Healthy, Hepatic Insufficiency
Conditions
Keywords
Palbociclib, PD-0332991, Hepatic Impairment
Brief summary
This is a phase 1 study to describe the plasma pharmacokinetics of a single oral 75mg dose of palbociclib administered to healthy volunteers, and subjects with mild, moderate, and severely impaired hepatic function.
Detailed description
This is a 4-cohort single period study. The four cohorts will consist of healthy volunteers, and subjects with mild, moderate, and severely impaired hepatic function. Each cohort will receive the same treatment consisting of a single oral 75mg dose of palbociclib administered with food. Serial PK samples will be drawn up to 120 hours post dose for the cohort consisting of healthy volunteers, and will continue until up to 192 hours post-dose for the cohorts of hepatic impairment subjects.
Interventions
DRUGPalbociclib 75 mg Capsule
Single oral 75 mg dose of palbociclib followed by serial PK sampling up to 192 hours post-dose (up to 120 hours post-dose for the healthy volunteer cohort).
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Body Mass Index (BMI) of 18 to 40 kg/m2; and a total body weight \>50 kg (110 lbs) * Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study * Subjects who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures
Exclusion criteria
* Any condition possibly affecting drug absorption (eg, gastrectomy) * A positive urine drug screen * Pregnant female subjects; breastfeeding female subjects; female subjects of childbearing potential; male subjects with partners currently pregnant; male subjects of childbearing potential who are unwilling or unable to use a highly effective method of contraception for the duration of the study and for 90 days after the last dose of investigational product * History of sensitivity to heparin or heparin-induced thrombocytopenia * Blood donation of approximately 1 pint (500 mL) or more within 56 days prior to dosing * Unwilling or unable to comply with the Lifestyle Guidelines described in this protocol * Use of tobacco or nicotine products in excess of 5 cigarettes per day (or equivalent) * History of sensitivity to palbociclib
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinite Time (AUCinf) | Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose. | AUCinf is area under the plasma concentration time curve from time 0 extrapolated infinite time. It is calculated as AUClast + (Clast/kel), where AUClast is area under the concentration-time curve from time 0 to the time of the last quantifiable concentration, Clast is the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. |
| Maximum Plasma Concentration (Cmax) | Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose. | Cmax is maximum plasma concentration. It is observed directly from data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Unbound AUClast (AUClast,u) | Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose. | AUClast,u is unbound AUClast, where AUClast is area under the concentration-time curve from time 0 to the time of the last quantifiable concentration. It is obtained by fu\*AUClast, where fu is the fraction of unbound drug in plasma. |
| Apparent Clearance After Oral Dose(CL/F) | Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose. | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance is obtained by dose/AUCinf, where AUCinf is the area under the concentration-time curve from time 0 extrapolated to infinite time. |
| Unbound CL/F (CLu/F) | Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose. | CLu/F is unbound CL/F, where CL/F is apparent clearance after oral dose. It is obtained by dose/AUCinf,u, where AUCinf,u is unbound AUCinf (area under the concentration-time curve from time 0 extrapolated to infinite time). |
| Unbound Cmax (Cmax,u) | Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose. | Cmax,u is unbound Cmax, where Cmax is maximum plasma concentration. It is obtained by fu\*Cmax, where fu is fraction of unbound drug in plasma. |
| Fraction of Unbound Drug in Plasma (fu) | Eight (8) hours post-dose. | Fu is the fraction of unbound drug in plasma. It is obtained from measurement of protein binding. |
| Terminal Half-Life (t1/2) | Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose. | T1/2 is terminal half-life. It is obtained by loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. |
| Time for Cmax (Tmax) | Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose. | Tmax is time for maximum plasma concentration. It is observed directly from data as time of first occurrence of maximum plasma concentration. |
| Apparent Volunm of Distribution After Oral Dose (Vz/F) | pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose. | Vz/F is 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. It is influenced by the fraction absorbed. It is obtained by dose/(AUCinf•kel), where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve, and AUCinf is the area under the concentration-time curve from time 0 extrapolated to infinite time. |
| Unbound AUCinf (AUCinf,u) | Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose. | AUCinf,u is unbound AUCinf, where AUCinf is area under the concentration-time curve from time 0 extrapolated to infinite time. It is obtained by fu\*AUCinf, where fu is the fraction of unbound drug in plasma. |
