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

Phase 1WithdrawnNCT01981486

Pfizer

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Conditions

Migraine

Interventions

Placebo TabletsDRUG

BID modified-release tablets

PF-05180999 TabletsDRUG

BID modified-release tablets (20 to 240 mg BID)

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

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).

Outcomes

Primary Outcomes

Maximum Observed Plasma Concentration (Cmax)

Single dose Cmax

Time frame: 0-12 hours post-dose on Day 1

Time to Reach Maximum Observed Plasma Concentration (Tmax)

Single dose Tmax

Time frame: 0-12 hours post-dose on Day 1

Area Under the Curve from Time Zero to end of dosing interval (AUCtau)

Single dose AUCtau

Time frame: 0-12 hours post-dose on Day 1

Maximum Observed Plasma Concentration at Steady-State (Cmax,ss)

Steady-state Cmax

Time frame: 0-12 hours post-dose on Day 14

Time to Reach Maximum Observed Plasma Concentration at Steady-State (Tmax,ss)

Steady-state Tmax

Time frame: 0-12 hours post-dose on Day 14

Minimum Observed Plasma Trough Concentration at Steady-State (Cmin,ss)

Steady-state Cmin

Time frame: 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

Time frame: 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.

Data from ClinicalTrials.gov

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Secondary Outcomes

Identification of metabolites of PF-05180999 in urine and plasma

Metabolite identification

Time frame: 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

Time frame: Day 13 and Day 14

Change from Baseline in Cytokine Levels in Blister Fluid

Cytokine levels in blister fluid

Time frame: 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

Time frame: 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

Time frame: 0-12 hours post-dose on Day 1 and Day 14

Urinary 6beta-hydroxycortisol/cortisol ratio

Urinary marker of CYP3A induction

Time frame: Day 14

Plasma 4beta-hydroxycholesterol/cholesterol ratio

Plasma marker of CYP3A induction

Time frame: Day 14