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CompletedNCT03309202Updated Aug 8, 2019Results posted

Study of PF-05221304 in Subjects With Varying Degrees of Hepatic Impairment

A Phase 1 interventional study of PF-05221304 in Hepatic Impairment, sponsored by Pfizer. Completed at 6 sites in 4 countries. Open to participants aged 18 Years to 70 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2019-08-08.

Sponsored by Pfizer · Phase 1, Interventional, and Basic science

Phase
Phase 1
Study type
Interventional
Enrollment
24
Allocation
Non-randomized
Ages
18 Years to 70 Years
Sex
All
01

Study summary

Hepatic impairment PK study

Read the detailed description

This is a non randomized, open label, single dose, parallel cohort, multisite study to investigate the effect of varying degrees of hepatic impairment on the plasma pharmacokinetics (total and unbound) of PF-05221304 after a single oral dose administered in the fed state.

02

Conditions studied

  • Hepatic Impairment

Browse trials for

03

Who can participate

Ages eligible
18 Years to 70 Years
Sexes eligible
All
Accepts healthy volunteers
Yes

Eligibility criteria

Key Exclusion Criteria:

All subjects -

  • Adults \<18 years of age and >70 years of age
  • BMI \< 17.5 and > 35.4 kg/m2
  • HIV positive
  • Conditions that affect drug absorption
  • Positive breath alcohol test

Healthy/ those without hepatic impairment -

  • Known or suspected hepatic impairment
  • Evidence of Hepatitis B or C
  • On any chronic medications

Those with varying degrees of hepatic impairment -

  • Not meeting Classification A, B, or C of hepatic impairment based on Child-Pugh Classification
  • Evidence of Hepatic carcinoma or hepatorenal syndrome or limited predicted life expectancy
  • Recent GI bleed
  • Moderate or severe renal impairment
  • Hepatic encephalopathy Grade 3 or higher
04

Study design

Phase
Phase 1
Primary purpose
Basic science
Allocation
Non-randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
24 participants (actual)

Study arms

  • Experimental
    Cohort 1_Without impairment

    Single, 25 mg dose of PF-05221304

    Drug: PF-05221304

  • Experimental
    Cohort 2_Mild impairment

    Single, 25 mg dose of PF-05221304

    Drug: PF-05221304

  • Experimental
    Cohort 3_Moderate impairment

    Single, 25 mg dose of PF-05221304

    Drug: PF-05221304

  • Experimental
    Cohort 4_Severe impairment

    Single, 25 mg dose of PF-05221304

    Drug: PF-05221304

Interventions

  • DrugPF-05221304

    25 mg dose

    Also known as: experimental drug

05

What researchers measure

Primary outcomes

  1. Maximum Plasma Concentration (Cmax) of PF-05221304

    Cmax was observed directly from data.

    Time frame: 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose

  2. Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-05221304

    AUCinf was calculated by AUClast + (Clast\*/kel), where AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

    Time frame: 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose

  3. Fraction Unbound (fu) of PF-05221304

    fu was the fraction of PF-05221304 unbound in plasma. fu was calculated based on the post-dialysis plasma concentrations, post-dialysis buffer concentrations, collected post-dialysis plasma and post-dialysis buffer sample volume (assuming no volume shift prior to and after dialysis), and the total plasma concentrations.

    Time frame: 4 hours postdose

  4. Unbound Cmax (Cmax,u) of PF-05221304

    Cmax,u was calculated by fu\*Cmax.

    Time frame: 4 hours postdose

  5. Unbound AUCinf (AUCinf,u) of PF-05221304

    AUCinf,u was calculated by fu\*AUCinf.

    Time frame: 4 hours postdose

Secondary outcomes

  1. Time to Reach Maximum Plasma Concentration (Tmax) of PF-05221304

    Tmax was observed directly from data as time of first occurrence.

    Time frame: 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose

  2. Area Under Concentration Time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) of PF-05221304

    AUClast was calculated by linear/Log trapezoidal method.

    Time frame: 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose

  3. Unbound AUClast ( AUClast,u) of PF-05221304

    AUClast,u was calculated by fu\*AUClast.

