Safety and Pharmacokinetic Study of PF-06651600 in Healthy Volunteers

Study Overview
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Brief Summary
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This study is a first in human study of PF-06651600. PF-06651600 is being developed for treatment of inflammatory bowel disease. This study will test single and multiple doses of PF-06651600. The goal of the study is to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-06651600 in healthy volunteers.

Official Title
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A Phase 1, Randomized, Double Blind, Third-party Open, Placebo-controlled, Single And Multiple Dose Escalation, Parallel Group Study To Evaluate The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Pf-06651600 In Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: PF-06651600 or Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male/female subjects between 18 and 55 years old, inclusive. Females must be of non-child bearing potential. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lbs). Evidence of personally signed and dated informed consent document. Willing and able to comply with scheduled visits, treatment plan, lab tests and other study procedures. Subjects must avoid high intensity UV light exposure (eg, active sunbathing, tanning beds/booths or sunlamps) from the first dose of study drug and for the duration of the study. Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, GI, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease. Use of tobacco/nicotine containing products in excess of 5 cigarettes/day. History of regular alcohol consumption exceeding 14 drinks/week for females or 21 drinks/week for males. Screening blood pressure >140/90 mm Hg. Screening laboratory abnormalities as defined by the protocol. Unwilling or unable to comply with the Lifestyle Guidelines as defined by the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: PF-06651600 or Placebo<br>Single ascending doses of PF-06651600 or placebo to evaluate safety, tolerability and PK. | Drug: PF-06651600 or Placebo<br>* PF-06651600 or placebo will be administered as an extemporaneously prepared solution in each cohort.<br>|
| Experimental: Cohort 2: PF-06651600 or Placebo<br>Single ascending doses of PF-06651600 or placebo to evaluate safety, tolerability and PK. | Drug: PF-06651600 or Placebo<br>* PF-06651600 or placebo will be administered as an extemporaneously prepared solution in each cohort.<br>|
| Experimental: Cohort 3: PF-06651600 or Placebo<br>Single ascending doses and multiple ascending doses of PF-06651600 or placebo to evaluate safety, tolerability and PK. | Drug: PF-06651600 or Placebo<br>* PF-06651600 or placebo will be administered as an extemporaneously prepared solution in each cohort.<br>|
| Experimental: Cohort 4: PF-06651600 or Placebo<br>Single ascending doses and multiple ascending doses of PF-06651600 or placebo to evaluate safety, tolerability and PK. | Drug: PF-06651600 or Placebo<br>* PF-06651600 or placebo will be administered as an extemporaneously prepared solution in each cohort.<br>|
| Experimental: Cohort 5: PF-06651600 or Placebo<br>Single ascending doses and multiple ascending doses of PF-06651600 or placebo to evaluate safety, tolerability and PK. | Drug: PF-06651600 or Placebo<br>* PF-06651600 or placebo will be administered as an extemporaneously prepared solution in each cohort.<br>|
| Experimental: Cohort 6: PF-06651600 or Placebo<br>Single ascending doses and multiple ascending doses of PF-06651600 or placebo to evaluate safety, tolerability and PK. | Drug: PF-06651600 or Placebo<br>* PF-06651600 or placebo will be administered as an extemporaneously prepared solution in each cohort.<br>|
| Experimental: Cohort 7: PF-06651600 or Placebo<br>Single ascending doses and multiple ascending doses of PF-06651600 or placebo to evaluate safety, tolerability and PK. | Drug: PF-06651600 or Placebo<br>* PF-06651600 or placebo will be administered as an extemporaneously prepared solution in each cohort.<br>|
| Experimental: Cohort 8: PF-06651600 or Placebo<br>Single ascending doses and multiple ascending doses of PF-06651600 or placebo to evaluate safety, tolerability and PK. | Drug: PF-06651600 or Placebo<br>* PF-06651600 or placebo will be administered as an extemporaneously prepared solution in each cohort.<br>|
| Experimental: Cohort 9: PF-06651600 or Placebo<br>Multiple ascending doses of PF-06651600 or placebo to evaluate safety, tolerability and PK. | Drug: PF-06651600 or Placebo<br>* PF-06651600 or placebo will be administered as an extemporaneously prepared solution in each cohort.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24 hour creatinine clearance (Single Dose) | 24 hour urine creatinine clearance in healthy subjects participating in the single dose periods. For the single dose period, assessment occurs on Study Days 0 and 1. | Single dose period, Day 0 (baseline) and 24 hours post dose Day 1. | 