| Number of Participants With Treatment Emergent Adverse Events | Adverse events were recorded on the Case Report Form from the time the participant had taken at least 1 dose of palbociclib through the participant's last visit. | An adverse event is any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. Any events occurring following start of treatment or increasing in severity are counted as treatment emergent. Relatedness to palbociclib is assessed by the investigator (Yes/No). Participants with multiple occurrences of an adverse event within a category are counted once within the category. |
| Number of Participants With Treatment Emergent Serious Adverse Events | The active reporting period for serious adverse events began from the time that the participant provided informed consent through and including 28 calendar days after the last administration of palbociclib. | A serious adverse event is any untoward medical occurrence at any dose that resulted in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; or results in congenital anomaly/birth defect. Any events occurring following start of treatment or increasing in severity are counted as treatment emergent. Relatedness to palbociclib is assessed by the investigator (Yes/No). |
| Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4, inclusive of baseline values. | 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 Physical Examination Test Abnormalities (Change From Prior Visit) | Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4. | A full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The limited or abbreviated physical examination was focused on general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. |
| Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4, not including baseline values. | The number of participants with post baseline vital signs values meeting the following criteria was reported: A. absolute value of supine systolic blood pressure less than (\<) 90 mmHg; B. absolute value of diastolic blood pressure \<50 mmHg; C. absolute value of supine pulse rate \<40 bmp; D. absolute value of supine pulse rate larger than (\>) 120 bmp; E. maximum increase from baseline in supine systolic blood pressure larger than and equal to (\>=) 30 mmHg; F. maximum increase from baseline in supine diastolic blood pressure \>=20 mmHg; G. maximum decrease from baseline in supine systolic blood pressure \>=30 mmHg; and H. maximum decrease from baseline in supine diastolic blood pressure \>=20 mmHg. |
| Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4, not including baseline values. | Maximum absolute values of post baseline electrocardiogram were summarized for PR interval, QRS complex, QT interval, QTcB (QT interval calculated using Bazett's correction factor), and QTcF (QT interval calculated using Fridericia's correction factor). The number of participants with maximum absolute values of post baseline electrocardiogram meeting the following criteria was reported: (1) PR interval \>=300 msec; (2) QRS complex \>=140 msec; (3) QT interval 450 to \<480 msec; (4) QT interval 480 to \<500 msec; (5) QT interval \>= 500 msec; (6) QTcB 450 to \<480 msec; (7) QTcB 480 to \<500 msec; (8) QTcB \>= 500 msec; (9) QTcF 450 to \<480 msec; (10) QTcF 480 to \<500 msec; and (11) QTcF \>=500 msec. Seven (7) participants in each cohort were evaluated for electrocardiogram tests except that 6 participants in the moderate hepatic impairment cohort (Cohort 3) were evaluated for PR interval. |
| Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4, not including baseline values. | Maximum increases from baseline for post baseline electrocardiogram values were summarized for PR interval, QRS complex, QT interval, QTcB (QT interval calculated using Bazett's correction factor), and QTcF (QT interval calculated using Fridericia's correction factor). The number of participants with maximum increase from baseline for post baseline electrocardiogram values meeting the following criteria was reported: (1) percent change of PR interval \>=25/50%; (2) percent change of QRS complex \>=50%; (3) QT interval 30 to \<60 msec; (4) QT interval \>= 60 msec; (5) QTcB 30 to \<60 msec; (6) QTcB \>= 60 msec; (7) QTcF 30 to \<60 msec; and (8) QTcF \>= 60 msec. Seven (7) participants in each cohort were evaluated for electrocardiogram tests except that 6 participants in the moderate hepatic impairment cohort (Cohort 3) were evaluated for PR interval. |
| Number of Participants With Concomitant Medications | From screening through and including Day 6 for Cohort 1, and from screening through and including Day 9 for Cohorts 2, 3, and 4. | Treatments taken after the first dose of study treatment were documented as concomitant treatments. |
| Unbound Vz/F (Vz,u/F) | Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose. | Vz,u/F is unbound Vz/F, where Vz/F is apparent volume of distribution after oral dose. It is obtained by dose/(AUCinf,u\*kel), where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve, and AUCinf,u is unbound AUCinf (area under the concentration-time curve from time 0 extrapolated to infinite time). |
| Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) | Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose. | AUClast is area under the plasma concentration time curve from time 0 to time of last quantifiable concentration. It is obtained from linear/log trapezoidal method. |
Countries
United States
Participant flow
Pre-assignment details
A total of 28 participants were assigned to and received the study treatment (7 participants in each cohort).
