A Study To Describe The Effect Of Impaired Hepatic Function Of The Pharmacokinetics Of Palbociclib

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1, Open-label, Single Dose, Parallel-cohort Study To Evaluate The Pharmacokinetics Of Palbociclib (Pd-0332991) In Subjects With Impaired Hepatic Function

Conditions
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Healthy, Hepatic Insufficiency

Intervention / Treatment
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* Drug: Palbociclib 75 mg Capsule


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy Volunteers<br>Cohort of Healthy Volunteers | Drug: Palbociclib 75 mg Capsule<br>* 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).<br>* Other names: Palbociclib, PD-0332991;|
| Experimental: Mild Hepatic Impairment<br>Cohort of mild hepatic impairment subjects meeting the criteria for Child-Pugh Class A | Drug: Palbociclib 75 mg Capsule<br>* 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).<br>* Other names: Palbociclib, PD-0332991;|
| Experimental: Moderate Hepatic Impairment<br>Cohort of moderate hepatic impairment subjects meeting the criteria for Child-Pugh Class B | Drug: Palbociclib 75 mg Capsule<br>* 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).<br>* Other names: Palbociclib, PD-0332991;|
| Experimental: Severe Hepatic Impairment<br>Cohort of severe hepatic impairment subjects meeting the criteria for Child-Pugh Class C | Drug: Palbociclib 75 mg Capsule<br>* 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).<br>* Other names: Palbociclib, PD-0332991;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| Maximum Plasma Concentration (Cmax) | Cmax is maximum plasma concentration. It is observed directly from data. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| 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. | 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. | 
| 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. | 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. | 
| 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. | 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. | 
| 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). | 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. | 
| 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. | 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. | 
| Fraction of Unbound Drug in Plasma (fu) | Fu is the fraction of unbound drug in plasma. It is obtained from measurement of protein binding. | Eight (8) hours post-dose. | 
| 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. | 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. | 
| 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. | 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. | 
| 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. | 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. | 
| 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). | 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. | 
| 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. | 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. | 
| 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). | 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. | 
| 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. | Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4, inclusive of baseline values. | 
| 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. | Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4. | 
| 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. | Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4, not including baseline values. | 
| 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. | Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4, not including baseline values. | 
| 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. | Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4, not including baseline values. | 
| Number of Participants With Concomitant Medications | Treatments taken after the first dose of study treatment were documented as concomitant treatments. | From screening through and including Day 6 for Cohort 1, and from screening through and including Day 9 for Cohorts 2, 3, and 4. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Palbociclib, PD-0332991, Hepatic Impairment