A Study To Compare Pharmacokinetics Of Dacomitinib (PF-00299804) Between Healthy Subjects And Subjects With Mild And Moderate Hepatic Impairment

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1 Study To Evaluate The Single Dose Pharmacokinetics Of Dacomitinib (PF-00299804) In Subjects With Impaired Hepatic Function

Conditions
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Healthy, Otherwise Healthy Volunteers With Mild or Moderate Hepatic Dysfunction

Intervention / Treatment
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* Drug: dacomitinib
* Drug: dacomitinib
* Drug: dacomitinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Healthy Subjects to receive dacomitinib | Drug: dacomitinib<br>* Subjects to receive 30 mg tablets of dacomitinib on Day 1 of Period 1.<br>|
| Experimental: Group 2<br>Subjects with mildly impaired hepatic function to receive dacomitinib | Drug: dacomitinib<br>* Subjects to receive 30 mg tablets of dacomitinib on Day 1 of Period 1.<br>|
| Experimental: Group 3<br>Subjects with moderately impaired hepatic function to receive dacomitinib | Drug: dacomitinib<br>* Subjects to receive 30 mg tablets of dacomitinib on Day 1 of Period 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) | Maximal plasma concentration (Cmax) for dacomitinib | 2 weeks | 
| Plasma area under plasma concentration-time curve from time zero to time infinity post dose (AUCinf) for dacomitinib |  | 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. | 2 weeks | 
| Plasma area under plasma concentration-time curve from time zero to 216 hours post dose (AUC216) for dacomitinib |  | 2 weeks | 
| Plasma area under plasma concentration-time curve from time zero to time of last quantifiable concentration post dose (AUClast) for dacomitinib |  | 2 weeks | 
| Time of first observed maximal plasma concentration (Tmax) for dacomitinib |  | 2 weeks | 
| Plasma elimination half life (t1/2) of dacomitinib |  | 2 weeks | 
| Apparent plasma clearance (CL/F) of dacomitinib |  | 2 weeks | 
| Apparent volume of distribution (Vz/F) of dacomitinib |  | 2 weeks | 
| Fraction of unbound dacomitinib in plasma (fu) |  | 2 weeks | 
| Unbound apparent plasma clearance (CL/F) of dacomitinib , |  | 2 weeks | 
| Unbound apparent volume of distribution (Vz/F) of dacomitinib |  | 2 weeks | 
| Unbound Plasma area under plasma concentration-time curve from time zero to time infinity post dose (AUCinf) for dacomitinib |  | 2 weeks | 
| Unbound plasma area under plasma concentration-time curve from time zero to 24 hours post dose (AUC24) for dacomitinib |  | 2 weeks | 
| Unbound plasma area under plasma concentration-time curve from time zero to 216 hours post dose (AUC216) for dacomitinib |  | 2 weeks | 
| Unbound plasma area under plasma concentration-time curve from time zero to time of last quantifiable concentration post dose (AUClast) for dacomitinib |  | 2 weeks | 
| Maximal unbound plasma concentration (Cmax) for dacomitinib |  | 2 weeks | 
| Plasma area under plasma concentration-time curve from time zero to time infinity post dose (AUCinf) for PF-05199265 |  | 2 weeks | 
| Plasma area under plasma concentration-time curve from time zero to 24 hours post dose (AUC24) for PF-05199265 |  | 2 weeks | 
| Plasma area under plasma concentration-time curve from time zero to 216 hours post dose (AUC216) for PF-05199265 |  | 2 weeks | 
| Plasma area under plasma concentration-time curve from time zero to time of last quantifiable concentration post dose (AUClast) for PF-05199265 |  | 2 weeks | 
| Maximal plasma concentration (Cmax) for PF-05199265 |  | 2 weeks | 
| Time of first observed maximal plasma concentration (Tmax) for PF-05199265 |  | 2 weeks | 
| Metabolite ratio for plasma area under plasma concentration-time curve from time zero to time infinity post dose (MRAUCinf) |  | 2 weeks | 
| Metabolite ratio for plasma area under plasma concentration-time curve from time zero to time of last quantifiable concentration post dose (MRAUClast) |  | 2 weeks | 
| Metabolite ratio for maximal plasma concentration (MRCmax) |  | 2 weeks | 
| Fraction of unbound PF-05199265 in plasma (fu) |  | 2 weeks | 
| Unbound plasma area under plasma concentration-time curve from time zero to 24 hours post dose (AUC24) for PF-05199265 |  | 2 weeks | 
| Unbound plasma area under plasma concentration-time curve from time zero to 216 hours post dose (AUC216) for PF-05199265 |  | 2 weeks | 
| Unbound plasma area under plasma concentration-time curve from time zero to time of last quantifiable concentration post dose (AUClast) for PF-05199265 |  | 2 weeks | 
| Unbound Plasma area under plasma concentration-time curve from time zero to time infinity post dose (AUCinf) for PF-05199265 |  | 2 weeks | 
| Maximal unbound plasma concentration (Cmax) for PF-05199265 |  | 2 weeks | 
| Overall safety profile as characterized by laboratory abnormalities, observed physical examination, vital signs, ECGs, and adverse event monitoring. |  | 6-8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dacomitinib, PF-00299804, hepatic impairment, pharmacokinetics