Participants by arm
| Arm | Count |
|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) Participants with normal hepatic function were enrolled in this cohort. Participants received single oral dose of palbociclib 75 mg approximately 10 minutes after completion of the moderate fat standard calorie breakfast, with approximately 240 mL of ambient temperature water. | 7 |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) Participants with Child-Pugh scores of 5 to 6 points were enrolled in this cohort. Participants received single oral dose of palbociclib 75 mg approximately 10 minutes after completion of the moderate fat standard calorie breakfast, with approximately 240 mL of ambient temperature water. | 7 |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) Participants with Child-Pugh scores of 7 to 9 points were enrolled in this cohort. Participants received single oral dose of palbociclib 75 mg approximately 10 minutes after completion of the moderate fat standard calorie breakfast, with approximately 240 mL of ambient temperature water. | 7 |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) Participants with Child-Pugh scores of 10 to 15 points were enrolled in this cohort. Participants received single oral dose of palbociclib 75 mg approximately 10 minutes after completion of the moderate fat standard calorie breakfast, with approximately 240 mL of ambient temperature water. | 7 |
| Total | 28 |
Baseline characteristics
| Characteristic | Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 57.6 years STANDARD_DEVIATION 2.6 | 53.9 years STANDARD_DEVIATION 5.1 | 57.9 years STANDARD_DEVIATION 4.2 | 57 years STANDARD_DEVIATION 5.3 | 56.6 years STANDARD_DEVIATION 4.5 |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 2 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 5 Participants | 3 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 7 | 0 / 7 | 2 / 7 | 1 / 7 |
| serious Total, serious adverse events | 0 / 7 | 0 / 7 | 1 / 7 | 0 / 7 |
Outcome results
Primary
Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinite Time (AUCinf)
AUCinf is area under the plasma concentration time curve from time 0 extrapolated infinite time. It is calculated as AUClast + (Clast/kel), where AUClast is area under the concentration-time curve from time 0 to the time of the last quantifiable concentration, Clast is the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Time frame: Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose.
Population: The pharmacokinetics parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the palbociclib pharmacokinetics parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinite Time (AUCinf) | 1031 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 24 |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinite Time (AUCinf) | 758.9 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 31 |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinite Time (AUCinf) | 1189 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 22 |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinite Time (AUCinf) | 1378 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 29 |
90% CI: [57.81, 93.71]
90% CI: [90.57, 146.79]
90% CI: [105, 170.19]
Primary
Maximum Plasma Concentration (Cmax)
Cmax is maximum plasma concentration. It is observed directly from data.
Time frame: Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose.
Population: The pharmacokinetics concentration population was defined as all participants enrolled and treated who had at least 1 palbociclib concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Maximum Plasma Concentration (Cmax) | 28.64 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 20 |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Maximum Plasma Concentration (Cmax) | 27.20 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 37 |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Maximum Plasma Concentration (Cmax) | 33.72 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 28 |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Maximum Plasma Concentration (Cmax) | 37.20 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 48 |
90% CI: [69.93, 129.03]
90% CI: [86.69, 159.95]
90% CI: [95.63, 176.43]
Secondary
Apparent Clearance After Oral Dose(CL/F)
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance is obtained by dose/AUCinf, where AUCinf is the area under the concentration-time curve from time 0 extrapolated to infinite time.
