Clinical trial NCT04095286: Relative Bioavailability Study of Marketed and Lower Dose Ambrisentan in Healthy Adult Participants
Official title: An Open-label, Randomized Three Period Cross-over Relative Bioavailability Study to Compare the Pharmacokinetic Parameters of a Lower Dose Formulation of Ambrisentan (GSK1325760) With Marketed Ambrisentan in Healthy Adult Participants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hypertension, Pulmonary
Keywords: Ambrisentan
Oral dosage forms
Pulmonary arterial hypertension
Bioavailability
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2019-09-19
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This is a three-period crossover study
Primary purpose: TREATMENT

Brief summary: This is a single center, open-label, randomized, single-dose, three-period cross-over study in healthy participants. The aim of this study is to provide clinically relevant information on the pharmacokinetic (PK) and safety profile of a new lower dose formulation ambrisentan (AMB) tablet, which is intended for pediatric use. The study will compare the relative bioavailability of the lower dose tablet, dispersed in water and administered orally, with the reference marketed AMB tablet in healthy adults. The total study duration for each participant is expected to be approximately 9 weeks.


Eligibility criteria: Inclusion Criteria:

* Participants must be 18 to 65 years of age inclusive, at the time of signing the informed consent.
* Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, vital signs and cardiac monitoring.
* Average systolic blood pressure between 100-160 millimeter of mercury (mmHg) and diastolic between 55-90 mmHg (inclusive) over 3 readings at Screening.
* Body weight \>=50 kilogram (kg) for men and \>= 45kg for women, and body mass index (BMI) within the range 18-30 kilogram per meter square (kg/m\^2) (inclusive).
* Male participants are eligible to participate if they agree to the following during the study and for at least 13 weeks afterwards corresponding to time needed to eliminate study intervention (5 terminal half-lives) plus an additional 90 days (a spermatogenesis cycle): 1. Refrain from donating sperm plus either 2. Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. OR
* Must agree to use contraception/barrier, as follows: Agree to use a male condom; and Female partner to use an additional highly effective contraceptive method with a failure rate of \<1% per year as described.
* A female participant is eligible to participate if she is not a woman of childbearing potential (WOCBP).
* Capable of giving signed informed consent.

Exclusion Criteria:

* History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal,endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention or interfering with the interpretation of data.
* History or presence of palpitations or tachyarrhythmia.
* Hemoglobin (Hb) below the normal range (Hb \<133 grams per liter \[g/L\] for male participants ; and Hb \<114 g/L for female participants).
* Alanine transaminase (ALT) \>1.5 times upper limit of normal (ULN)
* Bilirubin \>1.5 times ULN (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* 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 interval (QTc) \>450 millisecond (msec).
* Past or intended use of over-the-counter or prescription medication (including vitamins and dietary or herbal supplements but excluding paracetamol \<=2 grams/day) within 7 days (or 14 days if the drug is a potential enzyme inhibitor) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless approved by the Investigator in conjunction with GlaxoSmithKline Medical Monitor.
* Participation in the study would result in loss of blood or blood products in excess of 500 milliliter (mL) within a 56-day period.
* Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
* Current enrolment or past participation within 30 days before Screening in any other clinical study involving an investigational study intervention or any other type of medical research.
* Presence of Hepatitis B surface antigen (HBsAg) at Screening or within 3 months prior to first dose of study intervention.
* Positive Hepatitis C antibody test result at Screening or within 3 months prior to first dose of study intervention.
* Positive Hepatitis C Ribonucleic acid (RNA) test result at Screening or within 3 months prior to first dose of study intervention.
* Positive human immunodeficiency virus (HIV) antibody test.
* Positive pre-study drug/alcohol screen.
* Regular use of known drugs of abuse.
* Regular alcohol consumption within 6 months prior to the study defined as: An average weekly intake of \>14 units. One unit is equivalent to 8 grams of alcohol: a half-pint (equivalent to 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
* Smoking \> 5 cigarettes per week (or equivalent) and participants must be able to abstain from smoking for a 24-hour period prior to dose and any time whilst in the clinical unit.
* Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study

Primary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) After Administration of AMB Under Fasted Condition
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
measure: Time to Cmax (Tmax) After Administration of AMB Under Fasted Condition
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
measure: Time of Last Quantifiable Concentration (Tlast) After Administration of AMB Under Fasted Condition
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
measure: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [(AUC(0-inf)] After Administration of AMB Under Fasted Condition
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Last Time of Quantifiable Concentration [AUC(0-t)] After Administration of AMB Under Fasted Condition
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
measure: Apparent Terminal Phase Half-life (t1/2) After Administration of AMB Under Fasted Condition
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Secondary outcomes:
measure: Number of Participants With Serious Adverse Events (SAEs) and Non-Serious Adverse Events (Non-SAEs >=2%)
timeFrame: Up to 40 days
measure: Number of Participants With Worst Case Vital Sign Results Relative to Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline
timeFrame: Baseline (Day 1) and up to 40 days
measure: Number of Participants With Worst Case Post-Baseline Abnormal Electrocardiogram (ECG) Findings
timeFrame: Baseline (Day 1) and up to 40 days
measure: Number of Participants With Worst Case Hematology Results Relative to PCI Criteria Post-Baseline Relative to Baseline
timeFrame: Baseline (Day -1) and up to 40 days
measure: Number of Participants With Worst Case Clinical Chemistry Results Relative to PCI Criteria Post-Baseline Relative to Baseline
timeFrame: Baseline (Day -1) and up to 40 days
measure: Number of Participants With Worst Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline
timeFrame: Baseline (Day -1) and up to 40 days
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
state: Cambridgeshire
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: