Hepatic Impairment
Conditions
Brief summary
This is a Phase 1 non randomized, open label, single dose, parallel cohort study to investigate the effect of hepatic impairment on the PK, safety and tolerability of PF 04965842.
Detailed description
A minimum of 24 subjects with normal, mild or moderate hepatic function will be enrolled into the study, with approximately 8 subjects in each cohort. The Child Pugh classification score will be utilized to assess entry criteria and to assign subjects into the appropriate hepatic impairment group. For individual subjects, the total maximum duration of study participation from the Screening visit to the end of clinical research unit (CRU) stay is approximately 31 days and approximately 63 days from the Screening visit to the Follow up contact.
Interventions
DRUGPF-04965842
PF 04965842 is an orally bioavailable small molecule that selectively inhibits JAK1.
Sponsors
Pfizer
Study design
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Recruitment for subjects with moderate and mild hepatic impairment (Cohorts 1 and 2) will initiate first and these subjects will be enrolled in parallel.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Body mass index (BMI) of 17.5 to 40 kg/m2; and a total body weight \>50 kg (110 pounds). * Subjects who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures. Additional Inclusion Criteria for subjects with hepatic impairment: * Satisfy the criteria for Class A or Class B of the Child Pugh classification (mild: Child Pugh Scores 5 to 6 points, and moderate: Child Pugh Scores 7 to 9 points), within 14 days of investigational product administration. * A diagnosis of hepatic dysfunction due to hepatocellular disease (and not secondary to any acute ongoing hepatocellular process) documented by medical history, physical examination, liver biopsy, hepatic ultrasound, computerized tomography scan, or magnetic resonance imaging (MRI).
Exclusion criteria
* Subjects with clinically significant infections within the past 3 months (for example, those requiring hospitalization, or as judged by the Investigator), evidence of any infection (including influenza) within the past 7 days, history of disseminated herpes simplex infection or recurrent (\>1 episode) or disseminated herpes zoster. * Subjects with a malignancy or with a history of malignancy, with the exception of adequately treated or excised non metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ. Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) for PF-04965842 | 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24, 36, 48, 72 hours post-dose in each cohort | Cmax is maximum plasma concentration. It was observed directly from data. |
| Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUCinf) for PF-04965842 | 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24, 36, 48, 72 hours post-dose in each cohort | AUCinf is area under the concentration-time curve (AUC) from time 0 (pre-dose) extrapolated to infinite time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (AEs) for PF-04965842 | From screening (within 28 days prior to Day 1) till up to 36 days post-dose, the total maximum duration was approximately 63 days for individual participants. | Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent adverse events (TEAEs) were those with initial onset or increasing in severity between the first dose of investigational product and up to 36 days post-dose. |
| Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Screening (within 28 days prior to Day 1), Day -1, 2, 24, 72 hours post-dose. | Laboratory tests included tests that were performed under the categories of hematology, chemistry, urinalysis, other, and additional tests needed for Hy's law. |
| Number of Participants With Electrocardiogram (ECG) Findings of Potential Clinical Importance for PF-04965842 | Screening (within 28 days prior to Day 1), Day -1, 2, 72 hours post-dose. | 12-Lead ECGs were collected after the participants rested quietly for at least 10 minutes in a supine position. Clinical significance of ECG recordings was determined at the investigator's discretion. |
| Number of Participants With Vital Sign Findings of Potential Clinical Importance for PF-04965842 | Screening (within 28 days prior to Day 1), 0 (pre-dose), and 72 hours post-dose. | Vital signs (pulse rate, systolic and diastolic blood pressure) were obtained with participant following at least 5 minutes of supine rest. Clinical significance of vital signs was determined at the investigator's discretion. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PF-04965842 (Normal Hepatic Function Cohort) Participants with normal hepatic function were enrolled in this cohort. Participants received a single oral dose of PF-04965842 200 mg. | 8 |
| PF-04965842 (Mild Hepatic Impairment Cohort) Participants with Child-Pugh scores of 5 to 6 points were enrolled in this cohort. Participants received a single oral dose of PF-04965842 200 mg. | 8 |
| PF-04965842 (Moderate Hepatic Impairment Cohort) Participants with Child-Pugh scores of 7 to 9 points were enrolled in this cohort. Participants received a single oral dose of PF-04965842 200 mg. | 8 |
| Total | 24 |
Baseline characteristics
| Characteristic | PF-04965842 (Normal Hepatic Function Cohort) | PF-04965842 (Mild Hepatic Impairment Cohort) | PF-04965842 (Moderate Hepatic Impairment Cohort) | Total |
|---|---|---|---|---|
| Age, Continuous | 58.5 Years STANDARD_DEVIATION 5.86 | 57.9 Years STANDARD_DEVIATION 4.19 | 58.6 Years STANDARD_DEVIATION 8.21 | 58.3 Years STANDARD_DEVIATION 6.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 8 Participants | 8 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 4 Participants | 7 Participants | 18 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 3 Participants | 9 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 5 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 2 / 8 | 3 / 8 | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUCinf) for PF-04965842
AUCinf is area under the concentration-time curve (AUC) from time 0 (pre-dose) extrapolated to infinite time.