Time frame: Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose.
Population: The pharmacokinetics parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the palbociclib pharmacokinetics parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Apparent Clearance After Oral Dose(CL/F) | 72.64 liter/hour (L/hr) | Geometric Coefficient of Variation 24 |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Apparent Clearance After Oral Dose(CL/F) | 98.84 liter/hour (L/hr) | Geometric Coefficient of Variation 31 |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Apparent Clearance After Oral Dose(CL/F) | 63.15 liter/hour (L/hr) | Geometric Coefficient of Variation 22 |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Apparent Clearance After Oral Dose(CL/F) | 54.42 liter/hour (L/hr) | Geometric Coefficient of Variation 29 |
Secondary
Apparent Volunm of Distribution After Oral Dose (Vz/F)
Vz/F is 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. It is influenced by the fraction absorbed. It is obtained by dose/(AUCinf•kel), where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve, and AUCinf is the area under the concentration-time curve from time 0 extrapolated to infinite time.
Time frame: pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose.
Population: The pharmacokinetics parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the palbociclib pharmacokinetics parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Apparent Volunm of Distribution After Oral Dose (Vz/F) | 2679 liter (L) | Geometric Coefficient of Variation 18 |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Apparent Volunm of Distribution After Oral Dose (Vz/F) | 3814 liter (L) | Geometric Coefficient of Variation 36 |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Apparent Volunm of Distribution After Oral Dose (Vz/F) | 3168 liter (L) | Geometric Coefficient of Variation 26 |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Apparent Volunm of Distribution After Oral Dose (Vz/F) | 2627 liter (L) | Geometric Coefficient of Variation 29 |
Secondary
Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast)
AUClast is area under the plasma concentration time curve from time 0 to time of last quantifiable concentration. It is obtained from linear/log trapezoidal method.
Time frame: Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose.
Population: The pharmacokinetics parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the palbociclib pharmacokinetics parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) | 973.3 ng*hr/mL | Geometric Coefficient of Variation 24 |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) | 708.6 ng*hr/mL | Geometric Coefficient of Variation 34 |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) | 1125 ng*hr/mL | Geometric Coefficient of Variation 24 |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) | 1311 ng*hr/mL | Geometric Coefficient of Variation 31 |
90% CI: [56.43, 93.93]
90% CI: [89.58, 149.11]
90% CI: [104.38, 173.73]
Secondary
Fraction of Unbound Drug in Plasma (fu)
Fu is the fraction of unbound drug in plasma. It is obtained from measurement of protein binding.
Time frame: Eight (8) hours post-dose.
Population: The pharmacokinetics parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the palbociclib pharmacokinetics parameters of primary interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Fraction of Unbound Drug in Plasma (fu) | 0.1910 ratio | Standard Deviation 0.015 |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Fraction of Unbound Drug in Plasma (fu) | 0.2157 ratio | Standard Deviation 0.014 |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Fraction of Unbound Drug in Plasma (fu) | 0.2236 ratio | Standard Deviation 0.025 |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Fraction of Unbound Drug in Plasma (fu) | 0.2546 ratio | Standard Deviation 0.036 |
Secondary
Number of Participants With Concomitant Medications
Treatments taken after the first dose of study treatment were documented as concomitant treatments.
Time frame: From screening through and including Day 6 for Cohort 1, and from screening through and including Day 9 for Cohorts 2, 3, and 4.
Population: All participants who received at least 1 dose of study medication were included in the safety analyses and listings.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Concomitant Medications | 0 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Concomitant Medications | 3 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Concomitant Medications | 7 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Concomitant Medications | 7 participant |
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: Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4, inclusive of baseline values.