    Time frame: 4 hours postdose

  4. Apparent Clearance After Oral Dose (CL/F) of PF-05221304

    CL/F was calculated by Dose/AUCinf.

    Time frame: 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose

  5. Unbound CL/F (CLu/F) of PF-05221304

    CLu/F was calculated by fu\*CL/F.

    Time frame: 4 hours postdose

  6. Apparent Volume of Distribution After Oral Dose (Vz/F) of PF-05221304

    Vz/F was calculated by Dose/(AUCinf\*kel). kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

    Time frame: 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose

  7. Unbound Vz/F (Vz,u/F) of PF-05221304

    Vz,u/F was calculated by fu\*Vz/F.

    Time frame: 4 hours postdose

  8. Terminal Half-Life ( t½) of PF-05221304

    t1/2 was calculated by loge(2)/kel.

    Time frame: 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose

  9. Number of Participants With Treatment-emergent Adverse Events (TEAEs)

    An adverse event (AE) was any untoward medical occurrence in a study participant administered a product or medical device; the event did not need to have a causal relationship with the treatment or usage. A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and AEs. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Number of participants with both all-causality and treatment-related TEAEs are presented below.

    Time frame: Approximately 30 days

  10. Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)-Hematology

    Hematology evaluation included: hemoglobin, hematocrit, erythrocytes, reticulocytes, erythrocyte mean corpuscular volume, erythrocyte mean corpuscular hemoglobin concentration (MCHC), erythrocyte mean corpuscular hemoglobin, platelets, leukocytes, lymphocytes, neutrophils, basophils, eosinophils, monocytes, activated partial thromboplastin time and prothrombin time.

    Time frame: 7 days

  11. Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)-Clinical Chemistry

    Clinical chemistry evaluation included: bilirubin, direct/indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase , alkaline phosphatase, protein, albumin, blood urea nitrogen, creatinine, urate, sodium, potassium, chloride, calcium, phosphate, bicarbonate, creatine kinase, and fasting glucose.

    Time frame: 7 days

  12. Number of Paticipants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)-Urinalysis

    Urinalysis evaluation included: scalar urine glucose, scalar ketones, scalar urine protein, scalar urine hemoglobin, scalar urobilinogen, scalar urine bilirubin, scalar nitrite, scalar leukocyte esterase, urine erythrocytes, urine leukocytes, hyaline casts, and scalar bacteria.

    Time frame: 7 days

  13. Number of Participants With Clinical Significant Findings in Vital Signs

    Vital signs evaluation included: sitting systolic and diastolic blood pressure (BP), and sitting pulse rate. Clinically significant findings in vital signs were determined by the investigator.

    Time frame: 7 days

  14. Number of Participants With Clinically Significant Findings in Electrocardiogram (ECG) Data

    ECG evaluation included: PR interval, time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization (QRS interval), time between the start of the Q wave and the end of the T wave in the heart's electrical cycle (QT interval), QT interval corrected for heart rate using Fridericia's formula (QTcF interval), and heart rate. Clinically significant findings in ECG data were determined by the investigator.

    Time frame: 7 days

06

Results

Posted Aug 8, 2019

Participant flow

Recruitment for participants in Cohorts 3 and 4 initiated first and recruitment for participants in Cohort 2 started when approximately 50% of total participants across Cohorts 3 and 4 had been dosed. Participants in Cohort 1 were recruited last to match the average demographics across the pooled Cohorts 2 through 4.

Participant flow — Overall Study
MilestoneCohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Started6666
Completed5666
Not completed1000
Withdrew: Lost to follow-up1000

Outcome measures

PrimaryMaximum Plasma Concentration (Cmax) of PF-05221304

Cmax was observed directly from data.

