A PHASE 1, OPEN-LABEL, RANDOMIZED, 4-PERIOD, 4-WAY CROSSOVER, RELATIVE BIOAVAILABILITY STUDY OF ZAVEGEPANT (BHV-3500) ORAL FORMULATIONS UNDER FASTING CONDITIONS
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 52
- 试验地点
- 1
- 主要终点
- Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Zavegepant
研究概览
简要总结
This trial is designed to compare the rate and extent of absorption of four different formulations of zavegepant. 52 healthy male and female volunteers will receive a single dose of each formulation at least 7 days apart over a period of about 7 weeks and the amount of drug in their blood will be assessed over the 24 hour period after each dose.
详细描述
This is a Phase 1, single centre, open-label, single dose, 4-period, crossover study designed to compare the pharmacokinetics (PK) of zavegepant from three Test products and a Reference product (treatment D).
52 male and female healthy volunteers will be randomly assigned to one of 4 treatment sequences: ACBD, CDAB, BADC, and DBCA.
In each period, subjects will receive one of the following: Treatment A, B, C, or D on Day 1, followed by 24 hours of PK and safety assessments. On Day 2 subjects will be discharged from the clinical site and instructed to return after at least a 7 day washout time has passed for subsequent periods of treatment.
The study will include a screening visit from Day -28 to Day -2. Eligible subjects will be admitted to the clinical site on Day -1 and will be confined until completion of the assessments on Day 2. There will be a washout period of at least 7 days between doses. Study Exit procedures will be performed after the last assessment on the morning of Day 2 of Period 4. Study Exit procedures will be performed as soon as possible in case of Early Termination.
The total duration of study participation for each subject from Screening through Study Exit is anticipated to be approximately 6.5 weeks.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- None
盲法说明
All investigators, Sponsor personnel, clinical monitors, independent PK analyst, and participants in the study will be unblinded to the treatment allocation as the primary and secondary endpoints are based on objective criteria of laboratory findings.
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
- •Participants must provide Informed Consent Form (ICF) obtained prior to the conduct of any study activities.
- •Healthy Male or female participants at least 18 and less than 56 years of age,
- •Participants must be Non-smokers and not have used any nicotine-containing products for 3 months prior to screening.
- •Body Mass Index (BMI) >18.5 and <30.0kg/m2 and body weight ≥ 50.0kg for males and ≥ 45.0kg for females.
- •All females participants must not be breastfeeding and have a negative urine pregnancy test at Screening.
- •Females of childbearing potential must be willing to use acceptable contraceptive methods throughout the study and for 30 days after the last study drug administration.
- •Male participants with a female partner of childbearing potential must be willing to use acceptable contraceptive methods from the first study drug administration until at least 90 days after the last study drug administration.
排除标准
- •Current diagnosis of viral hepatitis or a history of liver disease.
- •Any history of seizure disorder (e.g., epilepsy) other than a single childhood febrile seizure.
- •Current or recent (within 3 months of the first study drug administration) gastrointestinal disease that may interfere with drug absorption.
- •Prior gastrointestinal surgery that interferes with absorption and motility (e.g., gastric bypass, duodenectomy or gastric banding).
- •History of drug or alcohol abuse.
- •History of anaphylaxis, a documented hypersensitivity reaction, or a clinically significant reaction to any drug or to any of the excipient supporting the zavegepant formulations.
- •Donation of plasma within 7 days prior to dosing, or donation or loss of blood (excluding volume drawn at Screening) of 50 mL to 499 mL of blood within 30 days, or more than 499 mL within 56 days prior to dosing.
- •Participation in a clinical research study involving the administration of an investigational or marketed drug or device within 30 days prior to the dosing, extended to 90 days for biological products.
- •Inability or difficulty to swallow tablets or capsules.
- •Subjects with any clinically significant abnormality or significant abnormal laboratory test results found during medical screening or Day-
- •Positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody during screening.
- •Inadequate renal function - estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Renal Disease (MDRD) study equation ≤ 60 mL/min/1.73 m2 at Screening.
- •Any of the following laboratory parameters greater than the upper limit of normal (ULN) values at Screening or Baseline (Day -1): alkaline phosphatase (ALP) aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, direct bilirubin, and indirect bilirubin, and alkaline phosphatase.
- •Any clinically significant abnormalities on 12-lead ECG or blood pressure (BP) at Screening or Baseline (Day -1) visits.
- •Any clinically significant abnormal haematological laboratory test values at Screening or Baseline (Day -1) visits.
- •Positive test for COVID-19 performed on Day -1 of each period.
研究组 & 干预措施
Sequence 1
Period 1 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 2 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 3 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 4 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D).
