| Eligibility |
Inclusion Criteria:
- Males or females, of any race, between 18 and 70 years of age, inclusive.
- BMI between 18.0 and 38.0 kg/m2, inclusive, and body weight = 50 kg.
- Females will not be pregnant (or planning to get pregnant) or lactating at Screening
or Check in (Day 1), and females of childbearing potential and males will agree to use
contraception .
- Male subjects must not donate sperm and female subjects must not donate ova from Check
in (Day 1) until 90 days after their dose of study drug.
Subjects with Normal Hepatic Function Only
- Matched to subjects with mild, moderate, or severe hepatic impairment in sex, age (±
10 years), and BMI (± 20%).
- In good health, determined by no clinically significant findings from medical history,
physical examination, 12 lead ECG, vital signs measurements, and clinical laboratory
evaluations (congenital non hemolytic hyperbilirubinemia [e.g., suspicion of Gilbert's
syndrome based on total and direct bilirubin] is not acceptable) at Screening and
Check in as assessed by the investigator (or designee).
Subjects with Hepatic Impairment Only
- Documented chronic stable liver disease (Child Pugh Class A [mild], B [moderate], or C
[severe] at Screening); diagnosis of cirrhosis due to parenchymal liver disease. This
will exclude biliary liver cirrhosis or other causes of hepatic impairment not related
to parenchymal disorder:
- 'Documented' is defined by at least one of the following: medical history, physical
examination, hepatic ultrasound, computed axial tomography scan, magnetic resonance
imaging, and/or liver biopsy.
- 'Chronic stable' is defined as no clinically significant change in disease status
within the last 30 days, as documented by the subject's recent medical history (e.g.,
no worsening of clinical signs of hepatic impairment, or no worsening of total
bilirubin or prothrombin time [PT] by more than 50%).
- Subjects with mild, moderate, or severe hepatic impairment may have medical findings
consistent with their hepatic dysfunction, as determined by medical history, physical
examination, 12 lead ECG, vital sign measurements, and clinical laboratory evaluations
at Screening and Check in (Day 1). Subjects with abnormal findings considered not
clinically significant by the investigator will be eligible.
Exclusion Criteria:
- Significant history or clinical manifestation of any metabolic, allergic,
dermatological, renal, hematological, pulmonary, cardiovascular, gastrointestinal,
neurological, respiratory, endocrine, or psychiatric disorder, as determined by the
investigator (or designee).
- History of significant hypersensitivity, intolerance, or allergy to any drug compound,
food, or other substance, unless approved by the investigator (or designee).
- History of stomach or intestinal surgery or resection that would potentially alter
absorption and/or excretion of orally administered drugs (cholecystectomy will not be
allowed; uncomplicated appendectomy and hernia repair will be allowed).
- Presence of any other condition (including surgery) known to interfere with the
absorption, distribution, metabolism, or excretion of medicines.
- Ventricular dysfunction or history of risk factors for Torsade de Pointes (TdP; e.g.,
unexplained syncope, known long QT syndrome, heart failure, and cardiomyopathy).
Subjects will be excluded if there is a family history of long QT syndrome.
- Evidence of hepatorenal syndrome and estimated glomerular filtration rate (eGFR) = 60
mL/min/1.73 m2 or abnormal sodium and potassium levels, as determined by the
investigator (or designee), calculated using the Chronic Kidney Disease Epidemiology
Collaboration (CKD EPI) equation at Screening or Check in (Day 1).
- Clinically significant physical examination abnormality, as determined by the
investigator (or designee).
- Use or intend to use any medications/products known to alter drug absorption,
metabolism, or elimination processes, including St. John's wort, within 30 days prior
to dosing, unless deemed acceptable by the investigator (or designee).
- Use of any sensitive substrates for cytochrome P450 (CYP)2C8, moderate or strong
inhibitors or inducers of CYP3A4/5, or substrates for p glycoprotein (P gp) within 30
days prior to study drug administration.
- Consumption of grapefruit, grapefruit products, star fruit, star fruit products, or
Seville oranges within 72 hours prior to study drug administration (Day 1) and
throughout the study (until after the Follow up Visit).
- History of alcoholism or drug/chemical abuse within 6 months prior to Check in (Day
1).
