| Eligibility |
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 Exclusion Criteria for Subjects with Hepatic Impairment Only:
25. Has fluctuating or rapidly deteriorating hepatic function, as indicated by recent
history or worsening of clinical (ie, abdominal pain, nausea, vomiting, anorexia, or
fever) and/or laboratory signs of hepatic impairment, as judged by the investigator.
26. Has symptoms or history of Stage II or worse degree of encephalopathy that would
prohibit informed consent within 6 months before check-in, as judged by the
investigator.
27. Has clinical evidence of ascites that requires paracentesis more frequently than every
3 weeks at screening or check-in.
28. Has a history of a surgical portosystemic shunt.
29. Has evidence of hepatorenal syndrome.
30. Has any of the following laboratory results:
- Estimated serum creatinine clearance (Cockcroft-Gault) <50 mL/min
- Absolute neutrophil count <1500 cells/mm3
- Platelet count <30,000 cells/mm3
- Hemoglobin <9 g/dL
- Activated partial thromboplastin time, international normalized ratio, partial
thromboplastin time, or prothrombin time clinically significant per investigator
discretion.
31. Has evidence of progressive liver disease (as available within the last 4 weeks,
including the time period between screening and check-in) as indicated by liver
transaminases, alkaline phosphatase, and gamma-glutamyl transpeptidase, as judged by
the investigator.
32. Has evidence of active acute or chronic hepatitis B virus.
33. Has a positive test result for drugs of abuse (except for positive results associated
with prescription medications that have been reviewed and approved by the
investigator) or positive alcohol urine or breath test at screening or check-in. A
positive tetrahydrocannabinol result at screening will not be exclusionary, but must
be negative at check-in.
34. Has a urinalysis with any result outside the normal range and deemed clinically
significant by the investigator. Results deemed not clinically significant by the
investigator in consultation with the sponsor may be allowed.
35. Has initiated any otherwise allowable prescription or over-the-counter medications
within 15 days of check-in. Some of these medications may have to be discontinued 12
to 48 hours before study drug dosing, or earlier. As medication regimens vary and
cannot be predicted, each subject will be discussed with the sponsor individually. The
dose of an approved medication must remain stable from 7 days before study drug dosing
and throughout the study.
Additional Exclusion Criteria for Healthy Subjects Only:
36. Has a positive test result for hepatitis B surface antigen and/or hepatitis C virus
antibodies.
37. Any screening or check-in laboratory results outside the normal range and deemed
clinically significant. Results outside the normal range and deemed not clinically
significant by investigator, in consultation with the sponsor, are allowable.
38. Has used any prescription medication within 30 days prior to check in.
39. Activated partial thromboplastin time, international normalized ratio, partial
thromboplastin time, or prothrombin time > 1.5 × ULN.
40. Has a positive test result for drugs of abuse or positive alcohol urine or breath test
prior to the first dose of study drug.
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