Hepatic Impairment
Conditions
Keywords
Pacritinib
Brief summary
This is a Phase 1 study designed to assess the effect of hepatic insufficiency on the PK of pacritinib by study of 14-day BID dosing of pacritinib in subjects with moderate and severe hepatic impairment compared to healthy matched control subjects with normal liver function. Safety and tolerability of multiple day dosing of pacritinib in the subject populations will also be evaluated.
Detailed description
This is a Phase 1, multi-center, open-label, multiple-dose, parallel-group study designed to assess the effect of hepatic insufficiency on the PK of 200 mg BID pacritinib. A total of approximately 22 to 32 subjects are planned, with approximately 8 moderate hepatically impaired subjects, approximately 6 to 8 severe hepatically impaired subjects, and approximately 8 to 16 healthy subjects with normal hepatic function. The primary objective of this study is to characterize and compare the steady-state PK profile of multiple doses (14 days) of 200 mg BID pacritinib in the study population, and the secondary objective is to evaluate the safety and tolerability of multiple doses (14 days) of 200 mg BID pacritinib. The study will consist of a screening period (Day -28 to Day -2), check-in (Day -1), a confinement period including treatment period (Day 1 through Day 14) and post-treatment period (Day 15 through Day 20), followed by a discharge visit (Day 21), and an EOS follow-up telephone call (Day 44). Serial blood samples for PK analysis of pacritinib will be collected pre dose through Day 21 at protocol-specified timepoints CK 18 will be collected . Safety and tolerability will be assessed by AEs, clinical laboratory tests, vital will occur 4 and 24 hours after the AM dose on Day 1, Day 10, Day 12, and Day 14 signs, ECGs, and physical examinations.
Interventions
DRUGoral dose of 200 mg pacritinib twice daily (BID)
Subjects will receive 200 mg BID pacritinib for 14 days.
Sponsors
PPD Development, LP
CTI BioPharma
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
Yes
Inclusion criteria
1. Able to provide written informed consent. 2. Able to communicate well with the investigator and understands and agrees to comply with all protocol requirements. 3. Is male or female ≥18 to ≤85 years of age, inclusive, at screening. 4. Has a BMI 18.0 to 42.0 kg/m2, inclusive, at screening. 5. Female subjects of childbearing potential must be surgically sterile, or postmenopausal, or agree use an acceptable method of birth control from the time of ICF or 10 days prior to check-in and until 30 days after Day 21. Female subjects of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test at check-in. 6. Male subjects with female partners of childbearing potential must be vasectomized, be willing to use an acceptable method of birth control, or to practice abstinence during the study from check-in until 90 days following Day 21. 7. Male subjects must refrain from sperm donation from check-in until 90 days following Day 21. Additional Inclusion Criteria for Subjects with Hepatic Impairment Only: 8. Has chronic (\>6 months) and stable hepatic impairment (ie, no acute episodes of illness within 30 days prior to screening due to deterioration of hepatic function) as assessed by a Child-Pugh classification score of moderate (7 to 9 points) or severe (10 to 15 points). 9. Is judged by the investigator to be in good general health, as determined by medical history, clinical laboratory assessments, vital sign measurements, 12 lead ECG results, and physical examination findings, except for findings that, as judged by the investigator, are consistent with the subject's hepatic impairment or other stable concomitant medical conditions at screening and check-in. Additional Inclusion Criteria for Healthy Subjects Only: 10. Has normal hepatic function. 11. Must match a subject in Group 1 and/or Group 2, with respect to sex, age (±10 years), and BMI (±20%). 12. Is judged by the investigator to be in good general health, as determined by medical history, clinical laboratory assessments, vital sign measurements, 12 lead ECG results, and physical examination findings at screening and check-in.
