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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Migraine
• Intervention / Treatment: Drug: Placebo Tablets; Drug: PF-05180999 Tablets

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Anticipated): January 1, 2015
• Study Completion (Anticipated): January 1, 2015

Study Registration Dates

• First Submitted: November 5, 2013
• First Submitted That Met QC Criteria: November 5, 2013
• First Posted (Estimate): November 11, 2013

Study Record Updates

• Last Update Posted (Estimate): May 23, 2014
• Last Update Submitted That Met QC Criteria: May 22, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Keywords: tolerability; safety; pharmacokinetics; migraine; cGMP; PF-05180999; PDE2; cantharidin; blister; cAMP; CYP3A induction
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders
• Other Study ID Numbers: B3441008