- Alcohol consumption of > 21 units per week for males and > 14 units for females. One
unit of alcohol equals 12 oz (360 mL) beer, 1½ oz (45 mL) liquor, or 5 oz (150 mL)
wine within the 6 months prior to Check in (Day 1).
- Positive urine drug screen or positive alcohol breath or urine test result at
Screening and Check in (Day 1), that is not otherwise explained by permitted
concomitant medications. A positive alcohol test may be repeated once at Screening. A
positive alcohol test may not be repeated at Check in (Day 1).
- Positive human immunodeficiency virus test (Appendix 2).
- Participation in a clinical study involving administration of an investigational drug
(new chemical entity) in the past 30 days or 10 half lives (if known), whichever is
longer, prior to dosing.
- Current enrollment in another clinical study.
- Receipt of blood products within 2 months prior to Check in.
- Donation or loss of = 550 mL blood from 3 months prior to Screening, plasma from 2
weeks prior to Screening, or platelets from 6 weeks prior to Screening.
Subjects with Normal Hepatic Function Only
- Confirmed supine blood pressure > 140 mmHg or < 90 mmHg and/or supine diastolic blood
pressure > 90 mmHg or < 50 mmHg, or resting (supine) heart rate < 45 beats per minute
(bpm) or > 100 bpm at Screening or Check in (Day 1), with a QT interval corrected for
heart rate using Fridericia's method (QTcF) > 450 ms for male subjects and > 470 ms
for female subjects.
- Positive hepatitis panel (Appendix 2).
- Use of tobacco or nicotine containing products within 6 months prior to Check in (Day
1), or positive cotinine at Screening or Check in (Day 1).
- Clinically significant abnormal laboratory values (clinical chemistry, hematology,
coagulation, and urinalysis), as determined by the investigator (or designee).
- Significant history or clinical manifestation of hepatic disorder, as determined by
the investigator (or designee).
- History or presence of liver disease or liver injury as indicated by any clinically
significant deviations from normal reference ranges in liver function tests, unless
approved by the investigator (or designee).
- History of diabetes mellitus.
- Use or intend to use any prescription medications/products other than prescribed
hormone replacement therapy, implantable, or intrauterine contraceptives within 30
days prior to dosing, unless deemed acceptable by the investigator (or designee).
- Use or intend to use slow release medications/products considered to still be active
within 30 days prior to Check in (Day 1), unless deemed acceptable by the investigator
(or designee).
- Use or intend to use any non prescription medications/products including vitamins,
minerals, and phytotherapeutic , herbal , or plant derived preparations within 7 days
prior to Check in (Day 1), unless deemed acceptable by the investigator (or designee).
Subjects with Hepatic Impairment Only
- Confirmed supine blood pressure > 150 mmHg or < 90 mmHg and/or supine diastolic blood
pressure > 90 mmHg or < 50 mmHg, or resting (supine) heart rate < 45 bpm or > 100 bpm
at Screening or Check in (Day 1), with a QTcF > 470 ms for both male and female
subjects.
- History of clinically significant left sided heart disease and/or clinically
significant cardiac disease.
- Values outside the normal range for liver function tests that are not consistent with
their hepatic condition, as determined by the investigator (or designee).
- Use of a new medication, or a change in dose, for the treatment of hepatic
encephalopathy within 90 days prior to Check in (Day 1).
- Use of prescription drugs within 30 days prior to Check in (Day 1), with the exception
of therapies for hepatic disease and treatment of associated disorders that had been
stable for at least 3 months prior to administration of study drug (Day 1) or
prescribed hormone replacement therapy, implantable, or intrauterine contraceptives.
- Recent history of, or the treatment of, esophageal bleeding (within the past 180
days), unless banded.
- History of unstable diabetes mellitus (as evidenced by hemoglobin A1c [HbA1c] = 9.0%
at Screening). Concomitant medications for the treatment of diabetes mellitus must be
approved by the investigator (or designee), Sponsor, and Covance Medical Monitor.
- Presence of a portosystemic shunt.
- Recent history of paracentesis within 90 days prior to Check in (Day 1).
- Current functioning organ transplant or awaiting an organ transplant.
- Evidence of severe ascites.
- Recent history of hepatic encephalopathy (Grade 2 or above) within 180 days prior to
Screening.
- Smoke more than 10 cigarettes or use the equivalent tobacco or nicotine containing
products per day or inability to refrain from tobacco use 2 hours pre dose until 4
hours post dose.
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