Time frame:
0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose
Reported as:
Geometric mean · Nanogram per milliliter (ng/mL)
Maximum Plasma Concentration (Cmax) of PF-05221304
Nanogram per milliliter (ng/mL)Cohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Maximum Plasma Concentration (Cmax) of PF-052213041220 ± 201591 ± 331433 ± 201592 ± 27
Statistical analysis
  • Cohort 1 (Without Hepatic Impairment) vs Cohort 2 (Mild Hepatic Impairment) · ANOVA · Mean difference (final values): 130.47 · 90% CI 101.57 to 167.60Estimate mean difference was derived from ratio (%) of adjusted geometric means of Test and Reference.Cohort 2 (Mild Hepatic Impairment) was Test and Cohort 1 (Without Hepatic Impairment) was Reference.
  • Cohort 1 (Without Hepatic Impairment) vs Cohort 3 (Moderate Hepatic Impairment) · ANOVA · Mean difference (final values): 117.49 · 90% CI 91.46 to 150.93Estimate mean difference was derived from ratio (%) of adjusted geometric means of Test and Reference.Cohort 3 (Moderate Hepatic Impairment) was Test and Cohort 1 (Without Hepatic Impairment) was Reference.
  • Cohort 1 (Without Hepatic Impairment) vs Cohort 4 (Severe Hepatic Impairment) · ANOVA · Mean difference (final values): 130.55 · 90% CI 101.63 to 167.70Estimate mean difference was derived from ratio (%) of adjusted geometric means of Test and Reference.Cohort 4 (Severe Hepatic Impairment) was Test and Cohort 1 (Without Hepatic Impairment) was Reference.
PrimaryArea Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-05221304

AUCinf was calculated by AUClast + (Clast\*/kel), where AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

Time frame:
0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose
Reported as:
Geometric mean · Nanogram*hour per milliliter (ng*hr/mL)
Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-05221304
Nanogram*hour per milliliter (ng*hr/mL)Cohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-0522130417520 ± 3623890 ± 4121770 ± 3120790 ± 43
Statistical analysis
  • Cohort 1 (Without Hepatic Impairment) vs Cohort 2 (Mild Hepatic Impairment) · ANOVA · Mean difference (final values): 136.37 · 90% CI 94.63 to 196.53Estimate mean difference was derived from ratio (%) of adjusted geometric means of Test and Reference.Cohort 2 (Mild Hepatic Impairment) was Test and Cohort 1 (Without Hepatic Impairment) was Reference.
  • Cohort 1 (Without Hepatic Impairment) vs Cohort 3 (Moderate Hepatic Impairment) · ANOVA · Mean difference (final values): 124.23 · 90% CI 86.20 to 179.03Estimate mean difference was derived from ratio (%) of adjusted geometric means of Test and Reference.Cohort 3 (Moderate Hepatic Impairment) was Test and Cohort 1 (Without Hepatic Impairment) was Reference.
  • Cohort 1 (Without Hepatic Impairment) vs Cohort 4 (Severe Hepatic Impairment) · ANOVA · Mean difference (final values): 118.65 · 90% CI 82.33 to 170.99Estimate mean difference was derived from ratio (%) of adjusted geometric means of Test and Reference.Cohort 4 (Severe Hepatic Impairment) was Test and Cohort 1 (Without Hepatic Impairment) was Reference.
PrimaryFraction Unbound (fu) of PF-05221304

fu was the fraction of PF-05221304 unbound in plasma. fu was calculated based on the post-dialysis plasma concentrations, post-dialysis buffer concentrations, collected post-dialysis plasma and post-dialysis buffer sample volume (assuming no volume shift prior to and after dialysis), and the total plasma concentrations.

Time frame:
4 hours postdose
Reported as:
Geometric mean · Ratio
Fraction Unbound (fu) of PF-05221304
RatioCohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Fraction Unbound (fu) of PF-052213040.005519 ± 440.006883 ± 550.008117 ± 450.01240 ± 26
Statistical analysis
  • Cohort 1 (Without Hepatic Impairment) vs Cohort 2 (Mild Hepatic Impairment) · ANOVA · Mean difference (final values): 124.7309 · 90% CI 82.5275 to 188.5165Estimate mean difference was derived from ratio (%) of adjusted geometric means of Test and Reference.Cohort 2 (Mild Hepatic Impairment) was Test and Cohort 1 (Without Hepatic Impairment) was Reference.
  • Cohort 1 (Without Hepatic Impairment) vs Cohort 3 (Moderate Hepatic Impairment) · ANOVA · Mean difference (final values): 147.0778 · 90% CI 97.3132 to 222.2911Estimate mean difference was derived from ratio (%) of adjusted geometric means of Test and Reference.Cohort 3 (Moderate Hepatic Impairment) was Test and Cohort 1 (Without Hepatic Impairment) was Reference.
  • Cohort 1 (Without Hepatic Impairment) vs Cohort 4 (Severe Hepatic Impairment) · ANOVA · Mean difference (final values): 224.7373 · 90% CI 148.6962 to 339.6647Estimate mean difference was derived from ratio (%) of adjusted geometric means of Test and Reference.Cohort 4 (Severe Hepatic Impairment) was Test and Cohort 1 (Without Hepatic Impairment) was Reference.
PrimaryUnbound Cmax (Cmax,u) of PF-05221304

Cmax,u was calculated by fu\*Cmax.

Time frame:
4 hours postdose
Reported as:
Geometric mean · ng/mL
Unbound Cmax (Cmax,u) of PF-05221304
ng/mLCohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Unbound Cmax (Cmax,u) of PF-052213046.731 ± 5710.94 ± 4411.63 ± 4819.74 ± 43
Statistical analysis
  • Cohort 1 (Without Hepatic Impairment) vs Cohort 2 (Mild Hepatic Impairment) · ANOVA · Mean difference (final values): 162.58 · 90% CI 103.12 to 256.32Estimate mean difference was derived from ratio (%) of adjusted geometric means of Test and Reference.Cohort 2 (Mild Hepatic Impairment) was Test and Cohort 1 (Without Hepatic Impairment) was Reference.
  • Cohort 1 (Without Hepatic Impairment) vs Cohort 3 (Moderate Hepatic Impairment) · ANOVA · Mean difference (final values): 172.74 · 90% CI 109.56 to 272.35Estimate mean difference was derived from ratio (%) of adjusted geometric means of Test and Reference.Cohort 3 (Moderate Hepatic Impairment) was Test and Cohort 1 (Without Hepatic Impairment) was Reference.
  • Cohort 1 (Without Hepatic Impairment) vs Cohort 4 (Severe Hepatic Impairment) · ANOVA · Mean difference (final values): 293.31 · 90% CI 186.04 to 462.44Estimate mean difference was derived from ratio (%) of adjusted geometric means of Test and Reference.Cohort 4 (Severe Hepatic Impairment) was Test and Cohort 1 (Without Hepatic Impairment) was Reference.
PrimaryUnbound AUCinf (AUCinf,u) of PF-05221304

AUCinf,u was calculated by fu\*AUCinf.

Time frame:
4 hours postdose
Reported as:
Geometric mean · ng*hr/mL
Unbound AUCinf (AUCinf,u) of PF-05221304
ng*hr/mLCohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Unbound AUCinf (AUCinf,u) of PF-0522130496.78 ± 75164.4 ± 34176.6 ± 51257.7 ± 45
Statistical analysis
  • Cohort 1 (Without Hepatic Impairment) vs Cohort 2 (Mild Hepatic Impairment) · ANOVA · Mean difference (final values): 169.84 · 90% CI 104.02 to 277.32Estimate mean difference was derived from ratio (%) of adjusted geometric means of Test and Reference.Cohort 2 (Mild Hepatic Impairment) was Test and Cohort 1 (Without Hepatic Impairment) was Reference.
  • Cohort 1 (Without Hepatic Impairment) vs Cohort 3 (Moderate Hepatic Impairment) · ANOVA · Mean difference (final values): 182.51 · 90% CI 111.78 to 298.02Estimate mean difference was derived from ratio (%) of adjusted geometric means of Test and Reference.Cohort 3 (Moderate Hepatic Impairment) was Test and Cohort 1 (Without Hepatic Impairment) was Reference.
  • Cohort 1 (Without Hepatic Impairment) vs Cohort 4 (Severe Hepatic Impairment) · ANOVA · Mean difference (final values): 266.29 · 90% CI 163.08 to 434.80Estimate mean difference was derived from ratio (%) of adjusted geometric means of Test and Reference.Cohort 4 (Severe Hepatic Impairment) was Test and Cohort 1 (Without Hepatic Impairment) was Reference.
SecondaryTime to Reach Maximum Plasma Concentration (Tmax) of PF-05221304

Tmax was observed directly from data as time of first occurrence.

