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

Primary Purpose

Healthy, Hepatic Insufficiency

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Palbociclib 75 mg Capsule

About this trial

This is an interventional basic science trial for Healthy, Hepatic Insufficiency focused on measuring Palbociclib, PD-0332991, Hepatic Impairment

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Orlando Clinical Research Center
Weston Diagnostics (Ultrasound Facility)

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Healthy Volunteers

Mild Hepatic Impairment

Moderate Hepatic Impairment

Severe Hepatic Impairment

Arm Description

Cohort of Healthy Volunteers

Cohort of mild hepatic impairment subjects meeting the criteria for Child-Pugh Class A

Cohort of moderate hepatic impairment subjects meeting the criteria for Child-Pugh Class B

Cohort of severe hepatic impairment subjects meeting the criteria for Child-Pugh Class C

Outcomes

Primary Outcome Measures

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.

Maximum Plasma Concentration (Cmax)

Cmax is maximum plasma concentration. It is observed directly from data.

Secondary Outcome Measures

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.

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.

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.

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.

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).

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.

Fraction of Unbound Drug in Plasma (fu)

Fu is the fraction of unbound drug in plasma. It is obtained from measurement of protein binding.

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 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.

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.

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).

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.

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).

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.

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.

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.

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.

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.

Number of Participants With Concomitant Medications

Treatments taken after the first dose of study treatment were documented as concomitant treatments.

Full Information

NCT ID

NCT02334800

First Posted

January 6, 2015

Last Updated

June 8, 2017

Sponsor

Pfizer

1. Study Identification

Unique Protocol Identification Number

NCT02334800

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2017

Overall Recruitment Status

Completed

Study Start Date

March 31, 2015 (Actual)

Primary Completion Date

October 9, 2016 (Actual)

Study Completion Date

October 9, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Pfizer

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Healthy, Hepatic Insufficiency

Keywords

Palbociclib, PD-0332991, Hepatic Impairment

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

28 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Healthy Volunteers

Arm Type

Experimental

Arm Description

Cohort of Healthy Volunteers

Arm Title

Mild Hepatic Impairment

Arm Type

Experimental

Arm Description

Cohort of mild hepatic impairment subjects meeting the criteria for Child-Pugh Class A

Arm Title

Moderate Hepatic Impairment

Arm Type

Experimental

Arm Description

Cohort of moderate hepatic impairment subjects meeting the criteria for Child-Pugh Class B

Arm Title

Severe Hepatic Impairment

Arm Type

Experimental

Arm Description

Cohort of severe hepatic impairment subjects meeting the criteria for Child-Pugh Class C

Intervention Type

Drug

Intervention Name(s)

Palbociclib 75 mg Capsule

Other Intervention Name(s)

Palbociclib, PD-0332991

Intervention Description

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).

Primary Outcome Measure Information:

Title

Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinite Time (AUCinf)

Description

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.

Title

Maximum Plasma Concentration (Cmax)

Description

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.

Secondary Outcome Measure Information:

Title

Unbound AUCinf (AUCinf,u)

Description

Time Frame

Title

Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast)

Description

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

Title

Unbound AUClast (AUClast,u)

Description

Time Frame

Title

Apparent Clearance After Oral Dose(CL/F)

Description

Time Frame

Title

Unbound CL/F (CLu/F)

Description

Time Frame

Title

Unbound Cmax (Cmax,u)

Description

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

Title

Fraction of Unbound Drug in Plasma (fu)

Description

Fu is the fraction of unbound drug in plasma. It is obtained from measurement of protein binding.

Time Frame

Eight (8) hours post-dose.

Title

Terminal Half-Life (t1/2)

Description

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

Title

Time for Cmax (Tmax)

Description

Tmax is time for maximum plasma concentration. It is observed directly from data as time of first occurrence of maximum plasma concentration.

Time Frame

Title

Apparent Volunm of Distribution After Oral Dose (Vz/F)

Description

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.

Title

Unbound Vz/F (Vz,u/F)

Description

Time Frame

Title

Number of Participants With Treatment Emergent Adverse Events

Description

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.

Title

Number of Participants With Treatment Emergent Serious Adverse Events

Description

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.

Title

Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)

Description

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.

Title

Number of Participants With Physical Examination Test Abnormalities (Change From Prior Visit)

Description

Time Frame

Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4.

Title

Number of Participants With Post Baseline Vital Signs Values Meeting Categorical Summarization Criteria

Description

Time Frame

Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4, not including baseline values.

Title

Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Absolute Values)

Description

Time Frame

Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4, not including baseline values.

Title

Number of Participants With Post Baseline Electrocardiogram Values Meeting Categorical Summarization Criteria (Maximum Increase From Baseline)

Description

Time Frame

Baseline up to Day 6 for Cohort 1 and to Day 9 for Cohorts 2, 3, and 4, not including baseline values.

Title

Number of Participants With Concomitant Medications

Description

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.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Pfizer CT.gov Call Center

Organizational Affiliation

Pfizer

Official's Role

Study Director

Facility Information:

Facility Name

Orlando Clinical Research Center

City

Orlando

State/Province

Florida

ZIP/Postal Code

32809

Country

United States

Facility Name

Weston Diagnostics (Ultrasound Facility)

City

Orlando

State/Province

Florida

ZIP/Postal Code

32825

Country

United States

12. IPD Sharing Statement

Links:

URL

https://trialinfoemail.pfizer.com/pages/landing.aspx?StudyID=A5481013&StudyName=A%20Phase%201%2C%20Open-label%2C%20Single%20Dose%2C%20Parallel-cohort%20Study%20To%20Evaluate%20The%20Pharmacokinetics%20Of%20Palbociclib%20%28pd-0332991%29%20In%20Subjects%20With%20Impaired%20Hepatic%20Function

Description

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

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