Population: All participants who received at least 1 dose of study medication were included in the safety analyses and listings.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | 6 participants |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | 6 participants |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | 5 participants |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | 7 participants |
Secondary
Number of Participants With Physical Examination Test Abnormalities (Change From Prior Visit)
A full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The limited or abbreviated physical examination was focused on general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms.
Time frame: Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4.
Population: All participants who received at least 1 dose of study medication were included in the safety analyses and listings.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Physical Examination Test Abnormalities (Change From Prior Visit) | 0 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Physical Examination Test Abnormalities (Change From Prior Visit) | 0 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Physical Examination Test Abnormalities (Change From Prior Visit) | 2 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Physical Examination Test Abnormalities (Change From Prior Visit) | 0 participant |
Secondary
Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values)
Maximum absolute values of post baseline electrocardiogram were summarized for PR interval, QRS complex, QT interval, QTcB (QT interval calculated using Bazett's correction factor), and QTcF (QT interval calculated using Fridericia's correction factor). The number of participants with maximum absolute values of post baseline electrocardiogram meeting the following criteria was reported: (1) PR interval \>=300 msec; (2) QRS complex \>=140 msec; (3) QT interval 450 to \<480 msec; (4) QT interval 480 to \<500 msec; (5) QT interval \>= 500 msec; (6) QTcB 450 to \<480 msec; (7) QTcB 480 to \<500 msec; (8) QTcB \>= 500 msec; (9) QTcF 450 to \<480 msec; (10) QTcF 480 to \<500 msec; and (11) QTcF \>=500 msec. Seven (7) participants in each cohort were evaluated for electrocardiogram tests except that 6 participants in the moderate hepatic impairment cohort (Cohort 3) were evaluated for PR interval.
Time frame: Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4, not including baseline values.
Population: All participants who received at least 1 dose of study medication were included in the safety analyses and listings. Seven (7) participants in each cohort were evaluated for electrocardiogram tests except that 6 participants in the moderate hepatic impairment cohort (Cohort 3) were evaluated for PR interval.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | PR interval >=300 msec | 0 participant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QT interval 480 to <500 msec | 0 participant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcB >= 500 msec | 0 participant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QRS complex >=140 msec | 0 participant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcB 480 to <500 msec | 0 participant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QT interval >= 500 msec | 0 participant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QT interval 450 to <480 msec | 0 participant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcF >=500 msec | 0 participant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcF 480 to <500 msec | 0 participant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcB 450 to <480 msec | 0 participant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcF 450 to <480 msec | 0 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcB 450 to <480 msec | 1 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcF 450 to <480 msec | 1 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcB 480 to <500 msec | 0 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcB >= 500 msec | 0 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QT interval 450 to <480 msec | 1 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcF >=500 msec | 0 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QT interval 480 to <500 msec | 2 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcF 480 to <500 msec | 0 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QT interval >= 500 msec | 0 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QRS complex >=140 msec | 0 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | PR interval >=300 msec | 0 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcF 480 to <500 msec | 0 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | PR interval >=300 msec | 0 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QRS complex >=140 msec | 0 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QT interval 450 to <480 msec | 1 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QT interval 480 to <500 msec | 0 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QT interval >= 500 msec | 0 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcB 450 to <480 msec | 2 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcB 480 to <500 msec | 0 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcB >= 500 msec | 0 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcF 450 to <480 msec | 0 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcF >=500 msec | 0 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcB 450 to <480 msec | 2 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcF >=500 msec | 0 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcF 450 to <480 msec | 5 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QT interval >= 500 msec | 0 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QT interval 480 to <500 msec | 0 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QT interval 450 to <480 msec | 4 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcF 480 to <500 msec | 0 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QRS complex >=140 msec | 0 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | PR interval >=300 msec | 0 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcB >= 500 msec | 0 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values) | QTcB 480 to <500 msec | 3 participant |
Secondary
Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline)
Maximum increases from baseline for post baseline electrocardiogram values were summarized for PR interval, QRS complex, QT interval, QTcB (QT interval calculated using Bazett's correction factor), and QTcF (QT interval calculated using Fridericia's correction factor). The number of participants with maximum increase from baseline for post baseline electrocardiogram values meeting the following criteria was reported: (1) percent change of PR interval \>=25/50%; (2) percent change of QRS complex \>=50%; (3) QT interval 30 to \<60 msec; (4) QT interval \>= 60 msec; (5) QTcB 30 to \<60 msec; (6) QTcB \>= 60 msec; (7) QTcF 30 to \<60 msec; and (8) QTcF \>= 60 msec. Seven (7) participants in each cohort were evaluated for electrocardiogram tests except that 6 participants in the moderate hepatic impairment cohort (Cohort 3) were evaluated for PR interval.
