dose of palovarotene whole capsule 30 minutes after the start of a standardized high-fat, high-caloric breakfast; and then followed by a single oral dose of palovarotene sprinkled on 1 teaspoon of apple sauce, administered 30 minutes after the start of a standardized high-fat, high-caloric breakfast.
干预措施: Palovarotene (Drug)
PK Cohort 2
Subjects received three single oral doses of palovarotene on Days 1, 6, and 11, separated by 5-day washout periods.
Sequence B-C-A: Subjects received a single oral dose of palovarotene whole capsule 30 minutes after the start of a standardized high-fat, high-caloric breakfast; followed by a single oral dose of palovarotene sprinkled on 1 teaspoon of apple sauce, administered 30 minutes after the start of a standardized high-fat, high-caloric breakfast; and then followed by a single oral dose of palovarotene whole capsule under fasting conditions (at least a 10-hour overnight fast).
干预措施: Palovarotene (Drug)
PK Cohort 3
Subjects received three single oral doses of palovarotene on Days 1, 6, and 11, separated by 5-day washout periods.
Sequence C-A-B: Subjects received a single oral dose of palovarotene sprinkled on 1 teaspoon of apple sauce, administered 30 minutes after the start of a standardized high-fat, high-caloric breakfast; followed by a single oral dose of palovarotene whole capsule under fasting conditions (at least a 10-hour overnight fast); and then followed by a single oral dose of palovarotene whole capsule 30 minutes after the start of a standardized high-fat, high-caloric breakfast.
干预措施: Palovarotene (Drug)
Drug-Drug interaction (DDI) Cohort
On the morning of Day 1, subjects received a single dose of midazolam 30 minutes after the start of a standardized breakfast. On Day 2 (after the 24-hour midazolam blood draw) through Day 15, subjects received a daily, single dose of palovarotene in the morning 30 minutes after the start of a standardized breakfast. A second dose of midazolam was administered on Day 15 in the morning (immediately following the palovarotene dose) 30 minutes after the start of a standardized breakfast.
干预措施: Palovarotene (Drug)
Drug-Drug interaction (DDI) Cohort
On the morning of Day 1, subjects received a single dose of midazolam 30 minutes after the start of a standardized breakfast. On Day 2 (after the 24-hour midazolam blood draw) through Day 15, subjects received a daily, single dose of palovarotene in the morning 30 minutes after the start of a standardized breakfast. A second dose of midazolam was administered on Day 15 in the morning (immediately following the palovarotene dose) 30 minutes after the start of a standardized breakfast.
干预措施: midazolam (Drug)
结局指标
主要结局
Minimum observed plasma concentration at steady state, taken as the lowest plasma concentration during dosing interval for DDI cohort
时间窗: Days 1, 2, 15, 16
Maximum (peak) observed plasma drug concentration
时间窗: Days 1, 2, 3, 6, 7, 8, 11, 12, 13.
Time to reach maximum (peak) (t max) observed plasma concentration following drug administration
时间窗: Days 1, 2, 3, 6, 7, 8, 11, 12, 13
Area under the plasma concentration time (AUC 0-last) curve from time zero to the last quantifiable time point, calculated by linear-log trapezoidal summation
时间窗: Days 1, 2, 3, 6, 7, 8, 11, 12, 13
Accumulation ratio for DDI cohort
时间窗: Days 1, 2, 15, 16
Apparent total clearance of the drug from plasma after oral administration (cLF)
时间窗: Days 1, 2, 3, 6, 7, 8, 11, 12, 13
Area under the plasma concentration time curve from time zero to infinity (AUC 0-infinity)
时间窗: Days 1, 2, 3, 6, 7, 8, 11, 12, 13
calculated by linear-log trapezoidal summation and extrapolated to infinity by addition of the last quantifiable plasma concentration divided by the elimination rate constant
Apparent terminal disposition rate constant/terminal rate constant yz
时间窗: Days 1, 2, 3, 6, 7, 8, 11, 12, 13
determined by linear regression of the terminal points of the log-linear plasma concentration-time curve
Apparent terminal elimination half-life (t1/2)
时间窗: Days 1, 2, 3, 6, 7, 8, 11, 12, 13
Apparent volume of distribution after oral administration (Vd/F)
时间窗: Days 1, 2, 3, 6, 7, 8, 11, 12, 13
Area under the plasma concentration time curve from time zero to 24 hours only for DDI cohort
时间窗: Days 1, 2, 15, 16
The last concentration before the next study drug administration at steady state for DDI cohort
时间窗: Days 1, 2, 15, 16
Maximum (peak) observed plasma drug concentration at steady state for DDI cohort
时间窗: Days 1, 2, 15, 16
Time to reach maximum (peak) observed plasma concentration following drug administration at steady state for DDI cohort
时间窗: Days 1, 2, 15, 16
次要结局
- Occurrence of Adverse Events (AEs)(from baseline until the end of study (16 days))