| Eligibility |
Inclusion Criteria:
- Physically and mentally healthy male and females, aged 18 to 45, inclusive;
- Body mass index (BMI) between 18 to 30 kg/m2, inclusive;
- Nicotine-free (cigarettes, pipe, cigar, chewing tobacco, nicotine patches, etc.) for
at least 6 months prior to Screening until the end of the study;
- Normal renal function as defined by estimated glomerular filtration rate >90
mL/min/1.73m2;
- Willing to remain in the study facility for the duration of the domicile period and
able to return for all out-patient visits;
- Ability to understand and sign written informed consent, which must be obtained prior
to any study-related procedures being completed;
- Willing to avoid adding salt substitutes that contain potassium chloride or potassium
lactate to food from 7 days prior to dosing through the duration of the study;
- Women of childbearing potential (WOCBP), must agree to 2 medically accepted, effective
methods of birth control during the study and for 90 days after the end of the study.
Adequate methods of contraception are defined as those that result in a low failure
rate (<1% per year) when used consistently and correctly. Such methods include the use
of oral contraceptives, other hormonal contraceptives (vaginal products, skin patches,
or implanted or injectable products), or mechanical products (such as an intrauterine
diaphragm, condoms, or spermicides);
- Women of childbearing potential are defined as women who are not surgically or
chemically sterilized, including hysterectomy or bilateral oophorectomy (tubal
ligation is not acceptable), and who are between menarche and 1 year post-menopause;
and
- Post-menopausal is defined as amenorrhoeic for at least 1 year prior to screening AND,
if aged under 45 years have a serum follicle stimulating hormone (FSH) level of at
least 30 IU/L. Women who are taking hormone replacement therapy (HRT) do not have to
have FSH assessments, but the amenorrhea (before starting HRT) must have been
naturally (spontaneously) occurring and have been accompanied by an appropriate
clinical profile (e.g., age appropriate, history of vasomotor symptoms);
- Males with partners who are WOCBP must agree to use condoms plus spermicide and their
female partner must also be using contraception (e.g., hormonal or intra-uterine
device). This double contraception must be used from the first dose of study drug
until at least 90 days after the last dose of study drug;
- Males must also refrain from donating sperm during the study and for 90 days after the
last dose;
- Negative urine test for drugs of abuse (opiates, benzodiazepines, amphetamines,
cannabinoids including tetrahydrocannabinol, cocaine, barbiturates, and
phencyclidine), nicotine/cotinine, and breath alcohol test at Screening and Check-in;
and
- Is in good general health as determined by the Investigator's review of medical
history, concomitant medications, physical examination, and clinical laboratory and
electrocardiogram (ECG) evaluations at the Screening Visit.
Exclusion Criteria:
- History of any illness, that, in the opinion of the Investigator, could confound the
results of the study or pose an additional risk to the subject by their participation
in the study ;
- History or presence of significant cardiovascular, pulmonary, hepatic, renal,
hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological,
or psychiatric disease;
- Any surgical or medical condition that could interfere with the absorption,
distribution, metabolism, or excretion of the IMP;
- History of any clinically significant drug allergy as per the Investigator's judgment;
- History of alcohol abuse or illicit drug use within 2 years of Screening;
- Use of marijuana (including prescribed marijuana) within 3 months prior to Screening;
- Use of nicotine within 6 months prior to screening;
- Use of any prescription or over-the-counter medication, vitamins/herbal supplements
(with the exception of hormonal contraceptives or HRT and sporadic use of
acetaminophen or ibuprofen) within 7 days (14 days if the drug is a potential enzyme
inducer) prior to study allocation;
- Has taken any investigational medicinal product (IMP) within 30 days or 5 half-lives
of that IMP (whichever is longer) prior to dosing;
- Donation of blood or blood products within 30 days of dosing;
- Acute illness within 14 days of dosing; acute illness occurring prior to the 14 days
before dosing must show signs of complete recovery;
- Regular caffeine consumption of >300 mg/day (i.e., approximately 3 cups [8 fluid
ounces] of coffee or 10 cans [12 fluid ounces] of cola) 7 days prior to dosing.
Inability to restrict consumption of caffeine during the domicile period;
- Positive serologic findings for human immunodeficiency virus (HIV), hepatitis B virus
(HBV) or hepatitis C virus (HCV);
- Diets that could alter metabolism (i.e., vegetarian, high protein, Slim Fast®,
Nutrisystem®, etc.) 7 days prior to dosing;
- Weight loss or gain of =10% in the 30 days prior to dosing;
- Strenuous exercise (>5 per week) within 2 weeks prior to dosing;
- Positive urinary cotinine level, breath alcohol, or drug screen at Screening and/or
admission (both admissions for subjects in the crossover treatment group);
- Systolic BP >140 mmHg or <90 mmHg or diastolic BP >90 mmHg or <60 mmHg at Screening
with 1 repeat allowed per Investigator discretion at Screening and Day -1 (and Day 14
for subjects in the crossover treatment group period 2);
- Heart rate <40 bpm or >100 bpm at Screening;
- Consumption of any nutrients known to modulate cytochrome P450 3A4 (CYP3A4) or any
strong inhibitors or inducers of CYP3A4, starting from 14 days prior to the first dose
of study drug at Day 1 until the end of study assessments. Inability to refrain from
consumption of grapefruit and Seville oranges or St. John's wort (14 days prior to
dosing and during the study);
- Positive pregnancy test result;
- Subject has any finding that, in the view of the Investigator and/or Medical Monitor,
would compromise the subject's safety; or
- The Investigator has any reason to believe that the subject may be unable to fulfill
the protocol visit schedule or requirements.
|