Time frame: Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4, not including baseline values.
Population: All participants who received at least 1 dose of study medication were included in the safety analyses and listings. Seven (7) participants in each cohort were evaluated for electrocardiogram tests except that 6 participants in the moderate hepatic impairment cohort (Cohort 3) were evaluated for PR interval.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | percent change of PR interval >=25/50% | 0 paticipant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | percent change of QRS complex >=50% | 0 paticipant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QT interval 30 to <60 msec | 0 paticipant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QT interval >= 60 msec | 0 paticipant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QTcB 30 to <60 msec | 0 paticipant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QTcB >= 60 msec | 0 paticipant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QTcF 30 to <60 msec | 0 paticipant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QTcF >= 60 msec | 0 paticipant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QTcB >= 60 msec | 0 paticipant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QTcB 30 to <60 msec | 0 paticipant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | percent change of QRS complex >=50% | 0 paticipant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QTcF >= 60 msec | 0 paticipant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QTcF 30 to <60 msec | 0 paticipant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QT interval >= 60 msec | 0 paticipant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QT interval 30 to <60 msec | 0 paticipant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | percent change of PR interval >=25/50% | 0 paticipant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QTcF 30 to <60 msec | 0 paticipant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QT interval 30 to <60 msec | 0 paticipant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QT interval >= 60 msec | 0 paticipant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QTcB 30 to <60 msec | 0 paticipant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QTcB >= 60 msec | 0 paticipant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QTcF >= 60 msec | 0 paticipant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | percent change of PR interval >=25/50% | 0 paticipant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | percent change of QRS complex >=50% | 0 paticipant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QT interval 30 to <60 msec | 2 paticipant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QT interval >= 60 msec | 0 paticipant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | percent change of QRS complex >=50% | 0 paticipant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | percent change of PR interval >=25/50% | 0 paticipant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QTcB 30 to <60 msec | 1 paticipant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QTcF >= 60 msec | 1 paticipant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QTcF 30 to <60 msec | 0 paticipant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline) | QTcB >= 60 msec | 1 paticipant |
Secondary
Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria
The number of participants with post baseline vital signs values meeting the following criteria was reported: A. absolute value of supine systolic blood pressure less than (\<) 90 mmHg; B. absolute value of diastolic blood pressure \<50 mmHg; C. absolute value of supine pulse rate \<40 bmp; D. absolute value of supine pulse rate larger than (\>) 120 bmp; E. maximum increase from baseline in supine systolic blood pressure larger than and equal to (\>=) 30 mmHg; F. maximum increase from baseline in supine diastolic blood pressure \>=20 mmHg; G. maximum decrease from baseline in supine systolic blood pressure \>=30 mmHg; and H. maximum decrease from baseline in supine diastolic blood pressure \>=20 mmHg.
Time frame: Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4, not including baseline values.