Exclusion criteria
1. Has a history or clinical manifestations of a significant neurological, renal, cardiovascular, gastrointestinal, pulmonary, hematologic, immunologic, or psychiatric disease that would preclude study participation, as judged by the investigator. 2. Has any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs or which may jeopardize the subjects participation in the study. The investigator should be guided by evidence of any of the following: * History of inflammatory bowel disease * History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection (esophageal varix surgery is allowable) * Clinical evidence of pancreatic injury or pancreatitis * Evidence of urinary obstruction or difficulty in voiding at screening 3. Has a baseline seated systolic blood pressure \>160 mm Hg or ≤90 mm Hg and a diastolic blood pressure of \>100 mm Hg or ≤50 mm Hg, inclusive, at screening and check in unless deemed not clinically significant by the investigator, as approved by the sponsor. 4. Has a baseline seated pulse rate of \<50 bpm or \>100 bpm and/or an oral body temperature \<35.0°C or \>37.5°C when vital signs are measured at screening and check in. 5. Has a significant QT interval prolongation (QTcF of \>480 msec) or other risks for QT prolongation at screening or check-in. 6. Has a history of being immunocompromised or has a positive serum test result for HIV types 1 or 2 antibodies at screening. 7. Has had a significant illness within the 2 weeks prior to check-in. 8. Has a history of alcoholism, drug abuse, or alcohol withdrawal within 3 months before screening, or excessive alcohol consumption (regular alcohol intake \>21 units per week for male subjects and \>14 units of alcohol per week for female subjects) (1 unit is equal to approximately ½ pint \[200 mL\] of beer, 1 small glass \[100 mL\] of wine, or 1 measure \[25 mL\] of spirits). 9. Is unable or unwilling to abstain from alcohol from 72 hours prior to check-in until Day 21. 10. Is unable or unwilling to abstain from caffeine, xanthine-containing beverages or food (eg, coffee, tea, chocolate, and caffeinated sodas, colas) from check in until Day 21. 11. Has consumed grapefruit, grapefruit juice, Seville oranges, or products containing any of these, from 7 days prior to check-in to the study site until Day 21. 12. Smokes \>10 cigarettes daily and is unwilling to reduce to ≤5 daily from the time of screening through Day 21. 13. Is involved in strenuous activity or contact sports within 24 hours prior to check-in or during the study. 14. Has donated blood or blood products \>450 mL within 30 days prior to the first dose of study drug. 15. Has used over-the-counter medications (except as prescribed by a physician or paracetamol \[up to 2 g per day\]), vitamins, or phyto-therapeutic/herbal/plant-derived preparations within 14 days of check-in. 16. Has used a potent CYP3A4 inducer within 30 days prior to check-in or used a potent CYP3A4 inhibitor within 15 days prior to check-in. 17. Has received treatment in another clinical study of an investigational drug (or medical device) or investigational vaccine within 30 days or 5 half-lives (whichever is longer) prior to check-in. 18. The subject has previously received pacritinib. 19. Has a known hypersensitivity to study drug (ie, allergy to pacritinib or any excipients or drugs similar to pacritinib). 20. Has had a recent bleeding event of Grade ≥2 within 3 months prior to first dose of study drug. 21. Has used antiplatelet or anticoagulant therapy within 14 days prior to check in with the exception of aspirin at doses ≤100 mg daily. 22. Has a history of heart failure with a New York Heart Association Class II or above. 23. Has a recent cardiac event of Grade ≥3 within 6 months prior to check in. 24. In the opinion of the investigator, the subject is not suitable for entry into the study. Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PK | Day 1- (Day 1: Cmax) | To characterize and compare the steady-state PK profile of multiple doses (14 days) of 200 mg BID pacritinib in subjects with moderate and severe hepatic impairment with that of healthy matched control subjects with normal liver function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of adverse events | Day 1-44 | Safety and tolerability of pacritinib, including monitoring of adverse events (AEs); 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 1-21 | Safety and tolerability of pacritinib, including hematology, coagulation, chemistry, and urinalysis parameters |
| Incidence of vital sign abnormalities | Day 1-21 | Safety and tolerability of pacritinib, including monitoring of blood pressure, heart rate, respiratory rate, and body temperature |
| Incidence of ECG abnormalities | Day1-21 | Safety and tolerability of pacritinib, including monitoring of RR interval, PR interval, QRS width, QT interval, and QTcF |
| Incidence of physical examination abnormalities | Day 1-21 | Safety and tolerability of pacritinib, including monitoring for abnormalities on physical examination |
Countries
United States
Outcome results
None listed