Healthy Volunteers
Conditions
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.
Interventions
DRUGitraconazole
itraconazole dosed at 200 mg
DRUGdiltiazem
diltiazem dosed at 240 mg
DRUGSR verapamil
SR verapamil dosed at 240 mg
DRUGPF-00489791
PF-00489791 20 mg single dose administration
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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 | — |
Countries
Belgium
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PF-00489791 20 mg + Itraconazole 200 mg All participants who received itraconazole 200 mg orally once daily for 7 days and a single-dose of PF-00489791 20 mg on Day 5 during Period 2. | 7 |
| PF-00489791 20 mg + Diltiazem 240 mg All participants who received diltiazem 240 mg MR tablet orally once daily for 13 days and a single-dose of PF-00489791 20mg on Day 11 during Period 2 | 7 |
| PF-00489791 20 mg + Verapamil 240 mg All participants who received verapamil 240 mg SR tablet orally once daily for 13 days and a single-dose of PF-00489791 20 mg on Day 11 during Period 2. | 8 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Second Intervention Period | Adverse event (AE) related to study drug | 0 | 0 | 1 | 1 |
| Second Intervention Period | No longer willing to participate | 0 | 1 | 0 | 0 |
| Second Intervention Period | Other | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | PF-00489791 20 mg + Itraconazole 200 mg | PF-00489791 20 mg + Diltiazem 240 mg | PF-00489791 20 mg + Verapamil 240 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 38.1 years STANDARD_DEVIATION 6.1 | 33.4 years STANDARD_DEVIATION 9.9 | 35.1 years STANDARD_DEVIATION 10.1 | 35.5 years STANDARD_DEVIATION 8.7 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 8 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 22 | 6 / 7 | 4 / 7 | 3 / 8 | 6 / 6 | 4 / 6 | 5 / 6 |
| serious Total, serious adverse events | 0 / 22 | 0 / 7 | 0 / 7 | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of PF-00489791
AUC is a measure of the plasma concentration of the drug over time. It is used to characterize drug absorption.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 12 hours after PF-00489791 administration
Population: The PK analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-00489791 20 mg | Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of PF-00489791 | 17880 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 36 |
| PF-00489791 20 mg + Itraconazole 200 mg | Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of PF-00489791 | 18140 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 24 |
| PF-00489791 20 mg + Diltiazem 240 mg | Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of PF-00489791 | 16840 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 20 |
| PF-00489791 20 mg + Verapamil 240 mg | Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of PF-00489791 | 19560 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 30 |
90% CI: [78.57, 103.46]Mixed Models Analysis
90% CI: [92.7, 122.07]Mixed Models Analysis
90% CI: [88.68, 116.66]Mixed Models Analysis
Primary
Maximum Observed Plasma Concentration (Cmax) of PF-00489791
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 12 hours after PF-00489791 administration
Population: The pharmacokinetic (PK) analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-00489791 20 mg | Maximum Observed Plasma Concentration (Cmax) of PF-00489791 | 1140 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 34 |
| PF-00489791 20 mg + Itraconazole 200 mg | Maximum Observed Plasma Concentration (Cmax) of PF-00489791 | 1238 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 33 |
| PF-00489791 20 mg + Diltiazem 240 mg | Maximum Observed Plasma Concentration (Cmax) of PF-00489791 | 1198 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 33 |
| PF-00489791 20 mg + Verapamil 240 mg | Maximum Observed Plasma Concentration (Cmax) of PF-00489791 | 1186 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 21 |
90% CI: [92.11, 120.34]Mixed Models Analysis
90% CI: [80.96, 105.77]Mixed Models Analysis
90% CI: [101.86, 132.92]Mixed Models Analysis
Secondary
Apparent Oral Clearance (CL/F) of PF-00489791
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.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 12 hours after PF-00489791 administration
Population: The PK analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-00489791 20 mg | Apparent Oral Clearance (CL/F) of PF-00489791 | 18.64 milliliter per minute (mL/min) | Geometric Coefficient of Variation 36 |
| PF-00489791 20 mg + Itraconazole 200 mg | Apparent Oral Clearance (CL/F) of PF-00489791 | 18.37 milliliter per minute (mL/min) | Geometric Coefficient of Variation 24 |
| PF-00489791 20 mg + Diltiazem 240 mg | Apparent Oral Clearance (CL/F) of PF-00489791 | 19.81 milliliter per minute (mL/min) | Geometric Coefficient of Variation 20 |
| PF-00489791 20 mg + Verapamil 240 mg | Apparent Oral Clearance (CL/F) of PF-00489791 | 17.02 milliliter per minute (mL/min) | Geometric Coefficient of Variation 30 |
Secondary
Apparent Volume of Distribution (Vz/F) of PF-00489791
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.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 12 hours after PF-00489791 administration
Population: The PK analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-00489791 20 mg | Apparent Volume of Distribution (Vz/F) of PF-00489791 | 18.06 liter | Geometric Coefficient of Variation 34 |
| PF-00489791 20 mg + Itraconazole 200 mg | Apparent Volume of Distribution (Vz/F) of PF-00489791 | 21.65 liter | Geometric Coefficient of Variation 18 |
| PF-00489791 20 mg + Diltiazem 240 mg | Apparent Volume of Distribution (Vz/F) of PF-00489791 | 19.98 liter | Geometric Coefficient of Variation 31 |
| PF-00489791 20 mg + Verapamil 240 mg | Apparent Volume of Distribution (Vz/F) of PF-00489791 | 19.23 liter | Geometric Coefficient of Variation 23 |
Secondary
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-00489791
Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 12 hours after PF-00489791 administration
Population: The PK analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-00489791 20 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-00489791 | 17580 ng.hr/mL | Geometric Coefficient of Variation 36 |