| 24 hour creatinine clearance (Multiple Dose) | 24 hour urine creatinine clearance in healthy subjects participating in the multiple dose period. For the multiple ascending dose period assessments occur on Study Days 7 and 14. | Multiple dose period, Days 0 (baseline), 7 and 14. | 
| Change from baseline in urine volume (Single Dose) | For the single dose period, assessment occurs on Study Days 0 and 1. | Single dose period, Day 0 (baseline) and 24 hours post dose Day 1. | 
| Change from baseline in urine electrolytes (Single Dose) | For the single dose period, assessment occurs on Study Days 0 and 1. | Single dose period, Day 0 (baseline) and 24 hours post dose Day 1. | 
| Change from baseline in urine osmolality (Single Dose) | For the single dose period, assessment occurs on Study Days 0 and 1. | Single dose period, Day 0 (baseline) and 24 hours post dose Day 1. | 
| Change from baseline of urine volume (Multiple Dose) | For the multiple ascending dose period assessments occur on Study Days 7 and 14. | Multiple dose period, Days 0 (baseline), 7 and 14. | 
| Change from baseline of urine electrolytes (Multiple Dose) | For the multiple ascending dose period assessments occur on Study Days 7 and 14. | Multiple dose period, Days 0 (baseline), 7 and 14. | 
| Change from baseline in urine osmolality (Multiple Dose) | For the multiple ascending dose period assessments occur on Study Days 7 and 14. | Multiple dose period, Days 0 (baseline), 7 and 14. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) for PF-06651600 (Single Dose) | Maximum Observed Plasma Concentration (Cmax) | 0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48 hours post dose | 
| Maximum Observed Plasma Concentration (Cmax) for PF-06651600 (Multiple Dose) | Maximum Observed Plasma Concentration (Cmax) | Days 1, 4, 6, 8, 10, 12 and 14 (0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post dose) | 
| Time to Reach Maximum Observed Plasma Concentration (Cmax) for PF-06651600 (Single Dose) | Time to Reach Maximum Observed Plasma Concentration (Cmax) | 0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48 hours post dose | 
| Time to Reach Maximum Observed Plasma Concentration (Cmax) for PF-06651600 (Multiple Dose) | Time to Reach Maximum Observed Plasma Concentration (Cmax) | Days 1, 4, 6, 8, 10, 12 and 14 (0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post dose) | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) for PF-06651600 (Single Dose) | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) | 0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48 hours post dose | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for PF-06651600 (Single Dose) | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48 hours post dose | 
| Dose Normalized Maximum Observed Plasma Concentration (Cmaxdn) for PF-06651600 (Single Dose) | Dose Normalized Maximum Observed Plasma Concentration (Cmaxdn) | 0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48 hours post dose | 
| Dose Normalized Maximum Observed Plasma Concentration (Cmaxdn) for PF-06651600 (Multiple Dose) | Dose Normalized Maximum Observed Plasma Concentration (Cmaxdn) | Days 1, 4, 6, 8, 10, 12 and 14 (0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post dose) | 
| Dose Normalized Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinfdn) for PF-06651600 (Single Dose) | Dose Normalized Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinfdn) | 0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48 hours post dose | 
| Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClastdn) for PF-06651600 (Single Dose) | Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClastdn) | 0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48 hours post dose | 
| Plasma Decay Half-Life (t1/2) for PF-06651600 (Single Dose) | Plasma Decay Half-Life (t1/2) | 0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48 hours post dose | 
| Plasma Decay Half-Life (t1/2) for PF-06651600 (Multiple Dose) | Plasma Decay Half-Life (t1/2) | Days 1, 4, 6, 8, 10, 12 and 14 (0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post dose) | 
| Mean Resonance Time (MRT) for PF-06651600 (Single Dose) | Mean Resonance Time (MRT) | 0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48 hours post dose | 
| Mean Resonance Time (MRT) for PF-06651600 (Multiple Dose) | Mean Resonance Time (MRT) | Days 1, 4, 6, 8, 10, 12 and 14 (0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post dose) | 
