Clinical trial NCT01571388: A Study To Compare Pharmacokinetics Of Dacomitinib (PF-00299804) Between Healthy Subjects And Subjects With Mild And Moderate Hepatic Impairment
Official title: A Phase 1 Study To Evaluate The Single Dose Pharmacokinetics Of Dacomitinib (PF-00299804) In Subjects With Impaired Hepatic Function
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Otherwise Healthy Volunteers With Mild or Moderate Hepatic Dysfunction
Keywords: dacomitinib
PF-00299804
hepatic impairment
pharmacokinetics
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2012-04-05
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: The study will determine if there are differences in how dacomitinib is absorbed and eliminated between healthy subjects and subjects with mild and moderately impaired hepatic function.


Eligibility criteria: Inclusion Criteria:

* Healthy male and/or female subjects of non-childbearing potential between the ages of 18 years of age to \<75 years of age. Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead ECG and clinical laboratory tests. Liver function tests, albumin and prothrombin time must be within normal range.
* Body Mass Index (BMI) of 18 to 35 kg/m2;
* An informed consent document signed and dated by the subject.
* Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
* Subjects in the normal hepatic function group (Group 1): No known or suspected hepatic impairment.
* For subjects in the hepatic impairment groups (Groups 2 and 3):

  * Should satisfy the criteria for Class A or B of the modified Child-Pugh classification
  * A diagnosis of hepatic dysfunction due to hepatocellular disease (and not secondary to any acute ongoing hepatocellular process) documented by medical history, physical examination, liver biopsy, hepatic ultrasound, CT scan, or MRI.
  * Stable hepatic impairment, defined as no clinically significant change in disease status within the last 30 days, as documented by the subject's recent medical history
  * Must be on a stable dose of medication and/or treatment regimen.

Exclusion Criteria:

* Any condition possibly affecting drug absorption (eg, gastrectomy, chronic diarrhea, rapid transit).
* A positive urine drug screen.
* Females of childbearing potential, including those with tubal ligation. \[To be considered for enrollment, women of at least 45 years of age who are postmenopausal (defined as being amenorrheic for at least 2 years) must have confirmatory FSH test results at screening\].
* In addition, subjects in the hepatic impairment groups (Groups 2 and 3) presenting with any of the following will not be included in the trial:

  * Hepatic carcinoma and hepatorenal syndrome or life expectancy \<1 year.
  * Undergone porta-caval shunt surgery.
  * History of gastrointestinal hemorrhage due to esophageal varices or peptic ulcers less than one month prior to study entry.