| PF-00489791 20 mg + Itraconazole 200 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-00489791 | 17980 ng.hr/mL | Geometric Coefficient of Variation 24 |
| PF-00489791 20 mg + Diltiazem 240 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-00489791 | 16760 ng.hr/mL | Geometric Coefficient of Variation 20 |
| PF-00489791 20 mg + Verapamil 240 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-00489791 | 19400 ng.hr/mL | Geometric Coefficient of Variation 30 |
90% CI: [79.49, 104.94]Mixed Models Analysis
90% CI: [93.1, 122.91]Mixed Models Analysis
90% CI: [89.42, 117.93]Mixed Models Analysis
Secondary
Number of Participants Who Used at Least 1 Concomitant Medication
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.
Time frame: Baseline up to Day 15 (final study evaluation)
Population: The safety analysis population included all participants who received the study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-00489791 20 mg | Number of Participants Who Used at Least 1 Concomitant Medication | Drug Treatments | 10 participants |
| PF-00489791 20 mg | Number of Participants Who Used at Least 1 Concomitant Medication | Non-Drug Treatments | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants Who Used at Least 1 Concomitant Medication | Non-Drug Treatments | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants Who Used at Least 1 Concomitant Medication | Drug Treatments | 2 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants Who Used at Least 1 Concomitant Medication | Drug Treatments | 4 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants Who Used at Least 1 Concomitant Medication | Non-Drug Treatments | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants Who Used at Least 1 Concomitant Medication | Drug Treatments | 2 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants Who Used at Least 1 Concomitant Medication | Non-Drug Treatments | 0 participants |
Secondary
Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern
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).
Time frame: Baseline up to 28 days after last study drug administration
Population: The safety analysis population included all participants who received the study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-00489791 20 mg | Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern | 3 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern | 2 participants |
Secondary
Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings
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.
Time frame: Pre-dose (Periods 1 and 2), 4, 72 and 96 hours post-dose in Period 2
Population: The safety analysis population included all participants who received the study medication; n=number of participants evaluated against criteria.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 450-<480 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval >=60 msec IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval >=500 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 480-<500 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 30-<60 msec IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS Complex >=140 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval >=300 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS Interval >=50% IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval >=25/50% IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval >=25/50% IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval >=300 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS Complex >=140 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 450-<480 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 480-<500 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval >=500 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS Interval >=50% IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 30-<60 msec IFB (n=22,6,6,7) | 1 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval >=60 msec IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval >=300 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval >=500 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval >=25/50% IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS Complex >=140 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS Interval >=50% IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval >=60 msec IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 30-<60 msec IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 480-<500 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 450-<480 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS Interval >=50% IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval >=300 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval >=500 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS Complex >=140 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 30-<60 msec IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval >=25/50% IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 480-<500 msec (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval >=60 msec IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 450-<480 msec (n=22,7,7,8) | 0 participants |
Secondary
Number of Participants With Potentially Clinically Significant Vital Signs Findings
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 frame: Baseline up to Day 9
