A Phase 1, Double Blind, Sponsor Open, Randomized, Placebo Controlled, Dose Escalation, Parallel Group Study To Investigate The Safety, Tolerability And Pharmacokinetics Of Repeat Doses Of Pf-06649751 In Healthy Western And Japanese Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 77
- 试验地点
- 1
- 主要终点
- Supine and standing vital sign measurements
研究概览
简要总结
This study is designed to evaluate the safety and plasma concentrations of PF-06649751 in healthy volunteers following one or two times daily oral dosing of PF-06649751 for 14 days (Cohorts 1 - 4), 21 days (Cohort 5), or 28 days (Cohorts 6 - 8). Cohort 9 will dose Japanese healthy volunteers in a manner identical to Cohort 4 and is intended to bridge the safety/tolerability and PK data from the Western and Japanese populations.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
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 males and/or female subjects of non childbearing potential between the ages of 18 and 55 years, inclusive (healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12 lead ECG and clinical laboratory tests).
- •Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lbs).
- •Cohort 9 only: Japanese subjects must have four biologic Japanese grandparents who were born in Japan.
排除标准
- •Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
- •Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
研究组 & 干预措施
Cohort 1
Dosing in healthy Western subjects.
干预措施: 0.15 mg PF-06649751 (Drug)
Cohort 2
Dosing in healthy Western subjects.
干预措施: 0.5 mg PF-06649751 (Drug)
Cohort 3
Dosing in healthy Western subjects.
干预措施: 0.5 mg PF-06649751 (Drug)
Cohort 4
Dosing in healthy Western subjects.
干预措施: 1.5 mg PF-06649751 (Drug)
Cohort 5
Dosing in healthy Western subjects.
干预措施: 1.5 mg PF-06649751 21 Days (Drug)
Cohort 6
Dosing in healthy Western subjects.
干预措施: 3.0 mg PF-06649751 (Drug)
Cohort 7
Dosing in healthy Western subjects.
干预措施: 5.0 mg PF-06649751 (Drug)
Optional Cohort 8
Dosing in healthy Western subjects. Cohort may not be conducted.
干预措施: 8.0 mg PF-06649751 (Drug)
Cohort 9
Dosing in healthy Japanese subjects.
干预措施: 1.5 mg PF-06649751 in healthy Japanese subjects (Drug)
结局指标
主要结局
Supine and standing vital sign measurements
时间窗: Days 1 - 18 (Cohorts 1 - 4, 9), Days 1 - 25 (Cohort 5), Days 1 - 32 (Cohorts 6 - 8) and follow-up
Measurement of blood pressure and pulse rate
Amount of unchanged drug excreted in urine relative to dose (Ae%)
时间窗: Day 14 (Cohorts 1 - 4, 9), Day 21 (Cohort 5), Day 28 (Cohorts 6 - 8)
Plasma Decay Half-Life (t1/2)
时间窗: Days 14 - 18 (Cohorts 1 - 4, 9), Days 21 - 25 (Cohort 5), Days 28 - 32 (Cohorts 6 - 8)
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Maximum Observed Plasma Concentration (Cmax)
时间窗: Day 1, Day 7, Day 14 (Cohorts 1 - 4, 9), Day 1 and 21 (Cohort 5), Day 1 and 28 (Cohorts 6 - 8)
Maximum plasma concentration
Apparent Oral Clearance (CL/F)
时间窗: Days 14 - 18 (Cohorts 1 - 4, 9), Days 21 - 25 (Cohort 5), Days 28 - 32 (Cohorts 6 - 8)
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: Days 1 - 18 (Cohorts 1 - 4, 9), Days 1 - 25 (Cohort 5), Days 1 - 32 (Cohorts 6 - 8) and follow-up
Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to \[study drug\] was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category.
