Migraine
Conditions
Keywords
PF-05180999, safety, tolerability, pharmacokinetics, migraine, PDE2, cAMP, cGMP, cantharidin, blister, CYP3A induction
Brief summary
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.
Interventions
DRUGPlacebo Tablets
BID modified-release tablets
DRUGPF-05180999 Tablets
BID modified-release tablets (20 to 240 mg BID)
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Renal Clearance (CLr) | 0-48 hours post-dose on Day 14 | Renal clearance is a quantitative measure of the rate at which a drug substance is removed from the blood via the renal route. |
| Minimum Observed Plasma Trough Concentration at Steady-State (Cmin,ss) | 0-12 hours post-dose on Day 14 | Steady-state Cmin |
| Area Under the Curve from Time Zero to End of Dosing Interval at Steady-State (AUCtau,ss) | 0-12 hours post-dose on Day 14 | Steady-state AUCtau |
| Apparent Oral Clearance (CL/F) | 0-48 hours post-final dose on Day 14 | 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. |
| Apparent Volume of Distribution (Vz/F) | 0-48 hours post-final dose on Day 14 | 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. |
| Accumulation Ratio (Racc) | 0-12 hours post-dose on Days 1 and 14 | Ratio of Day 14 AUCtau to Day 1 AUCtau |
| Amount Excreted in Urine (Ae) | 0-12 hours post-dose on Day 14 | Amount of drug excreted in urine |
| Percent of Dose Excreted in Urine (Ae%) | 0-12 hours post-dose on Day 14 | Percent of total dose excreted in urine |
| Plasma Decay Half-Life (t1/2) | 0-48 hours post-final dose on Day 14 | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. |
| Maximum Observed Plasma Concentration (Cmax) | 0-12 hours post-dose on Day 1 | Single dose Cmax |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | 0-12 hours post-dose on Day 1 | Single dose Tmax |
| Area Under the Curve from Time Zero to end of dosing interval (AUCtau) | 0-12 hours post-dose on Day 1 | Single dose AUCtau |
| Maximum Observed Plasma Concentration at Steady-State (Cmax,ss) | 0-12 hours post-dose on Day 14 | Steady-state Cmax |
| Time to Reach Maximum Observed Plasma Concentration at Steady-State (Tmax,ss) | 0-12 hours post-dose on Day 14 | Steady-state Tmax |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from Baseline in Total Leukocyte Levels and Leukocyte Subpopulations in Blister Fluid and Blood | Day 13 and Day 14 | Leukocyte levels in blister fluid and blood |
| Change from Baseline in Cytokine Levels in Blister Fluid | Day 13 and Day 14 | Cytokine levels in blister fluid |
| Time-Averaged Area Under the Effect Curve (AUEC/t) for Platelet cGMP and cAMP | 0-12 hours post-dose on Day 1 and Day 14 | Time-averaged area under the effect curve |
| AUEC/t Ratio | 0-12 hours post-dose on Day 1 and Day 14 | Ratio of Day 14 AUEC/t to Day 1 AUEC/t |
| Urinary 6beta-hydroxycortisol/cortisol ratio | Day 14 | Urinary marker of CYP3A induction |
| Plasma 4beta-hydroxycholesterol/cholesterol ratio | Day 14 | Plasma marker of CYP3A induction |
| Identification of metabolites of PF-05180999 in urine and plasma | 0-12 hours post-dose on Day 14 | Metabolite identification |
Outcome results
None listed