Population: The safety analysis population included all participants who received the study medication; n=number of participants evaluated against criteria.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP >=30 mm Hg IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing DBP <50 mm Hg (n=22,7,6,8) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP >=20 mm Hg DFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing Pulse Rate <40 or >120 bpm (n=22,7,6,8) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine Pulse Rate <40 or >120 bpm (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP >=30 mm Hg DFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing DBP >=20 mm Hg IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing SBP <90 mm Hg (n=22,7,6,8) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing DBP >=20 mm Hg DFB (n=22,6,6,7) | 1 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP >=20 mm Hg IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing SBP >=30 mm Hg IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP <50 mm Hg (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP <90 mm Hg (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing SBP >=30 mm Hg DFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP >=30 mm Hg IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP <90 mm Hg (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing SBP <90 mm Hg (n=22,7,6,8) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP <50 mm Hg (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing DBP <50 mm Hg (n=22,7,6,8) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine Pulse Rate <40 or >120 bpm (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing Pulse Rate <40 or >120 bpm (n=22,7,6,8) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing SBP >=30 mm Hg IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP >=20 mm Hg IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing DBP >=20 mm Hg IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP >=30 mm Hg DFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing SBP >=30 mm Hg DFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP >=20 mm Hg DFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing DBP >=20 mm Hg DFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing SBP <90 mm Hg (n=22,7,6,8) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP <90 mm Hg (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing DBP >=20 mm Hg DFB (n=22,6,6,7) | 1 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP >=30 mm Hg DFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP >=20 mm Hg IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing SBP >=30 mm Hg IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP >=30 mm Hg IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine Pulse Rate <40 or >120 bpm (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP >=20 mm Hg DFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing DBP <50 mm Hg (n=22,7,6,8) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing SBP >=30 mm Hg DFB (n=22,6,6,7) | 1 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing Pulse Rate <40 or >120 bpm (n=22,7,6,8) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing DBP >=20 mm Hg IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP <50 mm Hg (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP <50 mm Hg (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP >=30 mm Hg IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing SBP <90 mm Hg (n=22,7,6,8) | 1 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing SBP >=30 mm Hg DFB (n=22,6,6,7) | 1 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing SBP >=30 mm Hg IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP >=20 mm Hg IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP <90 mm Hg (n=22,7,7,8) | 1 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing DBP >=20 mm Hg IFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP >=20 mm Hg DFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP >=30 mm Hg DFB (n=22,6,6,7) | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing DBP <50 mm Hg (n=22,7,6,8) | 1 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing DBP >=20 mm Hg DFB (n=22,6,6,7) | 1 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine Pulse Rate <40 or >120 bpm (n=22,7,7,8) | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Standing Pulse Rate <40 or >120 bpm (n=22,7,6,8) | 0 participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
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.
Time frame: Baseline up to 28 days after last study drug administration
Population: The safety analysis population included all participants who received the study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-00489791 20 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 18 participants |
| PF-00489791 20 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 6 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 4 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 3 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 0 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 6 participants |
| PF-00489791 20 mg + Itraconazole 200 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 0 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 4 participants |
| PF-00489791 20 mg + Diltiazem 240 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 0 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 5 participants |
| PF-00489791 20 mg + Verapamil 240 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 0 participants |
Secondary
Terminal Elimination Half-Life (t1/2) of PF-00489791
t1/2 is the time measured for the plasma concentration to decrease by one half.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 12 hours after PF-00489791 administration
Population: The PK analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PF-00489791 20 mg | Terminal Elimination Half-Life (t1/2) of PF-00489791 | 11.39 hour | Standard Deviation 2.15 |
| PF-00489791 20 mg + Itraconazole 200 mg | Terminal Elimination Half-Life (t1/2) of PF-00489791 | 13.85 hour | Standard Deviation 2.79 |
| PF-00489791 20 mg + Diltiazem 240 mg | Terminal Elimination Half-Life (t1/2) of PF-00489791 | 11.75 hour | Standard Deviation 1.69 |
| PF-00489791 20 mg + Verapamil 240 mg | Terminal Elimination Half-Life (t1/2) of PF-00489791 | 13.29 hour | Standard Deviation 2.56 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-00489791
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 12 hours after PF-00489791 administration
Population: The PK analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PF-00489791 20 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-00489791 | 4.00 hour |
| PF-00489791 20 mg + Itraconazole 200 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-00489791 | 3.50 hour |
| PF-00489791 20 mg + Diltiazem 240 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-00489791 | 4.00 hour |
| PF-00489791 20 mg + Verapamil 240 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-00489791 | 4.00 hour |