Healthy Participants, Hepatic Impairment
Conditions
Keywords
PF-06651600, Pharmacokinetics, Hepatic impairment
Brief summary
The purpose of this study is to characterize the effect of hepatic impairment on the pharmacokinetic(s) (PK) of PF-06651600 following administration of multiple once daily doses of PF-06651600. The safety and tolerability of PF-06651600 will also be evaluated in this study.
Interventions
DRUGPF-06651600 30 mg
PF-06651600 in 10 mg oral tablets will be administered on days 1 to 10.
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations and other study procedures * Body mass index (BMI) of 17.5 to 40 kg/m2; and a total body weight \>50 kg (110 lb) Additional Inclusion Criteria for Participants with Normal Hepatic Function: * Healthy male or female participants * No known or suspected hepatic disease Additional Inclusion Criteria for Participants with Impaired Hepatic Function: * Stable hepatic impairment, defined as no clinically significant change in disease status within the last 30 days prior to the Screening visit * No other ongoing clinically significant abnormalities based on medical history, physical examination, vital signs, 12-lead ECG, and clinical laboratory tests except for the abnormal findings that are related to the participant's hepatic impairment. * Satisfy the criteria for Class A or Class B of the Child-Pugh classification (mild: Child-Pugh Scores 5-6 points, and moderate: Child Pugh Scores 7-9 points), within 28 days of investigational product administration.
Exclusion criteria
* Has active acute or chronic infection requiring treatment or history of systemic infection requiring hospitalization, incl. herpes zoster, herpes simplex, tuberculosis * Infection with hepatitis B, hepatitis C or HIV * Any condition affecting drug absorption, distribution, metabolism and excretion (eg, status post porta-caval shunt surgery, prior bariatric surgery, gastrectomy, ileal resection) * Has malignancy, lymphoproliferative disorder, surgery or other condition not allowed per protocol Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Profile From Time 0 to 24 Hours (AUC24) for PF-06651600 | Hour 0 (pre-dose) on Days 7, 8 and 9, and hour 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 14, 24 hours post-dose on Day 10 | AUC24 of PF-06651600 pre and post dose. |
| Maximum Plasma Concentration (Cmax) for PF-06651600 | Hour 0 (pre-dose) on Days 7, 8 and 9, and hour 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 14, 24 hours post-dose on Day 10 | Cmax is maximum observed plasma concentration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) | Baseline (Day 0) up to 28 days after last dose of study medication (Day 39) | AEs with all causalities were any untoward medical occurrences in a study participant administered a product which did not necessarily had causal relationship with the treatment or usage. An SAE was an AE resulting in any of the following endpoints or deemed significant for any other reason: death; life threatening (immediate risk of death); inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; or considered to be an important medical event. Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent are events between first dose of study drug and up to 35 days after last dose that were absent before treatment or that worsened relative to pretreatment state. |
| Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality) | Baseline (Day 0) up to 28 days after last dose of study medication (Day 39) | Laboratory parameters included: hematology (hemoglobin, hematocrit, erythrocytes, leukocytes, neutrophils, prothrombin time, prothrombin intl. normalized ratio), chemistry (bilirubin, direct bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, albumin, sodium, potassium, calcium, bicarbonate and glucose), urinalysis (glucose, ketones, protein, hemoglobin, urobilinogen, bilirubin and nitrite). Each parameter was evaluated against commonly used and widely accepted criteria. |
| Number of Participants With Out of Range Vital Signs | Baseline (Day 0) up to 28 days after last dose of study medication (Day 39) | Vital signs included supine blood pressure, pulse rate and temperature. The pre-specified out of range criterion for supine diastolic blood pressure was change from baseline equal to or over than (≥) 20 millimeter of mercury (mmHg). Clinical significance of vital signs and out of range criterion were determined at the investigator's discretion. |
| Number of Adverse Events Leading to Discontinuation | Baseline (Day 0) up to 28 days after last dose of study medication (Day 39) | Adverse events result in participants discontinuations from the study drug. |
Countries
United States
Participant flow
Pre-assignment details
Eight participants were originally enrolled in each cohort. Two participants in moderate hepatic impairment cohort who discontinued from study treatment were included as completed and 2 additional participants were enrolled to ensure an adequate number of evaluable participants.
Participants by arm
| Arm | Count |
|---|---|
| Moderate Hepatic Impairment Participants with moderate hepatic impairment were administered PF-06651600 30 milligram (mg) once daily (QD) for 10 treatment days. | 10 |
| Normal Hepatic Function Participants with normal hepatic function were administered PF-06651600 30 milligram (mg) once daily (QD) for 10 treatment days. | 8 |
| Total | 18 |
Baseline characteristics
| Characteristic | Moderate Hepatic Impairment | Normal Hepatic Function | Total |
|---|---|---|---|
| Age, Continuous | 59.0 Years STANDARD_DEVIATION 6.88 | 57.4 Years STANDARD_DEVIATION 6.48 | 58.3 Years STANDARD_DEVIATION 6.56 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 4 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 7 Participants | 4 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 8 |
| other Total, other adverse events | 3 / 10 | 2 / 8 |
| serious Total, serious adverse events | 1 / 10 | 0 / 8 |
Outcome results
Primary
Area Under the Plasma Concentration-time Profile From Time 0 to 24 Hours (AUC24) for PF-06651600
AUC24 of PF-06651600 pre and post dose.