Population: All participants who received at least 1 dose of study medication were included in the safety analyses and listings.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion A | 0 participant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion B | 0 participant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion C | 0 participant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion D | 0 participant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion E | 0 participant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion F | 0 participant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion G | 0 participant |
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion H | 0 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion F | 0 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion E | 0 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion B | 0 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion H | 0 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion G | 0 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion D | 0 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion C | 0 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion A | 1 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion G | 1 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion C | 0 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion D | 0 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion E | 0 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion F | 0 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion H | 0 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion A | 0 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion B | 0 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion C | 0 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion D | 0 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion B | 2 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion A | 0 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion E | 0 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion H | 1 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion G | 1 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria | criterion F | 0 participant |
Secondary
Number of Participants With Treatment Emergent Adverse Events
An adverse event is any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. Any events occurring following start of treatment or increasing in severity are counted as treatment emergent. Relatedness to palbociclib is assessed by the investigator (Yes/No). Participants with multiple occurrences of an adverse event within a category are counted once within the category.
Time frame: Adverse events were recorded on the Case Report Form from the time the participant had taken at least 1 dose of palbociclib through the participant's last visit.
Population: All participants who received at least 1 dose of study medication were included in the safety analyses and listings.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Treatment Emergent Adverse Events | 2 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Treatment Emergent Adverse Events | 0 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Treatment Emergent Adverse Events | 2 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Treatment Emergent Adverse Events | 1 participant |
Secondary
Number of Participants With Treatment Emergent Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that resulted in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; or results in congenital anomaly/birth defect. Any events occurring following start of treatment or increasing in severity are counted as treatment emergent. Relatedness to palbociclib is assessed by the investigator (Yes/No).
Time frame: The active reporting period for serious adverse events began from the time that the participant provided informed consent through and including 28 calendar days after the last administration of palbociclib.
Population: All participants who received at least 1 dose of study medication were included in the safety analyses and listings.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Number of Participants With Treatment Emergent Serious Adverse Events | 0 participant |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Number of Participants With Treatment Emergent Serious Adverse Events | 0 participant |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Number of Participants With Treatment Emergent Serious Adverse Events | 1 participant |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Number of Participants With Treatment Emergent Serious Adverse Events | 0 participant |
Secondary
Terminal Half-Life (t1/2)
T1/2 is terminal half-life. It is obtained by loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Time frame: Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose.
Population: The pharmacokinetics parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the palbociclib pharmacokinetics parameters of primary interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Terminal Half-Life (t1/2) | 25.84 hour (hr) | Standard Deviation 4.22 |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Terminal Half-Life (t1/2) | 27.23 hour (hr) | Standard Deviation 5.49 |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Terminal Half-Life (t1/2) | 35.03 hour (hr) | Standard Deviation 4.61 |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Terminal Half-Life (t1/2) | 33.84 hour (hr) | Standard Deviation 5.39 |
Secondary
Time for Cmax (Tmax)
Tmax is time for maximum plasma concentration. It is observed directly from data as time of first occurrence of maximum plasma concentration.
Time frame: Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose.
Population: The pharmacokinetics concentration population was defined as all participants enrolled and treated who had at least 1 palbociclib concentration
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Time for Cmax (Tmax) | 8.00 hr |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Time for Cmax (Tmax) | 6.00 hr |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Time for Cmax (Tmax) | 6.00 hr |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Time for Cmax (Tmax) | 6.00 hr |
Secondary
Unbound AUCinf (AUCinf,u)
AUCinf,u is unbound AUCinf, where AUCinf is area under the concentration-time curve from time 0 extrapolated to infinite time. It is obtained by fu\*AUCinf, where fu is the fraction of unbound drug in plasma.
Time frame: Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose.
Population: The pharmacokinetics parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the palbociclib pharmacokinetics parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Unbound AUCinf (AUCinf,u) | 196.6 ng*hr/mL | Geometric Coefficient of Variation 26 |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Unbound AUCinf (AUCinf,u) | 163.2 ng*hr/mL | Geometric Coefficient of Variation 32 |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Unbound AUCinf (AUCinf,u) | 264.1 ng*hr/mL | Geometric Coefficient of Variation 25 |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Unbound AUCinf (AUCinf,u) | 347.8 ng*hr/mL | Geometric Coefficient of Variation 23 |
90% CI: [65.37, 105.43]
90% CI: [105.73, 170.53]
90% CI: [139.28, 224.63]
Secondary
Unbound AUClast (AUClast,u)
AUClast,u is unbound AUClast, where AUClast is area under the concentration-time curve from time 0 to the time of the last quantifiable concentration. It is obtained by fu\*AUClast, where fu is the fraction of unbound drug in plasma.