| Apparent Volume of Distribution (Vz/F) for PF-06651600 (Single Dose) | 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. | 0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48 hours post dose | 
| Apparent Volume of Distribution (Vz/F) for PF-06651600 (Multiple Dose) | 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. | Days 1, 4, 6, 8, 10, 12 and 14 (0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post dose) | 
| Apparent Total Body Clearance (CL/F) for PF-06651600 (Single Dose) | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent total body clearance (CL/F) 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. | 0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48 hours post dose | 
| Apparent Total Body Clearance (CL/F) for PF-06651600 (Multiple Dose) | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent total body clearance (CL/F) 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. | Days 1, 4, 6, 8, 10, 12 and 14 (0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post dose) | 
| Minimum Observed Plasma Concentration (Cmin) for PF-06651600 (Multiple Dose) | Minimum Observed Plasma Concentration (Cmin) | Days 1, 4, 6, 8, 10, 12 and 14 (0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post dose) | 
| Average Concentration for Dosing Interval (12 or 24 hours) (Cav) for PF-06651600 (Multiple Dose) | Average Concentration for Dosing Interval (12 or 24 hours) (Cav) | Days 1, 4, 6, 8, 10, 12 and 14 (0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post dose) | 
| Area Under the Curve for Dosing Interval (12 or 24 hours) for PF-06651600 (Multiple Dose) | Area Under the Curve for Dosing Interval (12 or 24 hours) | Days 1, 4, 6, 8, 10, 12 and 14 (0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post dose) | 
| Dose Normalized Area Under the Curve for Dosing Interval (12 or 24 hours) for PF-06651600 (Multiple Dose) | Dose Normalized Area Under the Curve for Dosing Interval (12 or 24 hours) | Days 1, 4, 6, 8, 10, 12 and 14 (0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post dose) | 
| Peak to Trough Fluctuation (PTF) for PF-06651600 (Multiple Dose) | Peak to Trough Fluctuation (PTF) | Days 1, 4, 6, 8, 10, 12 and 14 (0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post dose) | 
| Observed Accumulation Ratio (Rac) for PF-06651600 (Multiple Dose) | Observed Accumulation Ratio (Rac) | Days 1, 4, 6, 8, 10, 12 and 14 (0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post dose) | 
| Observed Accumulation Ratio for Cmax (RacCmax) for PF-06651600 (Multiple Dose) | Observed Accumulation Ratio for Cmax (RacCmax) | Days 1, 4, 6, 8, 10, 12 and 14 (0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post dose) | 
| Steady State Accumulation Ratio (Rss) for PF-06651600 (Multiple Dose) | Steady State Accumulation Ratio (Rss) | Days 1, 4, 6, 8, 10, 12 and 14 (0, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post dose) | 
| Amount of PF-066561600 Excreted Unchanged (Multiple Dose) | Concentration in urine. | Day 14 (12, 24 hours post dose) | 
| Change from baseline of BCL2 gene expression in whole blood (Single Dose) |  | Days -1 and 1 (0, 1, 2, 4, 8, 12 and 24 hours post dose) | 
| Change from baseline of BCL2 gene expression in whole blood (Multiple Dose) |  | Days 1, 5, 10, 14 (0, 1, 2, 4, 8, 12 and 24 hours post dose), 16, and 28 | 
| Change from baseline of IP-10 protein concentration in serum (Multiple Dose) |  | Days 0, 2, 7, 14 (0, and 16 hours post dose) and 16 | 
| Change from baseline of hsCRP protein concentration in serum (Multiple Dose) |  | Days 0, 2, 7, 14 (0, and 16 hours post dose) and 16 | 
| Change from baseline of reticulocyte counts in whole blood (Single Dose) |  | Days 0, 2, 3, and 7 | 
| Change from baseline of neutrophil counts in whole blood (Single Dose) |  | Days 0, 2, 3, and 7 | 
| Change from baseline of hemoglobin level whole blood (Single Dose) |  | Days 0, 2, 3, and 7 | 
| Change from baseline of reticulocyte counts in whole blood (Multiple Dose) |  | Days 0, 4, 8, 12, 14 (pre-dose) 15, and 28 | 
| Change from baseline of neutrophil counts in whole blood (Multiple Dose) |  | Days 0, 4, 8, 12, 14 (pre-dose) 15, and 28 | 
| Change from baseline of hemoglobin level in whole blood (Multiple Dose) |  | Days 0, 4, 8, 12, 14 (pre-dose) 15, and 28 | 
| Renal Clearance (Multiple Dose) |  | Day 1, Day 14 (12, 24 hours post dose) | 
| Percentage of PF-066561600 Excreted Unchanged (Multiple Dose) | Concentration in urine. | Day 14 (12, 24 hours post dose) | 
| Change from baseline of IP-10 gene expression in blood (Multiple Dose) |  | Days 0, 5, 10, 14 (0, 1, 2, 4, 8 and 12 hours post dose) and 16 | 
| Change from baseline of IP-10 gene expression in blood (Single Dose) |  | Days 0, 1 (0, 1, 2, 4, 8 and 12 hours post dose) and 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inflammatory bowel disease