Area Under the Curve from Time Zero to end of dosing interval (AUCtau)
时间窗: Day 1, Day 14 (Cohorts 1 - 4, 9), Day 1 and Day 21 (Cohort 5), Day 1 and Day 28 (Cohorts 6 - 8)
Renal Clearance (CLR)
时间窗: Day 14 (Cohort 1 - 4, 9), Day 21 (Cohort 5) and Day 28 (Cohorts 6 - 8)
Time to Reach Maximum Observed Plasma Concentration (Tmax)
时间窗: Day 1, Day 7, Day 14 (Cohorts 1 - 4, 9), Day 1 and 21 (Cohort 5), Day 1 and 28 (Cohorts 6 - 8)
Time for Cmax
Ratio of accumulation for AUCtau (Rac AUCtau)
时间窗: Day 1 and 14 (Cohorts 1 - 4, 9), Day 1 and 21 (Cohort 5), Day 1 and 28 (Cohorts 6 - 8)
Ratio of accumulation for AUCtau. Corrected for titrated doses.
Ratio of accumulation for Cmax (Rac Cmax)
时间窗: Day 1, Day 7 and Day 14 (Cohorts 1 - 4, 9), Day 1 and 21 (Cohort 5), Day 1 and 28 (Cohorts 6 - 8)
Ratio of accumulation for Cmax. Corrected for titrated doses.
Peak-to-trough ratio (PTR)
时间窗: Day 7 and Day 14 (Cohorts 1 - 4, 9), Day 21 (Cohort 5), Day 28 (Cohorts 6 - 8)
Peak-to-trough ratio at steady state
Number of Participants with categorical scores on the Columbia Suicide Severity Rating Scale (C-SSRS)
时间窗: Day 0 and 14 (Cohorts 1 - 4, 9), Day 0 and 21 (Cohort 5), Day 0 and 28 (Cohort 6 - 8) and follow-up
C-SSRS assessed whether participant experienced following: completed suicide (1), suicide attempt (2) (response of "Yes" on "actual attempt"), preparatory acts toward imminent suicidal behavior (3)("Yes" on "preparatory acts or behavior"), suicidal ideation (4) ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent), any suicidal behavior or ideation, self-injurious behavior (7)("Yes" on "Has subject engaged in non-suicidal self-injurious behavior").
Changes from baseline in total cholesterol, High Density Lipoprotein (HDL) cholesterol, Low Density Lipoprotein (LDL) cholesterol, triglycerides
时间窗: Day 1 and Day 14 (Cohorts 1 - 4, 9), Day 1 and 21 (Cohort 5), Day 1 and 28 (Cohorts 6 - 8)
Apparent Volume of Distribution (Vz/F)
时间窗: Days 14 - 18 (Cohorts 1 - 4, 9), Days 21 - 25 (Cohort 5), Days 28 - 32 (Cohorts 6 - 8)
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
Electrocardiogram (ECG)
时间窗: Days 1 - 18 (Cohorts 1 - 4, 9), Days 1 - 25 (Cohort 5), Days 1 - 32 (Cohorts 6 - 8) and follow-up
Measurement of standard 12-lead ECG, single or triplicate
Number of Participants With Laboratory Test Values of Potential Clinical Importance
时间窗: Days 1 - 18 (Cohorts 1 - 4, 9), Days 1 - 25 (Cohort 5), Days 1 - 32 (Cohorts 6 - 8) and follow-up
Pre-defined criteria were established for each laboratory test to define the values that would be identified as of potential clinical importance.
Trough Concentration (Ctrough)
时间窗: Day 1 to 14 (Cohorts 1 - 4, 9), Day 1 to 21 (Cohort 5), Day 1 to 28 (Cohorts 6 - 8)
Minimum concentration pre-dose
Amount of unchanged drug excreted in urine relative to dose (Ae)
时间窗: Day 14 (Cohorts 1 - 4, 9), Day 21 (Cohort 5), Day 28 (Cohorts 6 - 8)
Calculated from urinary volumes and concentration
次要结局
- Metabolite Scouting(Day 1 (Cohorts 1 - 9) , Day 14 (Cohorts 1 - 4, 9), Day 21 (Cohort 5), Day 28 (Cohorts 6 - 8))