A Phase 1 Relative Bioavailability Study of Ambrisentan and Tadalfil Fixed Dose Combination Tablets in Healthy Subjects

GlaxoSmithKline (GSK)

Status and phase: Completed; Phase 1

Conditions: Hypertension, Pulmonary

Treatments: Drug: FDC (ambrisentan 10 mg-tadalafil 40 mg) single dose; Drug: Reference (ambrisentan 10 mg + tadalafil 40 mg given concurrently)

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT02688387

201964

Details and patient eligibility

About

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.

Enrollment: 112 patients

Sex: All

Ages: 18 to 60 years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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112 participants in 3 patient groups

Part 1

Experimental group

Description:

Enrolled subjects will receive single oral dose of 4 FDCs i.e., FDC1, FDC2, FDC3 and FDC4, and reference formulations of the 2 monotherapy components taken concurrently in the fasted state. The FDC and reference formulations contains 10 mg ambrisentan and 40 mg tadalafil. Each dosing period will be separated by 7 days wash out period.

Treatment:

Drug: Reference (ambrisentan 10 mg + tadalafil 40 mg given concurrently)

Drug: FDC (ambrisentan 10 mg-tadalafil 40 mg) single dose

Part 2

Experimental group

Description:

Enrolled subjects will receive single oral dose of 4 FDCs i.e., FDC5, FDC6, FDC7 and FDC8, and reference formulations of the 2 monotherapy components taken concurrently in the fasted state. The FDCs and reference formulations contains 10 mg ambrisentan and 40mg Tadalafil. OR Subjects will receive single dose of two FDCs from Part 1 in fed and fasted state. Each dosing period will be separated by 7 days wash out period.

Treatment:

Drug: Reference (ambrisentan 10 mg + tadalafil 40 mg given concurrently)

Drug: FDC (ambrisentan 10 mg-tadalafil 40 mg) single dose

Part 3

Experimental group

Description:

Enrolled subjects will receive single oral dose of 2 FDCs from Part 2 in fed and fasted state. The FDCs contains 10 mg ambrisentan and 40 mg Tadalafil. Each dosing period will be separated by 7 days wash out period.

Treatment:

Drug: FDC (ambrisentan 10 mg-tadalafil 40 mg) single dose