A Study Of The Safety, Tolerability, And Pharmacokinetics Of Multiple Doses Of PF-05180999 In Healthy Adults

Study Overview
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Brief Summary
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PF-05180999 is a novel phosphodiesterase-2 (PDE2) inhibitor. The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of multiple doses of PF-05180999 administered twice daily over 14 days. Exploratory measures of PDE2 inhibition will also be evaluated in blood and blister fluid.

Official Title
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A Phase I, Placebo Controlled, Randomized, Subject-And Investigator-Blind, Sponsor-Open, Multiple Ascending Dose Study To Evaluate The Safety, Tolerability, And Pharmacokinetics Of PF-05180999 In Healthy Adult Volunteers

Conditions
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Migraine

Intervention / Treatment
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* Drug: Placebo Tablets
* Drug: PF-05180999 Tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and/or female (of non-childbearing potential) subjects between the ages of 18 and 55 years Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lbs) Exclusion Criteria: Subjects with Gilbert's disease or 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. Subjects with very light skin or very dark skin (at the discretion of the investigator).

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo tablets | Drug: Placebo Tablets<br>* BID modified-release tablets<br>|
| Experimental: PF-05180999<br>Modified-release tablets of PF-05180999 | Drug: PF-05180999 Tablets<br>* BID modified-release tablets (20 to 240 mg BID)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) | Single dose Cmax | 0-12 hours post-dose on Day 1 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | Single dose Tmax | 0-12 hours post-dose on Day 1 | 
| Area Under the Curve from Time Zero to end of dosing interval (AUCtau) | Single dose AUCtau | 0-12 hours post-dose on Day 1 | 
| Maximum Observed Plasma Concentration at Steady-State (Cmax,ss) | Steady-state Cmax | 0-12 hours post-dose on Day 14 | 
| Time to Reach Maximum Observed Plasma Concentration at Steady-State (Tmax,ss) | Steady-state Tmax | 0-12 hours post-dose on Day 14 | 
| Minimum Observed Plasma Trough Concentration at Steady-State (Cmin,ss) | Steady-state Cmin | 0-12 hours post-dose on Day 14 | 
| Area Under the Curve from Time Zero to End of Dosing Interval at Steady-State (AUCtau,ss) | Steady-state AUCtau | 0-12 hours post-dose on Day 14 | 
| 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. | 0-48 hours post-final dose on Day 14 | 
| 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. | 0-48 hours post-final dose on Day 14 | 
| Plasma Decay Half-Life (t1/2) | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | 0-48 hours post-final dose on Day 14 | 
| Accumulation Ratio (Racc) | Ratio of Day 14 AUCtau to Day 1 AUCtau | 0-12 hours post-dose on Days 1 and 14 | 
| Amount Excreted in Urine (Ae) | Amount of drug excreted in urine | 0-12 hours post-dose on Day 14 | 
| Percent of Dose Excreted in Urine (Ae%) | Percent of total dose excreted in urine | 0-12 hours post-dose on Day 14 | 
| Renal Clearance (CLr) | Renal clearance is a quantitative measure of the rate at which a drug substance is removed from the blood via the renal route. | 0-48 hours post-dose on Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identification of metabolites of PF-05180999 in urine and plasma | Metabolite identification | 0-12 hours post-dose on Day 14 | 
| Change from Baseline in Total Leukocyte Levels and Leukocyte Subpopulations in Blister Fluid and Blood | Leukocyte levels in blister fluid and blood | Day 13 and Day 14 | 
| Change from Baseline in Cytokine Levels in Blister Fluid | Cytokine levels in blister fluid | Day 13 and Day 14 | 
| Time-Averaged Area Under the Effect Curve (AUEC/t) for Platelet cGMP and cAMP | Time-averaged area under the effect curve | 0-12 hours post-dose on Day 1 and Day 14 | 
| AUEC/t Ratio | Ratio of Day 14 AUEC/t to Day 1 AUEC/t | 0-12 hours post-dose on Day 1 and Day 14 | 
| Urinary 6beta-hydroxycortisol/cortisol ratio | Urinary marker of CYP3A induction | Day 14 | 
| Plasma 4beta-hydroxycholesterol/cholesterol ratio | Plasma marker of CYP3A induction | Day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PF-05180999, safety, tolerability, pharmacokinetics, migraine, PDE2, cAMP, cGMP, cantharidin, blister, CYP3A induction