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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
DOUBLE
Enrollment
77
Oral dosing of 0.15 mg PF-06649751 extemporaneously-prepared solution given once-daily for 14 days.
Oral dosing of 0.5 mg PF-06649751 extemporaneously-prepared solution given once-daily for 14 days.
Oral dosing of tablets up to 0.5 mg PF-06649751 given once-daily for 14 days.
Oral dosing of tablets up to 1.5 mg PF-06649751 given once-daily for 14 days.
Oral dosing of tablets up to 1.5 mg PF-06649751 given once-daily for 21 days.
Oral dosing of tablets up to 3.0 mg PF-06649751 given once-daily for 28 days.
Oral dosing of tablets up to 5.0 mg PF-06649751 given once-daily for 28 days.
Oral dosing of tablets up to 8.0 mg PF-06649751 given once-daily for 28 days.
Oral dosing of tablets up to 1.5 mg PF-06649751 given once-daily for 14 days given in healthy Japanese subjects.
New Haven Clinical Research Unit
New Haven, Connecticut, United States
Supine and standing vital sign measurements
Measurement of blood pressure and pulse rate
Time frame: Days 1 - 18 (Cohorts 1 - 4, 9), Days 1 - 25 (Cohort 5), Days 1 - 32 (Cohorts 6 - 8) and follow-up
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)
Renal Clearance (CLR)
Time frame: Day 14 (Cohort 1 - 4, 9), Day 21 (Cohort 5) and Day 28 (Cohorts 6 - 8)
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)
Maximum Observed Plasma Concentration (Cmax)
Maximum plasma concentration
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 to Reach Maximum Observed Plasma Concentration (Tmax)
Time for 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)
Plasma Decay Half-Life (t1/2)
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time frame: Days 14 - 18 (Cohorts 1 - 4, 9), Days 21 - 25 (Cohort 5), Days 28 - 32 (Cohorts 6 - 8)
Apparent Oral Clearance (CL/F)
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.
Time frame: Days 14 - 18 (Cohorts 1 - 4, 9), Days 21 - 25 (Cohort 5), Days 28 - 32 (Cohorts 6 - 8)
Apparent Volume of Distribution (Vz/F)
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.
Time frame: Days 14 - 18 (Cohorts 1 - 4, 9), Days 21 - 25 (Cohort 5), Days 28 - 32 (Cohorts 6 - 8)
Trough Concentration (Ctrough)
Minimum concentration pre-dose
Time frame: Day 1 to 14 (Cohorts 1 - 4, 9), Day 1 to 21 (Cohort 5), Day 1 to 28 (Cohorts 6 - 8)
Ratio of accumulation for AUCtau (Rac AUCtau)
Ratio of accumulation for AUCtau. Corrected for titrated doses.
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 Cmax (Rac Cmax)
Ratio of accumulation for Cmax. Corrected for titrated doses.
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)
Peak-to-trough ratio (PTR)
Peak-to-trough ratio at steady state
Time frame: Day 7 and Day 14 (Cohorts 1 - 4, 9), Day 21 (Cohort 5), Day 28 (Cohorts 6 - 8)
Number of Participants with categorical scores on the Columbia Suicide Severity Rating Scale (C-SSRS)
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").
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
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
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.
Time frame: Days 1 - 18 (Cohorts 1 - 4, 9), Days 1 - 25 (Cohort 5), Days 1 - 32 (Cohorts 6 - 8) and follow-up
Electrocardiogram (ECG)
Measurement of standard 12-lead ECG, single or triplicate
Time frame: Days 1 - 18 (Cohorts 1 - 4, 9), Days 1 - 25 (Cohort 5), Days 1 - 32 (Cohorts 6 - 8) and follow-up
Number of Participants With Laboratory Test Values of Potential Clinical Importance
Pre-defined criteria were established for each laboratory test to define the values that would be identified as 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
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)
Amount of unchanged drug excreted in urine relative to dose (Ae)
Calculated from urinary volumes and concentration
Time frame: Day 14 (Cohorts 1 - 4, 9), Day 21 (Cohort 5), Day 28 (Cohorts 6 - 8)
Metabolite Scouting
Identification of metabolites from blood and urine samples.
Time frame: Day 1 (Cohorts 1 - 9) , Day 14 (Cohorts 1 - 4, 9), Day 21 (Cohort 5), Day 28 (Cohorts 6 - 8)
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