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NCT02334800

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

Completed Phase 1 Results posted Last updated 24 January 2018
What this trial tests

Phase 1 trial testing Palbociclib 75 mg Capsule in Healthy, Hepatic Insufficiency in 28 participants. Completed in 9 October 2016.

Timeline
31 March 2015
Primary endpoint
9 October 2016
9 October 2016

Quick facts

Lead sponsorPfizer
PhasePhase 1
StatusCompleted
Study typeINTERVENTIONAL
Allocationnon randomized
Designparallel
Maskingnone
Primary purposebasic science
Enrollment28
Start date31 March 2015
Primary completion9 October 2016
Estimated completion9 October 2016
Sites2 locations across United States

Drugs / interventions tested

Conditions studied

Sponsor

Pfizer — full company profile →

Who can join

Adults 18 to 75, any sex, with Healthy, Hepatic Insufficiency. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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

GroupValue95% CI
Palbociclib 75 mg (Normal Hepatic Function, Cohort 1)1031± 24
Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2)758.9± 31
Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3)1189± 22
Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4)1378± 29
Maximum Plasma Concentration (Cmax) Primary · 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.

GroupValue95% CI
Palbociclib 75 mg (Normal Hepatic Function, Cohort 1)28.64± 20
Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2)27.20± 37
Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3)33.72± 28
Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4)37.20± 48
Unbound AUCinf (AUCinf,u) Secondary · 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.

GroupValue95% CI
Palbociclib 75 mg (Normal Hepatic Function, Cohort 1)196.6± 26
Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2)163.2± 32
Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3)264.1± 25
Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4)347.8± 23
Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) Secondary · 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.

GroupValue95% CI
Palbociclib 75 mg (Normal Hepatic Function, Cohort 1)973.3± 24
Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2)708.6± 34
Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3)1125± 24
Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4)1311± 31
Unbound AUClast (AUClast,u) Secondary · 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.

GroupValue95% CI
Palbociclib 75 mg (Normal Hepatic Function, Cohort 1)185.5± 26
Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2)152.4± 35
Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3)250.3± 26
Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4)331.0± 24
Apparent Clearance After Oral Dose(CL/F) Secondary · 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.

GroupValue95% CI
Palbociclib 75 mg (Normal Hepatic Function, Cohort 1)72.64± 24
Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2)98.84± 31
Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3)63.15± 22
Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4)54.42± 29
Unbound CL/F (CLu/F) Secondary · 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).

GroupValue95% CI
Palbociclib 75 mg (Normal Hepatic Function, Cohort 1)381.3± 26
Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2)459.2± 32
Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3)283.8± 25
Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4)215.8± 23
Unbound Cmax (Cmax,u) Secondary · 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.

GroupValue95% CI
Palbociclib 75 mg (Normal Hepatic Function, Cohort 1)5.456± 23
Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2)5.858± 37
Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3)7.501± 34
Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4)9.399± 47
Fraction of Unbound Drug in Plasma (fu) Secondary · Eight (8) hours post-dose.

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

GroupValue95% CI
Palbociclib 75 mg (Normal Hepatic Function, Cohort 1)0.1910± 0.015
Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2)0.2157± 0.014
Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3)0.2236± 0.025
Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4)0.2546± 0.036
Terminal Half-Life (t1/2) Secondary · 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.

GroupValue95% CI
Palbociclib 75 mg (Normal Hepatic Function, Cohort 1)25.84± 4.22
Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2)27.23± 5.49
Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3)35.03± 4.61
Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4)33.84± 5.39
Time for Cmax (Tmax) Secondary · 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.

GroupValue95% CI
Palbociclib 75 mg (Normal Hepatic Function, Cohort 1)8.006.00 – 12.0
Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2)6.006.00 – 6.00
Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3)6.002.00 – 6.00
Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4)6.002.00 – 8.00
Apparent Volunm of Distribution After Oral Dose (Vz/F) Secondary · 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.

GroupValue95% CI
Palbociclib 75 mg (Normal Hepatic Function, Cohort 1)2679± 18
Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2)3814± 36
Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3)3168± 26
Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4)2627± 29

Adverse events — posted to ClinicalTrials.gov

Time frame: For adverse event, from the time participant took at least 1 dose of palbociclib through the last visit. For serious adverse event, from the participant provided informed consent through 28 calendar days post last administration of palbociclib.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Palbociclib 75 mg (Normal Hepatic Function, Cohort 1)
Serious: 0/7 (0%)
Deaths:
Palbociclib 75 mg (Mild Hepatic Impairment, Cohort 2)
Serious: 0/7 (0%)
Deaths:
Palbociclib 75 mg (Moderate Hepatic Impairment, Cohort 3)
Serious: 1/7 (14%)
Deaths:
Palbociclib 75 mg (Severe Hepatic Impairment, Cohort 4)
Serious: 0/7 (0%)
Deaths:

Serious adverse events (1 terms)

ReactionSystemPalbociclib 75 mg (Normal …Palbociclib 75 mg (Mild He…Palbociclib 75 mg (Moderat…Palbociclib 75 mg (Severe …
PneumoniaInfections and infestations
Other adverse events (7 terms — click to expand)

ReactionSystemPalbociclib 75 mg (Normal …Palbociclib 75 mg (Mild He…Palbociclib 75 mg (Moderat…Palbociclib 75 mg (Severe …
NauseaGastrointestinal disorders
VomitingGastrointestinal disorders
Infusion site bruisingGeneral disorders
Infusion site reactionGeneral disorders
HeadacheNervous system disorders
Radial nerve compressionNervous system disorders
DiarrheaGastrointestinal disorders

Most-reported serious reactions: Pneumonia.

Data from ClinicalTrials.gov NCT02334800 adverse events section.

Sponsor's own description

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.

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

  1. Cyclin D1, cancer progression, and opportunities in cancer treatment.
    Qie S, Diehl JA. · · 2016 · cited 527× · PMID 27695879 · DOI 10.1007/s00109-016-1475-3

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