Time frame:
0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose
Reported as:
Median · Hours
Time to Reach Maximum Plasma Concentration (Tmax) of PF-05221304
HoursCohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Time to Reach Maximum Plasma Concentration (Tmax) of PF-052213044.01 (1.98 to 4.93)4.95 (2.95 to 5.00)4.50 (1.02 to 5.02)4.00 (0.917 to 5.00)
SecondaryArea Under Concentration Time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) of PF-05221304

AUClast was calculated by linear/Log trapezoidal method.

Time frame:
0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose
Reported as:
Geometric mean · ng*hr/mL
Area Under Concentration Time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) of PF-05221304
ng*hr/mLCohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Area Under Concentration Time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) of PF-0522130417400 ± 3623670 ± 4021680 ± 3120700 ± 43
SecondaryUnbound AUClast ( AUClast,u) of PF-05221304

AUClast,u was calculated by fu\*AUClast.

Time frame:
4 hours postdose
Reported as:
Geometric mean · ng*hr/mL
Unbound AUClast ( AUClast,u) of PF-05221304
ng*hr/mLCohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Unbound AUClast ( AUClast,u) of PF-0522130496.07 ± 75163.3 ± 34175.9 ± 51256.7 ± 45
SecondaryApparent Clearance After Oral Dose (CL/F) of PF-05221304

CL/F was calculated by Dose/AUCinf.

Time frame:
0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose
Reported as:
Geometric mean · Liter per hour (L/hr)
Apparent Clearance After Oral Dose (CL/F) of PF-05221304
Liter per hour (L/hr)Cohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Apparent Clearance After Oral Dose (CL/F) of PF-052213041.427 ± 361.048 ± 411.151 ± 311.202 ± 43
SecondaryUnbound CL/F (CLu/F) of PF-05221304

CLu/F was calculated by fu\*CL/F.

Time frame:
4 hours postdose
Reported as:
Geometric mean · L/hr
Unbound CL/F (CLu/F) of PF-05221304
L/hrCohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Unbound CL/F (CLu/F) of PF-05221304258.7 ± 75152.0 ± 33141.6 ± 5197.02 ± 45
SecondaryApparent Volume of Distribution After Oral Dose (Vz/F) of PF-05221304

Vz/F was calculated by Dose/(AUCinf\*kel). kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

Time frame:
0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose
Reported as:
Geometric mean · Liters
Apparent Volume of Distribution After Oral Dose (Vz/F) of PF-05221304
LitersCohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Apparent Volume of Distribution After Oral Dose (Vz/F) of PF-0522130434.94 ± 3524.53 ± 2423.16 ± 2823.97 ± 23
SecondaryUnbound Vz/F (Vz,u/F) of PF-05221304

Vz,u/F was calculated by fu\*Vz/F.

Time frame:
4 hours postdose
Reported as:
Geometric mean · Liters
Unbound Vz/F (Vz,u/F) of PF-05221304
LitersCohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Unbound Vz/F (Vz,u/F) of PF-052213046334 ± 693563 ± 512854 ± 591931 ± 37
SecondaryTerminal Half-Life ( t½) of PF-05221304

t1/2 was calculated by loge(2)/kel.

Time frame:
0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose
Reported as:
Mean · Hours
Terminal Half-Life ( t½) of PF-05221304
HoursCohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Terminal Half-Life ( t½) of PF-0522130417.43 ± 4.747117.25 ± 6.837214.30 ± 3.413514.76 ± 5.7937
SecondaryNumber of Participants With Treatment-emergent Adverse Events (TEAEs)

An adverse event (AE) was any untoward medical occurrence in a study participant administered a product or medical device; the event did not need to have a causal relationship with the treatment or usage. A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and AEs. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Number of participants with both all-causality and treatment-related TEAEs are presented below.

