Hepatic Impairment
Conditions
Keywords
Glasdegib, PF-04449913, Pharmacokinetics, Hepatic Impairment
Brief summary
This is a Phase 1, open-label, parallel group, single dose study to investigate the effect of moderate or severe hepatic impairment on the PK of glasdegib, compared to subjects with normal hepatic function.
Detailed description
This is a Phase 1, open-label, parallel group, single dose study to investigate the effect of hepatic impairment on the PK of glasdegib after administration of a single oral 100 mg dose. Subjects with moderate or severe hepatic impairment will be enrolled, followed by healthy subjects with normal hepatic function who serve as matched controls.
Interventions
DRUGGlasdegib 100 mg single oral dose
A single dose of 100 mg glasdegib tablet will be administered after an overnight fast, followed by serial PK collection, discharge and follow-up.
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy or hepatically impaired female subjects of non-child bearing potential and/or male subjects who, at the time of Screening, are between the ages of 18 and 75 years, inclusive. 2. Female subjects of nonchildbearing potential must meet at least 1 of the following criteria: 1. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; with a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state; 2. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 3. Have medically confirmed ovarian failure. All other female subjects (including females with tubal ligations) are considered to be of childbearing potential. 3. Body mass index (BMI) of 17.5 to 40 kg/m2; and a total body weight \>50 kg (110 lb). 4. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study. 5. Subjects who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures. Additional Inclusion Criteria for Subjects With Normal Hepatic Function: Subjects in the normal hepatic function cohort (Cohort 3) must be considered healthy and meet all of the following additional inclusion criteria to be eligible for enrollment into the study: 1. No known or suspected hepatic impairment based on liver function tests, albumin and prothrombin time, defined as the following: 1. ALT and AST \<= upper limit of normal (ULN); 2. Total bilirubin \<= 1.5 × ULN; subjects with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is not greater than 0.5 mg/dL; 3. Alkaline phosphatase \<= ULN; 4. Albumin within the normal range (local lab ranges); 5. Prothrombin time (PT) within the normal range (local lab ranges). 2. Subjects must fit the demographic-matching criteria, including: 1. A total body weight that is +/- 10 kg of the population median of the pooled hepatic impairment cohorts (Cohorts 1 and 2). 2. An age that is +/- 5 years of the population median of the pooled hepatic impairment cohorts (Cohorts 1 and 2). 3. No known or suspected hepatic impairment. 4. Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure (BP) and pulse rate (PR) measurement, 12 lead ECG or clinical laboratory tests. Additional Inclusion Criteria for Subjects with Impaired Hepatic Function: Subjects in the hepatic impairment cohorts (Cohorts 1 and 2) must meet the following additional inclusion criteria to be eligible for enrollment into the trial: 1. Satisfy the criteria for Class B, or C of the modified Child-Pugh Classification. 2. 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, computerized tomography (CT) scan, or magnetic resonance imaging (MRI). 3. Known stable hepatic impairment, defined as no evidence of clinically significant change in disease status within the last 30 days, as documented by the subject's recent medical history (eg, no worsening clinical signs of hepatic impairment, or no worsening of total bilirubin or prothrombin time by more than 50%). 4. Stable drug regimen defined as not starting a new drug or changing dosage within seven days or five half-lives (whichever is longer) prior to the dosing of investigational product. History of alcohol abuse is permissible providing that the results of alcohol test are negative at Screening and on Day -1, and the subject is willing and able to abide by the lifestyle guidelines.
Exclusion criteria
1. Any condition possibly affecting drug absorption (eg, gastrectomy). 2. A positive urine drug test. Subjects with hepatic impairment (Cohorts 1 and 2) will be eligible to participate if their urine drug test is positive with a drug for a prescribed substance that is not expected to interfere with the PK of glasdegib. 3. Pregnant female subjects; breastfeeding female subjects; fertile male subjects who are unwilling or unable to use at least one highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 90 days after the glasdegib dose and, refrain from sperm donation for the duration of the Study and for at least 90 days after the glasdegib dose. 4. History of sensitivity to heparin or heparin-induced thrombocytopenia. 5. Blood donation of approximately 1 pint (500 mL) or more within 56 days prior to dosing. 6. Unwilling or unable to comply with the Lifestyle Requirements. 7. Subjects who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees directly involved in the conduct of the study. 8. History of known sensitivity to glasdegib. 9. Treatment with an investigational drug within 30 days (or as determined by the local requirement) or 5 half-lives preceding the dose of glasdegib (whichever is longer). 10. Subjects with a history of or current positive results for human immunodeficiency virus (HIV). 11. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study. Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area under the plasma concentration-time curve from time 0 to infinity (AUCinf) of glasdegib | Day 1 to Day 6 | PK parameter of glasdegib to be calculated from the plasma concentration-time data |
| Maximum observed plasma concentration (Cmax) of glasdegib | Day 1 | PK parameter of glasdegib to be calculated from the plasma concentration-time data |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of adverse events | Day 1 to Day 35 | Safety and tolerability of glasdegib, including monitoring of adverse events (AE) and addition of concomitant medications; an AE is any untoward medical occurrence in a study subject administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage |
| Incidence of clinical laboratory abnormalities | Day 1 to Day 35 | Safety and tolerability of glasdegib including blood chemistry, hematology, coagulation, and urinalysis parameters |
| Incidence of vital sign abnormalities | Day 1 to Day 35 | Safety and tolerability of glasdegib including monitoring of blood pressure and pulse rate |
| Incidence of clinical ECG abnormalities | Day 1 to Day 35 | Safety and tolerability of glasdegib including monitoring of QT interval, RR, QTc, QTS, and PR |
Countries
United States
Outcome results
None listed