A Study to Estimate the Effect of CYP3A4 Inhibitors (Itraconazole, Diltiazem or Verapamil) on the Pharmacokinetics of Single Dose PF- 00489791 in Healthy Volunteers

Phase 1

Completed

Conditions: Healthy Volunteers

Interventions: Drug: itraconazole
Drug: SR verapamil
Drug: diltiazem
Drug: PF-00489791

Registration Number: NCT02319148

Lead Sponsor: Pfizer

Brief Summary: The primary objective of the study is to estimate the effects of different strong enzyme (CYP3A4) inhibitors, itraconazole, diltiazem, or verapamil on the single dose pharmacokinetics of PF-00489791 in healthy volunteers. The study will enroll approximately 18 subjects that are randomized to 1 of 3 treatment groups. The study is also intended to determine the safety and tolerability of single-dose PF- 00489791 when it is administered with steady-state itraconazole, diltiazem, or verapamil.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 22

Inclusion Criteria

Healthy male and/or female subjects between the ages of 18 and 55 years, inclusive (healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead ECG and clinical laboratory tests) with a Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lbs.) and with a personally signed and dated informed consent document and who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
Participating female subjects of non-childbearing potential must meet at least one of the following criteria: achieved postmenopausal status; have undergone a documented hysterectomy and/or bilateral oophorectomy; have medically confirmed ovarian failure. All other female subjects (including females with tubal ligations and females that do NOT have a documented hysterectomy, bilateral oophorectomy and/or ovarian failure) will be considered to be of childbearing potential.

Exclusion Criteria

Subjects cannot be included in the study if there is: the presence/ history of any disorder that prevents study completion
Evidence/history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease
Any surgical or medical condition that may interfere with the absorption distribution, metabolism, or excretion of the study drug
A positive urine drug screen or history of regular excessive alcohol consumption or use of tobacco-or nicotine-containing products in excess or from 24-hours prior to admission until discharge
Treatment with an investigational drug within 30 days (or as determined by the local requirement) or 5 halflives preceding the first dose of study med.
Out of range blood pressure including current evidence of orthostatic change in blood pressure
Abnormal ECG or history or current evidence of clinically important cardiac conduction abnormalities.
Also excluded are: pregnant or breastfeeding female subjects; male subjects with partners currently pregnant; male and female subjects of childbearing potential who are unwilling or unable to use a highly effective method of contraception as described in the protocol for the duration of the study and for at least 28 days after the last dose of investigational product.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Treatment C	PF-00489791	Treatment C subjects receive single dose administration of 20 mg PF-00489791 and multiple dose administration of diltiazem (240 mg once daily).
Treatment B	itraconazole	Treatment B subjects receive single dose administration of 20 mg PF-00489791 and multiple dose administration of itraconazole (200 mg once daily).
Treatment D	SR verapamil	Treatment D subjects receive single dose administration of 20 mg PF-00489791 and multiple dose administration of verapamil (240 mg once daily).
Treatment C	diltiazem	Treatment C subjects receive single dose administration of 20 mg PF-00489791 and multiple dose administration of diltiazem (240 mg once daily).
Treatment B	PF-00489791	Treatment B subjects receive single dose administration of 20 mg PF-00489791 and multiple dose administration of itraconazole (200 mg once daily).
Treatment D	PF-00489791	Treatment D subjects receive single dose administration of 20 mg PF-00489791 and multiple dose administration of verapamil (240 mg once daily).

Primary Outcome Measures

Name	Time	Method
Maximum Observed Plasma Concentration (Cmax) of PF-00489791	Pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 12 hours after PF-00489791 administration
Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of PF-00489791	Pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 12 hours after PF-00489791 administration	AUC is a measure of the plasma concentration of the drug over time. It is used to characterize drug absorption.

Secondary Outcome Measures

Name	Time	Method
Apparent Oral Clearance (CL/F) of PF-00489791	Pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 12 hours after PF-00489791 administration	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.
Terminal Elimination Half-Life (t1/2) of PF-00489791	Pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 12 hours after PF-00489791 administration	t1/2 is the time measured for the plasma concentration to decrease by one half.
Apparent Volume of Distribution (Vz/F) of PF-00489791	Pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 12 hours after PF-00489791 administration	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.
Number of Participants With Potentially Clinically Significant Vital Signs Findings	Baseline up to Day 9	Vital signs assessment included pulse rate and blood pressure. Criteria for vital sign values meeting potential clinical concern included: supine/sitting pulse rate \<40 or \>120 beats per minute (bpm), standing pulse rate \<40 or \>140 bpm; systolic blood pressure (SBP) of \>=30 millimeters of mercury (mm Hg) change from baseline in same posture or SBP \<90 mm Hg, diastolic blood pressure (DBP) \>=20 mmHg change from baseline in same posture or DBP \<50 mm Hg.
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-00489791	Pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 12 hours after PF-00489791 administration
Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern	Baseline up to 28 days after last study drug administration	The following laboratory parameters were analyzed: hematology (hemoglobin, hematocrit, red blood cell \[RBC\] count, RBC morphology, platelet count, white blood cell \[WBC\] count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (blood urea nitrogen \[BUN\], creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], total bilirubin, alkaline phosphatase, uric acid, albumin, and total protein; urinalysis (pH, glucose, protein, blood, ketones, nitrites, leukocyte esterase, microscopy \[if urine dipstick was positive for blood, protein, nitrites or leukocyte esterase\]); others (coagulation panel, circulating immune complex, and complement activation).
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-00489791	Pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 12 hours after PF-00489791 administration	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).
Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings	Pre-dose (Periods 1 and 2), 4, 72 and 96 hours post-dose in Period 2	ECG parameters included PR interval, QRS interval, and corrected QT interval using Fridericia's formula (QTcF). Criteria for ECG changes meeting potential clinical concern included: PR interval greater than or equal to (\>=)300 milliseconds (msec) or \>=25% increase when baseline is greater than (\>)200 msec and \>=50% increase when baseline is less than or equal to (≤)200 msec; QRS interval \>=140 msec or \>=50% increase from baseline (IFB); and QTcF \>=450 msec or \>=30 msec increase. The number of participants with potentially clinically significant ECG findings at any visit were reported.
Number of Participants Who Used at Least 1 Concomitant Medication	Baseline up to Day 15 (final study evaluation)	Participants were to abstain from all concomitant treatments, except for the treatment of AEs. Treatments taken after the first dose of study treatment were documented as concomitant treatments.
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)	Baseline up to 28 days after last study drug administration	An AE was any untoward medical occurrence in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. AEs included both SAEs and non-SAEs.