The Safety Evaluation of Aminophylline and Ambrisentan When Administered Orally Alone and in Combination to Healthy Volunteers
Condition: High Altitude Pulmonary Hypertension
MeSH terms: Hypertension, Pulmonary; Hypertension
Intervention: Aminophylline; Ambrisentan; Aminophylline plus ambrisentan
Intervention description: Drug will be administered as a single oral dose of 500mg, followed by a 48h washout period.; Drug will be administered as a single dose of 5mg, followed by a 48h washout period; Drugs will be given as single doses of 500mg (aminophylline) and 5mg (ambrisentan), followed by a 48h washout period
Intervention MeSH terms: Ambrisentan; Aminophylline
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Maximum age: 40 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: High altitude induced fatigue; High altitude induced pulmonary Hypertension

Summary:

      This is a Phase I, three period, two sequence, open-label, randomized, crossover study, with
      the primary objective of testing the safety and tolerability of combined oral doses of
      aminophylline and ambrisentan in healthy human subjects. The secondary objective is to assess
      the pharmacokinetic profiles of theophylline (aminophylline) and ambrisentan when
      administered alone or in combination. It is hypothesized that the combination of these drugs
      is generally safe, and that no drug interaction can be observed.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subjects must give written informed consent to participation in the study prior to
             screening. Consent will be documented by the subject's dated signature that will be
             counter-signed and dated by a witness. The appropriate HIPAA authorization forms must
             be signed and dated by the subject.

          -  Subjects must be healthy non-smoking adult male and female volunteers between the ages
             of 18 and 40 years, with a BMI of 18-30 kg/m2 and weighing at least 150 lbs. Subjects
             health status will be determined by the medical history, physical examination, vital
             signs, electrocardiogram, blood chemistry, hematology, and urinalysis performed at
             screening.

          -  Subjects must be willing to fast a minimum of 8 hours prior to screening.

          -  Subjects must be willing to abstain from alcohol and xanthine-containing food and
             beverages from the time of admission to the clinical research inpatient unit through
             at least 48 hours following discharge.

          -  Subjects must be willing to remain in the clinical research unit continuously for the
             inpatient portion of the study from admission to discharge.

          -  Women who are of non-childbearing potential, must be either surgically sterile
             (removal of both ovaries and/ or uterus at least 12 months prior to dosing), or
             naturally postmenopausal (spontaneous cessation of menses) for at least 24 consecutive
             months prior to dosing on Day -1, with an FSH level at screening of ≥ 40 mIU/mL.

          -  Women of child-bearing potential must have a negative serum pregnancy test within 48
             hours of receiving study drug and must agree to avoid pregnancy during study and for
             one month after the last dose of study drug

          -  Male subjects of child-fathering potential must agree to avoid causing pregnancy
             during study and for three months after the last dose of study drug.

          -  Subjects must agree not to donate blood, plasma, platelets, or any other blood
             components during the study and for 4 weeks after the last dose.

          -  Male subjects must agree not to donate sperm during the study and for 12 weeks after
             the last dose.

        Exclusion Criteria:

          -  Subjects with laboratory results outside the normal range, if considered clinically
             significant by the Investigator. In addition, subjects must have a normal hematocrit
             and hemoglobin concentration and be ≥ 36% and ≥ 12.0 g/dL, respectively.

          -  A mental capacity that is limited to the extent that the subject cannot provide legal
             consent or understand information regarding the side effects of the study drug.

          -  Currently abusing drugs or alcohol or with a history of drug or alcohol abuse within
             the past two years.

          -  Unwillingness or lack of ability to comply with the protocol, or to reside in the
             inpatient unit during the required time period, or to cooperate fully with the
             Principle Investigator and site personnel.

          -  Use of any of the following: Any concomitant medication including oral contraceptive
             hormones. Subjects who have received any prescribed or non-prescribed
             (over-the-counter [OTC]) systemic medication, topical medications, or herbal
             supplements within 14 days from Day 1. St. John's Wort (hypericin) must not have been
             taken for at least 30 days prior to Period 1, Day 1. Any drugs, foods or substances
             known to be strong inhibitors or strong inducers of CYP enzymes (also known as
             cytochrome P450 enzymes); especially CYP 1A2, or Pgp within 30 days prior to Period 1,
             Day 1

          -  Clinically significant ECG abnormality in the opinion of the Investigator. Vital signs
             or clinically significant laboratory values at the screening visit that in the opinion
             of the Investigator would make the subject an inappropriate candidate for the study.

          -  Has taken any other investigational drug during the 30 days prior to the screening
             visit or is currently participating in another investigational clinical trial.

          -  Made any significant donation (including plasma) or have had a significant loss of
             blood within 30 or 90 days prior to Period 1, Day 1.

          -  History or manifestation of clinically significant neurological, gastrointestinal,
             renal, hepatic, cardiovascular, psychological, pulmonary, metabolic, endocrine,
             hematologic or other medical disorders.

          -  Subjects who are carriers of the Hepatitis B surface antigen (HbsAg), Hepatitis C
             antibody, or HIV antibody

          -  Serious mental or physical illness within the past year.

          -  Male subjects who consume more than 28 units of alcohol per week and female subjects
             who consume more than 21 units of alcohol per week (one unit of alcohol equals 250 mL
             of beer, 100 mL or a medium glass of wine, or 25 mL of spirits) or those subjects who
             have a significant history of alcoholism or drug/ chemical abuse within the last 2
             years

          -  Failure to agree to abstain from alcohol, cola, tea, coffee, chocolate and other
             caffeinated drink/ food from 2 days before dosing and throughout confinement

          -  Positive results on screening tests for drugs of abuse, cotinine or alcohol at
             screening or the pre-dose assessment at check-in

          -  Subjects who have used tobacco products or nicotine-containing products (including
             smoking cessation aids, such as gums or patches) within 12 months prior to Period 1,
             Day 1

          -  Women of childbearing potential who are pregnant (as based on test results) or are
             breast feeding

          -  Subjects who have a history of hypersensitivity or idiosyncratic reaction to any of
             the products administered during the study.

          -  Subjects who, in the opinion of the Investigator, should not participate in the study.

          -  Subjects who are employed by the DCRU

          -  Subjects who have a history of unexplained syncope; i.e., autonomic dysfunction.

          -  Subjects who have a history of hypotension, including orthostatic hypotension

          -  A positive test for hepatitis B surface antigen, hepatitis C antibody, or HIV antibody
             at screening.

          -  Lack of ability to understand verbal and/ or written English

          -  History of severe hypersensitivity or allergic reaction to study medication

          -  Failure to agree to abstain from grapefruit and grapefruit juice as well as oranges
             and orange juice from 10 days before the first dose and throughout the study

          -  History of clinically significant illness within 4 weeks prior to Day 1

          -  Receipt of a transfusion or any blood products within 90 days prior to Period 1, Day 1

          -  History of participation in another investigational study or who have participated in
             an investigational study within the past 30 days prior to Period 1, Day 1