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
Overview
- Phase
- Phase 1
- Intervention
- 0.15 mg PF-06649751
- Conditions
- Healthy
- Sponsor
- Pfizer
- Enrollment
- 77
- Locations
- 1
- Primary Endpoint
- Supine and standing vital sign measurements
- Status
- Completed
- Last Updated
- 10 years ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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.
Exclusion Criteria
- •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.
Arms & Interventions
Cohort 1
Dosing in healthy Western subjects.
Intervention: 0.15 mg PF-06649751
Cohort 2
Dosing in healthy Western subjects.
Intervention: 0.5 mg PF-06649751
Cohort 3
Dosing in healthy Western subjects.
Intervention: 0.5 mg PF-06649751
Cohort 4
Dosing in healthy Western subjects.
Intervention: 1.5 mg PF-06649751
Cohort 5
Dosing in healthy Western subjects.
Intervention: 1.5 mg PF-06649751 21 Days
Cohort 6
Dosing in healthy Western subjects.
Intervention: 3.0 mg PF-06649751
Cohort 7
Dosing in healthy Western subjects.
Intervention: 5.0 mg PF-06649751
Optional Cohort 8
Dosing in healthy Western subjects. Cohort may not be conducted.
Intervention: 8.0 mg PF-06649751
Cohort 9
Dosing in healthy Japanese subjects.
Intervention: 1.5 mg PF-06649751 in healthy Japanese subjects
Outcomes
Primary Outcomes
Supine and standing vital sign measurements
Time Frame: 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%)
Time Frame: Day 14 (Cohorts 1 - 4, 9), Day 21 (Cohort 5), Day 28 (Cohorts 6 - 8)
Plasma Decay Half-Life (t1/2)
Time Frame: 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)
Time Frame: 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)
Time Frame: 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)
Time Frame: 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)
Time Frame: 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)
Time Frame: Day 14 (Cohort 1 - 4, 9), Day 21 (Cohort 5) and Day 28 (Cohorts 6 - 8)
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time Frame: 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)
Time Frame: 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)
Time Frame: 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)
Time Frame: 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)
Time Frame: 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
Time Frame: 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)
Time Frame: 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)
Time Frame: 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
Time Frame: 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)
Time Frame: 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)
Time Frame: Day 14 (Cohorts 1 - 4, 9), Day 21 (Cohort 5), Day 28 (Cohorts 6 - 8)
Calculated from urinary volumes and concentration
Secondary Outcomes
- Metabolite Scouting(Day 1 (Cohorts 1 - 9) , Day 14 (Cohorts 1 - 4, 9), Day 21 (Cohort 5), Day 28 (Cohorts 6 - 8))