A Study of the Safety, Tolerability, Pharmacokinetics, And Effects On Histamine-Induced Wheal Of PF-05180999 In Healthy Adults

Study Overview
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Brief Summary
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PF-05180999 is a phosphodiesterase-2 inhibitor that is hypothesized to be able to reduce vascular permeability. The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and effects on histamine-induced wheal of single doses of PF-05180999 in healthy adult subjects. Histamine-induced wheals are biomarkers of vascular permeability.

Official Title
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A Phase 1, Placebo-Controlled, Crossover, Subject- And Investigator-Blind, Sponsor-Open Study To Evaluate The Safety, Tolerability, Pharmacokinetics, And Effects On Histamine-Induced Wheal Of A Modified-Release Formulation Of PF-05180999 In Healthy Adult Subjects

Conditions
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Migraine

Intervention / Treatment
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* Drug: PF-05180999
* Drug: Placebo
* Drug: 120 mg MR PF-05180999
* Drug: 360 mg MR PF-05180999
* Drug: 10 mg cetirizine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male subjects between the ages of 18 and 55 years No history of clinically-relevant atopic or dermatological disease Positive reaction to intradermal injection of histamine Exclusion Criteria: Subjects with screening laboratory test results that deviate from the upper and/or lower limits of the reference or acceptable range. The exception is that all liver function tests must not exceed the upper limit of normal. Subjects with evidence of, or history of, hepatic disorder, including acute or chronic hepatitis B or hepatitis C Intolerance to intradermal histamine injection. Subjects with dark skin (Part B only).

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

Sexes Eligible for Study
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Male

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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A1<br>Part A of study to assess safety, tolerability, and pharmacokinetics of PF-05180999 | Drug: PF-05180999<br>* Ascending single oral doses of 120, 240, and 420 mg modified-release tablets<br>|
| Placebo Comparator: Arm A2<br>Part A of study to assess safety, tolerability, and pharmacokinetics of PF-05180999 relative to placebo | Drug: Placebo<br>* Placebo tablets<br>|
| Experimental: Arm B1<br>Part B of study to assess effects of PF-05180999 on histamine-induced wheal | Drug: 120 mg MR PF-05180999<br>* Single 120 mg dose administered as modified release formulation<br>|
| Experimental: Arm B2<br>Part B of study to assess effects of PF-05180999 on histamine-induced wheal | Drug: 360 mg MR PF-05180999<br>* Single 360 mg dose administered as modified release formulation<br>|
| Experimental: Arm B3<br>Positive control to ensure histamine-induced wheal assay integrity | Drug: 10 mg cetirizine<br>* Single 10 mg dose of cetirizine<br>|
| Experimental: Arm B4<br>Placebo control | Drug: Placebo<br>* Placebo tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) | Maximum observed plasma concentration | 0-72 hours post-dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | Time when Cmax occurred | 0-72 hours post-dose | 
| Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) | Measure of drug absorption and drug exposure | 0-72 hours post-dose | 
| Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) | Measure of drug absorption and drug exposure | 0-infinity hours post-dose | 
| Plasma Half-Life (t1/2) | Time for the plasma concentration to decrease by one-half. | 0-72 hours post-dose | 
| Area Under the Effect Curve (AUEC) for Histamine-Induced Wheal | Measure of drug effect | 2-12 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-response, exposure-response, and maximum response for PF-05180999 against histamine-induced wheal | Measures of drug effect | 0-72 hours post-dose | 
| Area Under the Effect Curve (AUEC) for histamine-induced flare; Dose-response, exposure-response, and maximum response for PF-05180999 against histamine-induced flare | Measures of drug effect | 0-72 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PF-05180999, safety, tolerability, pharmacokinetics, histamine, wheal, flare, migraine, PDE2