Time frame: Hour 0 (pre-dose) on Days 7, 8 and 9, and hour 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 14, 24 hours post-dose on Day 10
Population: The analysis population was defined as all participants treated who have at least 1 of the pharmacokinetic (PK) parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Moderate Hepatic Impairment | Area Under the Plasma Concentration-time Profile From Time 0 to 24 Hours (AUC24) for PF-06651600 | 454.5 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 45 |
| Normal Hepatic Function | Area Under the Plasma Concentration-time Profile From Time 0 to 24 Hours (AUC24) for PF-06651600 | 383.6 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 16 |
90% CI: [87.96, 159.64]ANOVA
Primary
Maximum Plasma Concentration (Cmax) for PF-06651600
Cmax is maximum observed plasma concentration.
Time frame: Hour 0 (pre-dose) on Days 7, 8 and 9, and hour 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 14, 24 hours post-dose on Day 10
Population: The analysis population was defined as all participants treated who have at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Moderate Hepatic Impairment | Maximum Plasma Concentration (Cmax) for PF-06651600 | 194.3 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 49 |
| Normal Hepatic Function | Maximum Plasma Concentration (Cmax) for PF-06651600 | 186.9 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 24 |
90% CI: [74.48, 145.23]ANOVA
Secondary
Number of Adverse Events Leading to Discontinuation
Adverse events result in participants discontinuations from the study drug.
Time frame: Baseline (Day 0) up to 28 days after last dose of study medication (Day 39)
Population: All participants assigned to investigational product and who took at least 1 dose of investigational product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Moderate Hepatic Impairment | Number of Adverse Events Leading to Discontinuation | 2 adverse events |
| Normal Hepatic Function | Number of Adverse Events Leading to Discontinuation | 0 adverse events |
Secondary
Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality)
Laboratory parameters included: hematology (hemoglobin, hematocrit, erythrocytes, leukocytes, neutrophils, prothrombin time, prothrombin intl. normalized ratio), chemistry (bilirubin, direct bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, albumin, sodium, potassium, calcium, bicarbonate and glucose), urinalysis (glucose, ketones, protein, hemoglobin, urobilinogen, bilirubin and nitrite). Each parameter was evaluated against commonly used and widely accepted criteria.
Time frame: Baseline (Day 0) up to 28 days after last dose of study medication (Day 39)
Population: All participants assigned to investigational product and who took at least 1 dose of investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Moderate Hepatic Impairment | Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality) | 9 Participants |
| Normal Hepatic Function | Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality) | 2 Participants |
Secondary
Number of Participants With Out of Range Vital Signs
Vital signs included supine blood pressure, pulse rate and temperature. The pre-specified out of range criterion for supine diastolic blood pressure was change from baseline equal to or over than (≥) 20 millimeter of mercury (mmHg). Clinical significance of vital signs and out of range criterion were determined at the investigator's discretion.
Time frame: Baseline (Day 0) up to 28 days after last dose of study medication (Day 39)
Population: All participants assigned to investigational product and who took at least 1 dose of investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Moderate Hepatic Impairment | Number of Participants With Out of Range Vital Signs | 1 Participants |
| Normal Hepatic Function | Number of Participants With Out of Range Vital Signs | 0 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related)
AEs with all causalities were any untoward medical occurrences in a study participant administered a product which did not necessarily had causal relationship with the treatment or usage. An SAE was an AE resulting in any of the following endpoints or deemed significant for any other reason: death; life threatening (immediate risk of death); inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; or considered to be an important medical event. Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent are events between first dose of study drug and up to 35 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Time frame: Baseline (Day 0) up to 28 days after last dose of study medication (Day 39)
Population: All participants assigned to investigational product and who took at least 1 dose of investigational product.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moderate Hepatic Impairment | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) | AEs (all causalities) | 4 Participants |
| Moderate Hepatic Impairment | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) | AEs (treatment related) | 4 Participants |
| Moderate Hepatic Impairment | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) | SAEs (all causalities) | 1 Participants |
| Moderate Hepatic Impairment | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) | SAEs (treatment related) | 1 Participants |
| Normal Hepatic Function | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) | SAEs (treatment related) | 0 Participants |
| Normal Hepatic Function | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) | AEs (all causalities) | 2 Participants |
| Normal Hepatic Function | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) | SAEs (all causalities) | 0 Participants |
| Normal Hepatic Function | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) | AEs (treatment related) | 1 Participants |