A Phase 1 Relative Bioavailability Study of Ambrisentan and Tadalfil Fixed Dose Combination Tablets in Healthy Subjects
Condition: Hypertension, Pulmonary
MeSH terms: Hypertension, Pulmonary
Intervention: FDC (ambrisentan 10 mg-tadalafil 40 mg) single dose; Reference (ambrisentan 10 mg + tadalafil 40 mg given concurrently)
Intervention description: The four FDCs in part 1 will have the following formulation designation: FDC1, FDC2, FDC3 and FDC4. They are film-coated tablets. The dose will be administered orally. Study treatment for Part2 and Part 3 will be amended after Part 1 study; Ambrisentan is a film-coated tablet. Each tablet of ambrisentan contains 10 mg of ambrisentan, approximately 95 mg of lactose (as monohydrate), 0.25 mg of lecithin and 0.11 mg of Allura red AC Aluminium Lake. Tadalafil is also a film-coated tablet. Each tablet of Tadalafil contains 20 mg tadalafil and 233 mg lactose. Both the tablets will be administered orally concurrently.
Intervention MeSH terms: Ambrisentan; Tadalafil
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 112.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Ambrisentan; Bioavailability; Tadalafil; Fixed Dose combination

Summary:

      This study is designed to understand the relative bioavailability (proportion of the
      administered dose that is absorbed into the bloodstream) of several fixed dose combinations
      (FDCs) tablets of ambrisentan and tadalafil for further development and to provide
      pharmacokinetic (PK - what the body does to the drug) data to enable a pivotal bioequivalence
      (BE - the relationship between two preparations of the same drug in the same dosage form that
      have a similar bioavailability) study. Depending on formulation work, the study will allow up
      to 8 new FDCs to be compared with the reference of ambrisentan and tadalafil monotherapies.
      The study will also evaluate up to 2 of the new formulations, that may be taken in to a BE
      study, to be tested for any effect on pharmacokinetics of the FDC in both fed and fasted
      state. This is a single centre, Phase 1, single dose, randomised, open label crossover study
      with 3 study parts; each study part will have up to a 5 way crossover in healthy subjects.
      Part 1 of the study will evaluate four formulations of the FDC (ambrisentan 10 milligram [mg]
      + tadalafil 40 mg) and the reference of the 2 monotherapy components taken concurrently
      (ambrisentan 10 mg and tadalafil 40 mg) in the fasted stated. If successful formulations are
      identified in this part of the study, then they will be re-formulated and tested in part 2.
      If no successful formulations are identified in part 1 of the study, then part 2 will be
      utilized to look at up to 4 new FDC formulations. However, if only two formulations, or less,
      are evaluated in part 2 then the FDC formulations may be tested both fed and fasted to assess
      food effect and part 3 will not be required. If successful formulations are identified in
      this study part, then up to 2 of these may be tested, for food effect, in Part 3 if not
      already assessed in this part. Therefore, part 3 is optional and utility is dependent on the
      results of the previous study parts.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Between 18 and 60 years of age inclusive, at the time of signing the informed consent.

          -  Healthy as determined by a responsible and experienced physician, based on a medical
             evaluation including medical history, physical examination, laboratory tests, vital
             signs and cardiac monitoring (ECG and 24 hour Holter). A subject with a clinical
             abnormality or laboratory parameter(s) which is/are not specifically listed in the
             inclusion or exclusion criteria, outside the reference range for the population being
             studied may be included only if the Investigator, in consultation with Medical Monitor
             if required, judges and documents that the finding is unlikely to introduce additional
             risk factors and will not interfere with the study procedures.

          -  Body weight >= 50 Kilogram (kg) (110 pounds [lbs]) for men and >= 45 kg (99lbs) for
             women and body mass index (BMI) within the range 18 - 30 kg per square metre (m^2)
             (inclusive)

          -  Male or Female. Female with non-reproductive potential defined as, Pre-menopausal
             females with one of the following: Documented tubal ligation or Documented
             hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal
             occlusion or Hysterectomy or Documented Bilateral Oophorectomy, Documented
             Postmenopausal defined as 12 months of spontaneous amenorrhea

          -  Capable of giving signed informed consent.

        Exclusion Criteria:

          -  A blood pressure <100/55 millimetre of Mercury (mm Hg).

          -  Haemoglobin (Hb) below normal range: Hb <133 (gram per litre) g/L for males and Hb
             <114 g/L for females

          -  Alanine amino transferase (ALT) and bilirubin >1.5 x upper limit of normal (ULN)
             (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct
             bilirubin is <35 percentage [%]).

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones)

          -  Corrected QT (QTc) >450 milliseconds (msec). The QTc is the QT interval corrected for
             heart rate according to Bazett's formula (QTcB), Fridericia's formula (QTcF), and/or
             another method, machine-read or manually over-read.

          -  Use of prescription or non-prescription drugs, including vitamins, herbal and dietary
             supplements (including St John's Wort) within 7 days (or 14 days if the drug is a
             potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first
             dose of study medication, unless in the opinion of the Investigator and Medical
             Monitor the medication will not interfere with the study procedures or compromise
             subject safety.

          -  History of regular alcohol consumption within 6 months of the study defined as: An
             average weekly intake of >21 units for males or >14 units for females. One unit is
             equivalent to 8 gram (g) of alcohol: a half-pint (~240 millilitre [mL]) of beer, 1
             glass (125 mL) of wine or 1 (25 mL) measure of spirits.

          -  Smoking more than 5 cigarettes per week and subjects must be able to abstain from
             smoking for a 24 hour period prior to dose and any time whilst in the clinical unit.

          -  History of sensitivity to any of the study medications, or components thereof or a
             history of drug or other allergy that, in the opinion of the Investigator or Medical
             Monitor, contraindicates their participation.

          -  Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test
             result at Screening or within 3 months prior to first dose of study treatment.

          -  A positive test for human immuno-deficiency virus (HIV) antibody

          -  A positive pre-study drug/alcohol screen.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 mL within previous 3 months

          -  The subject has participated in a clinical trial and has received an investigational
             product within the following time period prior to the first dosing day in the current
             study: 3 months, 5 half-lives or twice the duration of the biological effect of the
             investigational product (whichever is longer).

          -  Exposure to more than four new chemical entities within 12 months prior to the first
             dosing day.