Time frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24, 36, 48, 72 hours post-dose in each cohort
Population: The pharmacokinetic parameter analysis population was defined as all participants dosed who had at least 1 of the pharmocokinetics parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-04965842 (Normal Hepatic Function Cohort) | Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUCinf) for PF-04965842 | 5587 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 74 |
| PF-04965842 (Mild Hepatic Impairment Cohort) | Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUCinf) for PF-04965842 | 7449 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 29 |
| PF-04965842 (Moderate Hepatic Impairment Cohort) | Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUCinf) for PF-04965842 | 8603 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 55 |
Comparison: Mild Hepatic Impairment (Test) versus Normal Hepatic Function (Reference)90% CI: [86.17, 206.28]ANOVA
Comparison: Moderate Hepatic Impairment (Test) versus Normal Hepatic Function (Reference)90% CI: [99.52, 238.25]ANOVA
Primary
Maximum Observed Plasma Concentration (Cmax) for PF-04965842
Cmax is maximum plasma concentration. It was observed directly from data.
Time frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24, 36, 48, 72 hours post-dose in each cohort
Population: The pharmacokinetic concentration population was defined as all participants who received 1 dose of PF-04965842 and in whom at least 1 plasma concentration value was reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-04965842 (Normal Hepatic Function Cohort) | Maximum Observed Plasma Concentration (Cmax) for PF-04965842 | 1352 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 44 |
| PF-04965842 (Mild Hepatic Impairment Cohort) | Maximum Observed Plasma Concentration (Cmax) for PF-04965842 | 1276 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 41 |
| PF-04965842 (Moderate Hepatic Impairment Cohort) | Maximum Observed Plasma Concentration (Cmax) for PF-04965842 | 1426 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 63 |
Comparison: Mild Hepatic Impairment (Test) versus Normal Hepatic Function (Reference)90% CI: [62.96, 141.55]ANOVA
Comparison: Moderate Hepatic Impairment (Test) versus Normal Hepatic Function (Reference)90% CI: [70.38, 158.24]ANOVA
Secondary
Number of Participants With Electrocardiogram (ECG) Findings of Potential Clinical Importance for PF-04965842
12-Lead ECGs were collected after the participants rested quietly for at least 10 minutes in a supine position. Clinical significance of ECG recordings was determined at the investigator's discretion.
Time frame: Screening (within 28 days prior to Day 1), Day -1, 2, 72 hours post-dose.
Population: All participants who received PF-04965842 were included in the safety analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-04965842 (Normal Hepatic Function Cohort) | Number of Participants With Electrocardiogram (ECG) Findings of Potential Clinical Importance for PF-04965842 | 0 Participants |
| PF-04965842 (Mild Hepatic Impairment Cohort) | Number of Participants With Electrocardiogram (ECG) Findings of Potential Clinical Importance for PF-04965842 | 0 Participants |
| PF-04965842 (Moderate Hepatic Impairment Cohort) | Number of Participants With Electrocardiogram (ECG) Findings of Potential Clinical Importance for PF-04965842 | 0 Participants |
Secondary
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)
Laboratory tests included tests that were performed under the categories of hematology, chemistry, urinalysis, other, and additional tests needed for Hy's law.
Time frame: Screening (within 28 days prior to Day 1), Day -1, 2, 24, 72 hours post-dose.
Population: All participants who received PF-04965842 were included in the safety analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-04965842 (Normal Hepatic Function Cohort) | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | 4 Participants |
| PF-04965842 (Mild Hepatic Impairment Cohort) | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | 7 Participants |
| PF-04965842 (Moderate Hepatic Impairment Cohort) | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | 8 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (AEs) for PF-04965842
Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent adverse events (TEAEs) were those with initial onset or increasing in severity between the first dose of investigational product and up to 36 days post-dose.
Time frame: From screening (within 28 days prior to Day 1) till up to 36 days post-dose, the total maximum duration was approximately 63 days for individual participants.