Time frame:
Approximately 30 days
Reported as:
Count of participants · Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
ParticipantsCohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
All-causality TEAE0120
Treatment-related TEAE0110
SecondaryNumber of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)-Hematology

Hematology evaluation included: hemoglobin, hematocrit, erythrocytes, reticulocytes, erythrocyte mean corpuscular volume, erythrocyte mean corpuscular hemoglobin concentration (MCHC), erythrocyte mean corpuscular hemoglobin, platelets, leukocytes, lymphocytes, neutrophils, basophils, eosinophils, monocytes, activated partial thromboplastin time and prothrombin time.

Time frame:
7 days
Reported as:
Count of participants · Participants
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)-Hematology
ParticipantsCohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Hemoglobin <0.8*lower limit of normal (LLN)0001
Hematocrit <0.8*LLN0001
Erythrocytes <0.8*LLN0011
Reticulocytes <0.5*LLN0000
Reticulocytes >1.5*upper limit of normal (ULN)0000
Erythrocyte Mean Corpuscular Volume <0.9*LLN0000
Erythrocyte Mean Corpuscular Volume >1.1*ULN0000
Erythrocyte MCHC <0.9*LLN0000
Erythrocyte MCHC >1.1*ULN0000
Erythrocyte Mean Corpuscular Hemoglobin <0.9*LLN0000
Erythrocyte Mean Corpuscular Hemoglobin >1.1*ULN0010
Platelets <0.5*LLN0032
Platelets >1.75*ULN0000
Leukocytes <0.6*LLN0000
Leukocytes >1.5*ULN0000
Lymphocytes <0.8*LLN0021
Lymphocytes >1.2*ULN0000
Neutrophils <0.8*LLN0010
Neutrophils >1.2*ULN0000
Basophils >1.2*ULN0000
Eosinophils >1.2*ULN0000
Monocytes >1.2*ULN0000
Activated Partial Thromboplastin Time >1.1*ULN0000
Prothrombin Time >1.1*ULN0013
SecondaryNumber of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)-Clinical Chemistry

Clinical chemistry evaluation included: bilirubin, direct/indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase , alkaline phosphatase, protein, albumin, blood urea nitrogen, creatinine, urate, sodium, potassium, chloride, calcium, phosphate, bicarbonate, creatine kinase, and fasting glucose.

Time frame:
7 days
Reported as:
Count of participants · Participants
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)-Clinical Chemistry
ParticipantsCohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Bilirubin >1.5*ULN0015
Direct Bilirubin >1.5*ULN—000
Indirect Bilirubin >1.5*ULN0002
Aspartate Aminotransferase >3.0*ULN0012
Alanine Aminotransferase >3.0*ULN0000
Gamma Glutamyl Transferase >3.0*ULN0102
Alkaline Phosphatase >3.0*ULN0000
Protein <0.8*LLN0000
Protein >1.2*ULN0000
Albumin <0.8*LLN0000
Albumin >1.2*ULN0000
Blood Urea Nitrogen >1.3*ULN0000
Creatinine >1.3*ULN0000
Urate >1.2*ULN0000
Sodium <0.95*LLN0000
Sodium >1.05*ULN0000
Potassium <0.9*LLN0000
Potassium >1.1*ULN0000
Chloride <0.9*LLN0000
Chloride >1.1*ULN0000
Calcium <0.9*LLN0000
Calcium >1.1*ULN0000
Phosphate <0.8*LLN0000
Phosphate >1.2*ULN0000
Bicarbonate <0.9*LLN0000
Bicarbonate >1.1*ULN0000
Creatine Kinase >2.0*ULN0000
Fasting Glucose <0.6*LLN0000
Fasting-Glucose >1.5*ULN0100
SecondaryNumber of Paticipants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)-Urinalysis

Urinalysis evaluation included: scalar urine glucose, scalar ketones, scalar urine protein, scalar urine hemoglobin, scalar urobilinogen, scalar urine bilirubin, scalar nitrite, scalar leukocyte esterase, urine erythrocytes, urine leukocytes, hyaline casts, and scalar bacteria.