Time frame: Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose.
Population: The pharmacokinetics parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the palbociclib pharmacokinetics parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Unbound AUClast (AUClast,u) | 185.5 ng*hr/mL | Geometric Coefficient of Variation 26 |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Unbound AUClast (AUClast,u) | 152.4 ng*hr/mL | Geometric Coefficient of Variation 35 |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Unbound AUClast (AUClast,u) | 250.3 ng*hr/mL | Geometric Coefficient of Variation 26 |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Unbound AUClast (AUClast,u) | 331.0 ng*hr/mL | Geometric Coefficient of Variation 24 |
90% CI: [63.83, 105.71]
90% CI: [104.82, 173.6]
90% CI: [138.62, 229.57]
Secondary
Unbound CL/F (CLu/F)
CLu/F is unbound CL/F, where CL/F is apparent clearance after oral dose. It is obtained by dose/AUCinf,u, where AUCinf,u is unbound AUCinf (area under the concentration-time curve from time 0 extrapolated to infinite time).
Time frame: Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose.
Population: The pharmacokinetics parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the palbociclib pharmacokinetics parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Unbound CL/F (CLu/F) | 381.3 L/hr | Geometric Coefficient of Variation 26 |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Unbound CL/F (CLu/F) | 459.2 L/hr | Geometric Coefficient of Variation 32 |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Unbound CL/F (CLu/F) | 283.8 L/hr | Geometric Coefficient of Variation 25 |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Unbound CL/F (CLu/F) | 215.8 L/hr | Geometric Coefficient of Variation 23 |
Secondary
Unbound Cmax (Cmax,u)
Cmax,u is unbound Cmax, where Cmax is maximum plasma concentration. It is obtained by fu\*Cmax, where fu is fraction of unbound drug in plasma.
Time frame: Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose.
Population: The pharmacokinetics parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the palbociclib pharmacokinetics parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Unbound Cmax (Cmax,u) | 5.456 ng/mL | Geometric Coefficient of Variation 23 |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Unbound Cmax (Cmax,u) | 5.858 ng/mL | Geometric Coefficient of Variation 37 |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Unbound Cmax (Cmax,u) | 7.501 ng/mL | Geometric Coefficient of Variation 34 |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Unbound Cmax (Cmax,u) | 9.399 ng/mL | Geometric Coefficient of Variation 47 |
90% CI: [78.06, 147.68]
90% CI: [99.96, 189.12]
90% CI: [125.25, 236.96]
Secondary
Unbound Vz/F (Vz,u/F)
Vz,u/F is unbound Vz/F, where Vz/F is apparent volume of distribution after oral dose. It is obtained by dose/(AUCinf,u\*kel), where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve, and AUCinf,u is unbound AUCinf (area under the concentration-time curve from time 0 extrapolated to infinite time).
Time frame: Pre-dose and 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose for for all participants. Additional pharmacokinetics samples were collected from participants in hepatic impairment cohorts (Cohorts 2, 3 and 4) at 144, 168, and 192 hours post-dose.
Population: The pharmacokinetics parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the palbociclib pharmacokinetics parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Palbociclib 75 mg (Normal Hepatic Function, Cohort 1) | Unbound Vz/F (Vz,u/F) | 14060 L | Geometric Coefficient of Variation 24 |
| Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2) | Unbound Vz/F (Vz,u/F) | 17730 L | Geometric Coefficient of Variation 36 |
| Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3) | Unbound Vz/F (Vz,u/F) | 14260 L | Geometric Coefficient of Variation 32 |
| Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4) | Unbound Vz/F (Vz,u/F) | 10410 L | Geometric Coefficient of Variation 30 |