Population: All participants who received PF-04965842 were included in the safety analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-04965842 (Normal Hepatic Function Cohort) | Number of Participants With Treatment-Emergent Adverse Events (AEs) for PF-04965842 | AEs (all causalities) | 2 Participants |
| PF-04965842 (Normal Hepatic Function Cohort) | Number of Participants With Treatment-Emergent Adverse Events (AEs) for PF-04965842 | AEs (treatment related) | 1 Participants |
| PF-04965842 (Mild Hepatic Impairment Cohort) | Number of Participants With Treatment-Emergent Adverse Events (AEs) for PF-04965842 | AEs (all causalities) | 3 Participants |
| PF-04965842 (Mild Hepatic Impairment Cohort) | Number of Participants With Treatment-Emergent Adverse Events (AEs) for PF-04965842 | AEs (treatment related) | 3 Participants |
| PF-04965842 (Moderate Hepatic Impairment Cohort) | Number of Participants With Treatment-Emergent Adverse Events (AEs) for PF-04965842 | AEs (all causalities) | 0 Participants |
| PF-04965842 (Moderate Hepatic Impairment Cohort) | Number of Participants With Treatment-Emergent Adverse Events (AEs) for PF-04965842 | AEs (treatment related) | 0 Participants |
Secondary
Number of Participants With Vital Sign Findings of Potential Clinical Importance for PF-04965842
Vital signs (pulse rate, systolic and diastolic blood pressure) were obtained with participant following at least 5 minutes of supine rest. Clinical significance of vital signs was determined at the investigator's discretion.
Time frame: Screening (within 28 days prior to Day 1), 0 (pre-dose), and 72 hours post-dose.
Population: All participants who received PF-04965842 were included in the safety analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-04965842 (Normal Hepatic Function Cohort) | Number of Participants With Vital Sign Findings of Potential Clinical Importance for PF-04965842 | 0 Participants |
| PF-04965842 (Mild Hepatic Impairment Cohort) | Number of Participants With Vital Sign Findings of Potential Clinical Importance for PF-04965842 | 0 Participants |
| PF-04965842 (Moderate Hepatic Impairment Cohort) | Number of Participants With Vital Sign Findings of Potential Clinical Importance for PF-04965842 | 0 Participants |
Post Hoc
Unbound AUCinf (AUCinf,u) for Active Moiety
AUCinf,u is unbound AUCinf. The active moiety is comprised of parent drug PF-04965842, active metabolites PF-06471658 and PF-07055087.
Time frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24, 36, 48, 72 hours post-dose in each cohort
Population: The analysis population was defined as all participants contributing to the summary statistics for AUCinf,u.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-04965842 (Normal Hepatic Function Cohort) | Unbound AUCinf (AUCinf,u) for Active Moiety | 12010 nanomolar*hour (nM*hr) | Geometric Coefficient of Variation 40 |
| PF-04965842 (Mild Hepatic Impairment Cohort) | Unbound AUCinf (AUCinf,u) for Active Moiety | 11500 nanomolar*hour (nM*hr) | Geometric Coefficient of Variation 24 |
| PF-04965842 (Moderate Hepatic Impairment Cohort) | Unbound AUCinf (AUCinf,u) for Active Moiety | 13790 nanomolar*hour (nM*hr) | Geometric Coefficient of Variation 30 |
Comparison: Mild Hepatic Impairment (Test) versus Normal Hepatic Function (Reference)90% CI: [72.71, 126.08]ANOVA
Comparison: Moderate Hepatic Impairment (Test) versus Normal Hepatic Function (Reference)90% CI: [87.19, 151.2]ANOVA
Post Hoc
Unbound Cmax (Cmax,u) for Active Moiety
Cmax,u is unbound Cmax. The active moiety is comprised of parent drug PF-04965842, active metabolites PF-06471658 and PF-07055087.
Time frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24, 36, 48, 72 hours post-dose in each cohort
Population: The pharmacokinetic parameter analysis population was defined as all participants dosed who had at least 1 of the pharmocokinetic parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-04965842 (Normal Hepatic Function Cohort) | Unbound Cmax (Cmax,u) for Active Moiety | 2390 nanomolar (nM) | Geometric Coefficient of Variation 20 |
| PF-04965842 (Mild Hepatic Impairment Cohort) | Unbound Cmax (Cmax,u) for Active Moiety | 1815 nanomolar (nM) | Geometric Coefficient of Variation 36 |
| PF-04965842 (Moderate Hepatic Impairment Cohort) | Unbound Cmax (Cmax,u) for Active Moiety | 2011 nanomolar (nM) | Geometric Coefficient of Variation 41 |
Comparison: Mild Hepatic Impairment (Test) versus Normal Hepatic Function (Reference)90% CI: [57.39, 100.47]ANOVA
Comparison: Moderate Hepatic Impairment (Test) versus Normal Hepatic Function (Reference)90% CI: [63.59, 111.33]ANOVA