Time frame:
7 days
Reported as:
Count of participants · Participants
Number of Paticipants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)-Urinalysis
ParticipantsCohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Scalar Urine Glucose >=10010
Scalar Ketones >=10000
Scalar Urine Protein >=10000
Scalar Urine Hemoglobin >=10001
Scalar Urobilinogen >=10013
Scalar Urine Bilirubin >=10000
Scalar Nitrite >=11000
Scalar Leukocyte Esterase >=11121
Urine Erythrocytes >=20 (/high power field [HPF])0—00
Urine Leukocytes >=20 (/HPF)0100
Hyaline Casts >1 (/low power field [LPF])—11—
Scalar Bacteria >200000
SecondaryNumber of Participants With Clinical Significant Findings in Vital Signs

Vital signs evaluation included: sitting systolic and diastolic blood pressure (BP), and sitting pulse rate. Clinically significant findings in vital signs were determined by the investigator.

Time frame:
7 days
Reported as:
Count of participants · Participants
Number of Participants With Clinical Significant Findings in Vital Signs
ParticipantsCohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Number of Participants With Clinical Significant Findings in Vital Signs0000
SecondaryNumber of Participants With Clinically Significant Findings in Electrocardiogram (ECG) Data

ECG evaluation included: PR interval, time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization (QRS interval), time between the start of the Q wave and the end of the T wave in the heart's electrical cycle (QT interval), QT interval corrected for heart rate using Fridericia's formula (QTcF interval), and heart rate. Clinically significant findings in ECG data were determined by the investigator.

Time frame:
7 days
Reported as:
Count of participants · Participants
Number of Participants With Clinically Significant Findings in Electrocardiogram (ECG) Data
ParticipantsCohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
Number of Participants With Clinically Significant Findings in Electrocardiogram (ECG) Data0000

Adverse events

Collected over 30 days. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Cohort 1 (Without Hepatic Impairment)0/6 (0%)0/6 (0%)0/6 (0%)
Cohort 2 (Mild Hepatic Impairment)0/6 (0%)0/6 (0%)1/6 (16.7%)
Cohort 3 (Moderate Hepatic Impairment)0/6 (0%)0/6 (0%)2/6 (33.3%)
Cohort 4 (Severe Hepatic Impairment)0/6 (0%)0/6 (0%)0/6 (0%)
Most frequent other events
Most frequent other events
EventCohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)
InfluenzaInfections and infestations0/60/61/60/6
SomnolenceNervous system disorders0/60/61/60/6
BlisterSkin and subcutaneous tissue disorders0/61/60/60/6

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)Cohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)Total
<=18 years00000
Between 18 and 65 years664521
>=65 years00213
Age, Continuous
Age, Continuous(Years)Cohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)Total
Mean56.17 ± 2.2355.50 ± 9.7360.00 ± 5.9755.33 ± 7.5056.75 ± 6.74
Sex: Female, Male
Sex: Female, Male(Participants)Cohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)Total
Female21216
Male454518
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Cohort 1 (Without Hepatic Impairment)Cohort 2 (Mild Hepatic Impairment)Cohort 3 (Moderate Hepatic Impairment)Cohort 4 (Severe Hepatic Impairment)Total
White456621
Black or African American20002
Asian01001
07

Study locations

6 sites
  • Orlando Clinical Research Center
    Orlando, Florida 32809, United States
  • Pfizer Clinical Research Unit
    Brussels, B-1070, Belgium
  • Pharmaceutical Research Associates CZ, s.r.o.
    Praha 7, 170 00, Czechia
  • Nemocnice Na Bulovce
    Praha 8, 180 81, Czechia
  • Summit Clinical Research s.r.o.
    Bratislava, 83101, Slovakia
  • Univerzitná Nemocnica Bratislava
    Bratislava, 83305, Slovakia
08

References and documents

Study documents

  • Statistical analysis plan · Apr 29, 2019
  • Study protocol · Sep 18, 2017

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No — Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

09

Registry details

Key details

Study ID
NCT03309202
Lead sponsor
Pfizer
Responsible party
Sponsor
First posted
Oct 13, 2017
Start date
Dec 19, 2017
Primary completion
Jun 26, 2018
Completion
Jul 18, 2018
Results posted
Aug 8, 2019
Last update
Aug 8, 2019

Study contacts

Pfizer CT.gov Call Center
study director · Pfizer

Oversight

Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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