干预措施: Zavegepant 100mg non-enteric coated soft gel capsule (Drug)
Sequence 1
Period 1 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 2 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 3 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 4 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D).
干预措施: Zavegepant 100mg immediate release tablet (Drug)
Sequence 1
Period 1 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 2 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 3 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 4 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D).
干预措施: Zavegepant 2 x 100mg immediate release tablets (Drug)
Sequence 1
Period 1 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 2 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 3 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 4 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D).
干预措施: Zavegepant 4 x 25mg enteric coated soft gel capsule (Drug)
Sequence 2
Period 1 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 2 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 3 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 4 - Single zavegepant 100mg immediate release tablet (Treatment B).
干预措施: Zavegepant 100mg non-enteric coated soft gel capsule (Drug)
Sequence 2
Period 1 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 2 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 3 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 4 - Single zavegepant 100mg immediate release tablet (Treatment B).
干预措施: Zavegepant 100mg immediate release tablet (Drug)
Sequence 2
Period 1 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 2 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 3 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 4 - Single zavegepant 100mg immediate release tablet (Treatment B).
干预措施: Zavegepant 2 x 100mg immediate release tablets (Drug)
Sequence 2
Period 1 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 2 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 3 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 4 - Single zavegepant 100mg immediate release tablet (Treatment B).
干预措施: Zavegepant 4 x 25mg enteric coated soft gel capsule (Drug)
Sequence 3
Period 1 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 2 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 3 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 4 - Two zavegepant 100mg immediate release tablets (Treatment C).
干预措施: Zavegepant 100mg non-enteric coated soft gel capsule (Drug)
Sequence 3
Period 1 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 2 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 3 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 4 - Two zavegepant 100mg immediate release tablets (Treatment C).
干预措施: Zavegepant 100mg immediate release tablet (Drug)
Sequence 3
Period 1 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 2 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 3 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 4 - Two zavegepant 100mg immediate release tablets (Treatment C).
干预措施: Zavegepant 2 x 100mg immediate release tablets (Drug)
Sequence 3
Period 1 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 2 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 3 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 4 - Two zavegepant 100mg immediate release tablets (Treatment C).
干预措施: Zavegepant 4 x 25mg enteric coated soft gel capsule (Drug)
Sequence 4
Period 1 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 2 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 3 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 4 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A).
干预措施: Zavegepant 100mg non-enteric coated soft gel capsule (Drug)
Sequence 4
Period 1 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 2 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 3 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 4 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A).
干预措施: Zavegepant 100mg immediate release tablet (Drug)
Sequence 4
Period 1 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 2 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 3 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 4 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A).
干预措施: Zavegepant 2 x 100mg immediate release tablets (Drug)
Sequence 4
Period 1 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 2 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 3 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 4 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A).
干预措施: Zavegepant 4 x 25mg enteric coated soft gel capsule (Drug)
结局指标
主要结局
Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Zavegepant
时间窗: Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours post dose
AUCinf was calculated as AUClast+(Clast\*/kel), where AUClast is the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast\* is the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. AUClast was calculated using Linear/Log trapezoidal method.
Maximum Observed Concentration (Cmax) of Zavegepant
时间窗: Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours post dose
Cmax was observed directly from data.
AUClast of Zavegepant
时间窗: Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours post dose
AUClast was calculated using linear/log trapezoidal method.
次要结局
- Time to Reach Cmax (Tmax) of Zavegepant(Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours post dose)
- Terminal Phase Half-Life (t1/2) of Zavegepant(Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours post dose)
- Apparent Clearance (CL/F) of Zavegepant From Plasma(Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours post-dose)
- Apparent Volume of Distribution (Vz/F) of Zavegepant(Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours post dose)
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs)(Baseline up to study exit (approximately 6.5 weeks))
- Number of Participants With Clinically Significant Laboratory Abnormalities(Baseline up to study exit (approximately 6.5 weeks))
- Blood Pressure on Day -1 and Day 1 of Each Period(Day -1, pre-dose and 2 hours post dose on Day 1 of each period)
- Heart Rate (HR) on Day -1 and Day 1 of Each Period(Day -1, pre-dose and 2 hours post dose on Day 1 of each period)
- HR at Screening and Study Exit(Screening and study exit)
- Blood Pressure at Screening and Study Exit(Screening and study exit)
- Respiratory Rate (RR) on Day -1 of Each Period(Day -1 of each period)
- RR at Screening and Study Exit(Screening and study exit)
- Temperature on Day -1 of Each Period(Day -1 of each period)
- Temperature at Screening and Study Exit(Screening and study exit)
- Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG)(Screening up to study exit (approximately 6.5 weeks))