Primary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: 2 weeks
measure: Plasma area under plasma concentration-time curve from time zero to time infinity post dose (AUCinf) for dacomitinib
timeFrame: 2 weeks
Secondary outcomes:
measure: Area under the Concentration-Time Curve (AUC);Plasma area under plasma concentration-time curve from time zero to 24 hours post dose (AUC24) for dacomitinib
timeFrame: 2 weeks
measure: Plasma area under plasma concentration-time curve from time zero to 216 hours post dose (AUC216) for dacomitinib
timeFrame: 2 weeks
measure: Plasma area under plasma concentration-time curve from time zero to time of last quantifiable concentration post dose (AUClast) for dacomitinib
timeFrame: 2 weeks
measure: Time of first observed maximal plasma concentration (Tmax) for dacomitinib
timeFrame: 2 weeks
measure: Plasma elimination half life (t1/2) of dacomitinib
timeFrame: 2 weeks
measure: Apparent plasma clearance (CL/F) of dacomitinib
timeFrame: 2 weeks
measure: Apparent volume of distribution (Vz/F) of dacomitinib
timeFrame: 2 weeks
measure: Fraction of unbound dacomitinib in plasma (fu)
timeFrame: 2 weeks
measure: Unbound apparent plasma clearance (CL/F) of dacomitinib ,
timeFrame: 2 weeks
measure: Unbound apparent volume of distribution (Vz/F) of dacomitinib
timeFrame: 2 weeks
measure: Unbound Plasma area under plasma concentration-time curve from time zero to time infinity post dose (AUCinf) for dacomitinib
timeFrame: 2 weeks
measure: Unbound plasma area under plasma concentration-time curve from time zero to 24 hours post dose (AUC24) for dacomitinib
timeFrame: 2 weeks
measure: Unbound plasma area under plasma concentration-time curve from time zero to 216 hours post dose (AUC216) for dacomitinib
timeFrame: 2 weeks
measure: Unbound plasma area under plasma concentration-time curve from time zero to time of last quantifiable concentration post dose (AUClast) for dacomitinib
timeFrame: 2 weeks
measure: Maximal unbound plasma concentration (Cmax) for dacomitinib
timeFrame: 2 weeks
measure: Plasma area under plasma concentration-time curve from time zero to time infinity post dose (AUCinf) for PF-05199265
timeFrame: 2 weeks
measure: Plasma area under plasma concentration-time curve from time zero to 24 hours post dose (AUC24) for PF-05199265
timeFrame: 2 weeks
measure: Plasma area under plasma concentration-time curve from time zero to 216 hours post dose (AUC216) for PF-05199265
timeFrame: 2 weeks
measure: Plasma area under plasma concentration-time curve from time zero to time of last quantifiable concentration post dose (AUClast) for PF-05199265
timeFrame: 2 weeks
measure: Maximal plasma concentration (Cmax) for PF-05199265
timeFrame: 2 weeks
measure: Time of first observed maximal plasma concentration (Tmax) for PF-05199265
timeFrame: 2 weeks
measure: Metabolite ratio for plasma area under plasma concentration-time curve from time zero to time infinity post dose (MRAUCinf)
timeFrame: 2 weeks
measure: Metabolite ratio for plasma area under plasma concentration-time curve from time zero to time of last quantifiable concentration post dose (MRAUClast)
timeFrame: 2 weeks
measure: Metabolite ratio for maximal plasma concentration (MRCmax)
timeFrame: 2 weeks
measure: Fraction of unbound PF-05199265 in plasma (fu)
timeFrame: 2 weeks
measure: Unbound plasma area under plasma concentration-time curve from time zero to 24 hours post dose (AUC24) for PF-05199265
timeFrame: 2 weeks
measure: Unbound plasma area under plasma concentration-time curve from time zero to 216 hours post dose (AUC216) for PF-05199265
timeFrame: 2 weeks
measure: Unbound plasma area under plasma concentration-time curve from time zero to time of last quantifiable concentration post dose (AUClast) for PF-05199265
timeFrame: 2 weeks
measure: Unbound Plasma area under plasma concentration-time curve from time zero to time infinity post dose (AUCinf) for PF-05199265
timeFrame: 2 weeks
measure: Maximal unbound plasma concentration (Cmax) for PF-05199265
timeFrame: 2 weeks
measure: Overall safety profile as characterized by laboratory abnormalities, observed physical examination, vital signs, ECGs, and adverse event monitoring.
timeFrame: 6-8 weeks
Other outcomes:
Locations:
city: Anaheim
country: United States
facility: Pfizer Investigational Site
state: California
city: South Miami
country: United States
facility: Pfizer Investigational Site
state: Florida
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Piscitelli J, Chen J, LaBadie RR, Salageanu J, Chung CH, Tan W. The Effect of Hepatic Impairment on the Pharmacokinetics of Dacomitinib. Clin Drug Investig. 2022 Mar;42(3):221-235. doi: 10.1007/s40261-022-01125-x. Epub 2022 Feb 23.
citation: Giri N, Masters JC, Plotka A, Liang Y, Boutros T, Pardo P, O'Connell J, Bello C. Investigation of the impact of hepatic impairment on the pharmacokinetics of dacomitinib. Invest New Drugs. 2015 Aug;33(4):931-41. doi: 10.1007/s10637-015-0256-0. Epub 2015 Jun 6.