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

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ClinicalTrials.gov Identifier: NCT02334800
Recruitment Status : Completed
First Posted : January 8, 2015
Results First Posted : January 24, 2018
Last Update Posted : January 24, 2018
Sponsor:
Information provided by (Responsible Party):
Pfizer

Tracking Information
First Submitted Date  ICMJE January 6, 2015
First Posted Date  ICMJE January 8, 2015
Results First Submitted Date  ICMJE June 8, 2017
Results First Posted Date  ICMJE January 24, 2018
Last Update Posted Date January 24, 2018
Actual Study Start Date  ICMJE March 31, 2015
Actual Primary Completion Date October 9, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 8, 2017)
  • Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinite Time (AUCinf) [ 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. ]
    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) [ 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. ]
    Cmax is maximum plasma concentration. It is observed directly from data.
Original Primary Outcome Measures  ICMJE
 (submitted: January 6, 2015)
  • AUCinf [ Time Frame: pre-dose until 192 hours post-dose ]
    The area under the concentration-time curve from time zero extrapolated to time infinity.
  • Cmax [ Time Frame: pre-dose until 192 hours post-dose ]
    Maximum observed plasma concentration
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 8, 2017)
  • Unbound AUCinf (AUCinf,u) [ 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. ]
    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) [ 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. ]
    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) [ 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. ]
    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) [ 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. ]
    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) [ 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. ]
    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) [ 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. ]
    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) [ Time Frame: 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) [ 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. ]
    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) [ 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. ]
    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) [ 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. ]
    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) [ 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. ]
    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 [ 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. ]
    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 [ 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. ]
    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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ 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. ]
    Treatments taken after the first dose of study treatment were documented as concomitant treatments.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 6, 2015)
  • T 1/2 [ Time Frame: pre-dose until 192 hours post-dose ]
    terminal elimination half-life
  • AUClast [ Time Frame: pre-dose until 192 hours post-dose ]
    Area under the concentration-time curve from time zero until the time of the last observed quantifiable concentration.
  • Tmax [ Time Frame: pre-dose until 192 hours post-dose ]
    Time post-dose of the maximum observed concentration.
  • Cl/F [ Time Frame: pre-dose until 192 hours post-dose ]
    Apparent oral clearance
  • Vz/F [ Time Frame: pre-dose until 192 hours post-dose ]
    Volume of distribution
  • fu [ Time Frame: 8 hours post-dose ]
    fraction of drug unbound in plasma
  • unbound AUCinf [ Time Frame: pre-dose until 192 hours post-dose ]
    area under the unbound concentration-time curve from time zero extrapolated until time infinity.
  • unbound AUClast [ Time Frame: pre-dose until 192 hours post-dose ]
    area under the unbound concentration-time curve from time zero until the time of the last observed quantifiable concentration.
  • unbound Cmax [ Time Frame: pre-dose until 192 hours post-dose ]
    maximum observed unbound concentration
  • unbound Cl/F [ Time Frame: pre-dose until 192 hours post-dose ]
    unbound apparent oral clearance
  • unbound Vz/F [ Time Frame: pre-dose until 192 hours post-dose ]
    unbound volume of distribution
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study To Describe The Effect Of Impaired Hepatic Function Of The Pharmacokinetics Of Palbociclib
Official Title  ICMJE A Phase 1, Open-label, Single Dose, Parallel-cohort Study To Evaluate The Pharmacokinetics Of Palbociclib (Pd-0332991) In Subjects With Impaired Hepatic Function
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Healthy, Hepatic Insufficiency
Intervention  ICMJE Drug: Palbociclib 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).
Other Name: Palbociclib, PD-0332991
Study Arms  ICMJE
  • Experimental: Healthy Volunteers
    Cohort of Healthy Volunteers
    Intervention: Drug: Palbociclib 75 mg Capsule
  • Experimental: Mild Hepatic Impairment
    Cohort of mild hepatic impairment subjects meeting the criteria for Child-Pugh Class A
    Intervention: Drug: Palbociclib 75 mg Capsule
  • Experimental: Moderate Hepatic Impairment
    Cohort of moderate hepatic impairment subjects meeting the criteria for Child-Pugh Class B
    Intervention: Drug: Palbociclib 75 mg Capsule
  • Experimental: Severe Hepatic Impairment
    Cohort of severe hepatic impairment subjects meeting the criteria for Child-Pugh Class C
    Intervention: Drug: Palbociclib 75 mg Capsule
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 6, 2015)
28
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE October 9, 2016
Actual Primary Completion Date October 9, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02334800
Other Study ID Numbers  ICMJE A5481013
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Pfizer CT.gov Call Center Pfizer
PRS Account Pfizer
Verification Date May 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP