| Eligibility |
Inclusion Criteria:
- Subject has a Body Mass Index (BMI) range of 18.5 to 36.0 kg/m^2, inclusive and weighs
at least 50 kg at screening.
- Female subject is not pregnant and at least one of the following conditions apply:
- Not a woman of childbearing potential (WOCBP)
- WOCBP who agrees to follow the contraceptive guidance for at least 30 days prior
to day -1 through at least 30 days after IP administration.
- Female subject must agree not to breastfeed starting at screening and throughout the
study period and for 30 days after IP administration.
- Female subject must not donate ova starting at first dose of IP and throughout the
study period and for 30 days after IP administration.
- Subject agrees not to participate in another interventional study while participating
in the present study.
Additional Criterion for Subjects with Hepatic Impairment:
- Subject has mild (Child-Pugh classification Class A, score 5 or 6) or moderate
(Child-Pugh classification Class B, score 7 to 9) hepatic impairment.
Exclusion Criteria:
- Subject has received any investigational therapy within 28 days or five half-lives,
whichever is longer, prior to Day -1.
- Subject has any condition which makes the subject unsuitable for study participation.
- Female subject who has been pregnant within six months prior to screening or
breastfeeding within three months prior to screening.
- Subject has a known or suspected hypersensitivity to fezolinetant or any components of
the formulation used.
- Subject has had previous exposure with fezolinetant.
- Subject has used any inducer of cytochrome P450 (CYP) 1A2 in the three months prior or
inhibitors of CYP 1A2 in the two weeks or five half-lives of the inhibitor, whichever
is longer, prior to Day -1.
- Subject has any clinically significant history of allergic conditions (including drug
allergies, asthma, eczema or anaphylactic reactions, but excluding untreated,
asymptomatic, seasonal allergies) prior to IP administration.
- Subject has/had febrile illness or symptomatic, viral (excluding chronic hepatitis B
and C), bacterial (including upper respiratory infection) or fungal (noncutaneous)
infection within one week prior to Day -1.
- Subject has smoked, used tobacco-containing products and nicotine or
nicotine-containing products (e.g., electronic vapes) within six months prior to
screening or the subject tests positive for cotinine at screening or on Day -1.
- Subject has had significant blood loss, donated = 1 unit (450 mL) of whole blood or
donated plasma within seven days prior to Day -1 and/or received a transfusion of any
blood or blood products within 60 days.
- Subject is an employee of Astellas, the study-related contract research organizations
(CROs) or the clinical unit.
- Subject has creatinine level outside normal limits on Day -1. In such a case, the
assessment may be repeated once.
Additional Criteria for Subjects with Hepatic Impairment:
- Subject has any history or evidence of any clinically significant cardiovascular,
gastrointestinal, endocrinologic, hematologic, immunologic, metabolic, dermatologic,
psychiatric, renal and/or other major disease or malignancy, not related to current
disease state.
- Subject has a history of consuming > 7 units of alcoholic beverages per week within
three months prior to screening or has a history of alcoholism or
drug/chemical/substance abuse within one year prior to screening (note: 1 unit = 12
ounces of beer, 4 ounces of wine, 1 ounce of spirits/hard liquor) or the subject tests
positive for alcohol at screening or on Day -1.
- Subject has a mean pulse < 45 or > 90 beats per minute (bpm); mean systolic blood
pressure (SBP) > 160 millimeters of mercury (mmHg); mean diastolic blood pressure
(DBP) > 100 mmHg (measurements taken in triplicate after subject has been resting in
the supine position for at least five minutes; pulse will be measured automatically)
on Day -1. If the mean blood pressure exceeds the limits above, one additional
triplicate may be taken.
- Subject has a mean corrected QT interval using Fridericia's formula (QTcF) of > 480
millisecond (msec) on Day -1. If the mean QTcF exceeds the limits above, one
additional triplicate electrocardiogram (ECG) may be taken.
- Subject has used any drugs of abuse (amphetamines, barbiturates, benzodiazepines,
cannabinoids, cocaine and/or opiates) within three months prior to Day -1 or the
subject tests positive for drugs of abuse (amphetamines, barbiturates,
benzodiazepines, cannabinoids, cocaine and opiates) at screening or on Day -1, unless
the positive test is due to prescription drug use that is approved by the principal
investigator and sponsor.
- Subject has a positive serology test for hepatitis A virus (HAV) antibodies
(immunoglobulin M [IgM]) or antibodies to human immunodeficiency virus (HIV) type 1
and/or type 2 at screening.
- Subject has fluctuating or rapidly deteriorating hepatic function, as indicated by
strongly varying or worsening of clinical and/or laboratory signs of hepatic
impairment within the screening period (e.g., advanced ascites, infection of ascites,
fever, active gastrointestinal bleeding).
- Subject who has had a change in dose regimen of medically required medication(s) in
the two weeks prior to screening (permitted concomitant medications) and/or subject
for whom dose changes are likely to occur during the study (minor dose changes are
allowed in agreement with the sponsor) and/or subject has used nonpermitted
concomitant medication(s) in the three weeks prior to admission to the clinical unit
(nonpermitted concomitant medications include any known hepatic enzyme-altering agents
or compounds known to restrict metabolism, vitamins, hormonal contraceptives, hormone
replacement therapy [HRT] and natural and herbal remedies, e.g., St. John's Wort).
- Subject has a presence of a hepatocellular carcinoma, or an acute liver disease caused
by an infection or drug toxicity.
- Subject has severe portal hypertension or surgical portosystemic shunts, including
transjugular intrahepatic portosystemic shunt.
- Subject has biliary liver cirrhosis, biliary obstruction or other cause of hepatic
impairment not related to parenchymal disorder and/or disease of the liver.
- Subject has signs of significant hepatic encephalopathy (hepatic encephalopathy Grade
= 2).
- Subject has severe ascites and/or pleural effusion.
- Subject has esophageal/gastric variceal bleeding in the past six months prior to
screening, unless banded.
- Subject has thrombocyte level below 40 × 10^9 per liter and /or hemoglobin < 90 grams
per liter.
- Subject has previous liver transplantation.
Additional Criteria for Healthy Subjects with Normal Hepatic Function:
- Subject has any of the liver function tests (alkaline phosphatase [ALP], alanine
aminotransferase [ALT], aspartate aminotransferase [AST] and total bilirubin [TBL]) =
1.5 × the Upper Limit of Normal (ULN) or international normalized ratio (INR) > 1.1 on
Day -1. In such a case, the assessment may be repeated once.
- Subject has any history or evidence of any clinically significant cardiovascular,
gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic,
urologic, pulmonary, neurologic, dermatologic, psychiatric, renal and/or other major
disease or malignancy.
- Subject has a history of consuming > 7 units of alcoholic beverages per week within
six months prior to screening or has a history of alcoholism or
drug/chemical/substance abuse within two years prior to screening (note: 1 unit = 12
ounces of beer, 4 ounces of wine, 1 ounce of spirits/hard liquor) or the subject tests
positive for alcohol at screening or on Day -1.
- Subject has any clinically significant abnormality following the physical examination,
ECG and protocol-defined clinical laboratory tests at screening or on Day -1.
- Subject has a mean pulse < 45 or > 90 bpm; mean SBP > 140 mmHg; mean DBP > 90 mmHg
(measurements taken in triplicate after subject has been resting in the supine
position for at least five minutes; pulse will be measured automatically) on Day -1.
If the mean blood pressure exceeds the limits above, one additional triplicate may be
taken.
- Subject has a mean QTcF of > 450 msec on Day -1. If the mean QTcF exceeds the limits
above, one additional triplicate ECG may be taken.
- Subject has used any prescribed or nonprescribed drugs (including vitamins, hormonal
contraceptives, HRT and natural and herbal remedies, e.g., St. John's Wort) in the two
weeks prior to IP administration, except for occasional use of acetaminophen (up to 2
g/day) and topical dermatological products, including corticosteroid products.
- Subject has used any drugs of abuse (amphetamines, barbiturates, benzodiazepines,
cannabinoids, cocaine and/or opiates) within three months prior to Day -1 or the
subject tests positive for drugs of abuse (amphetamines, barbiturates,
benzodiazepines, cannabinoids, cocaine and opiates) at screening or on Day -1.
- Subject has a positive serology test for HAV antibodies (IgM), hepatitis B surface
antigen, hepatitis C virus antibodies or antibodies to HIV type 1 and/or type 2 at
screening.
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