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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
29
AMB tablets will be available at a unit dose strength of 1 mg. Participants will orally administer 5 tablets of 1 mg unit dose.
AMB reference tablet will be available as film-coated tablet at unit dose strength of 5 mg. Participants will orally administer 1 tablet of 5 mg unit dose
GSK Investigational Site
Cambridge, Cambridgeshire, United Kingdom
Maximum Observed Plasma Concentration (Cmax) After Administration of AMB Under Fasted Condition
Blood samples were collected at indicated time-points for PK analysis of AMB. PK parameters were calculated by standard non-compartmental analysis. PK Parameter Population included all participants who provided PK parameter data.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Time to Cmax (Tmax) After Administration of AMB Under Fasted Condition
Blood samples were collected at indicated time-points for PK analysis of AMB. PK parameters were calculated by standard non-compartmental analysis.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Time of Last Quantifiable Concentration (Tlast) After Administration of AMB Under Fasted Condition
Blood samples were collected at indicated time-points for PK analysis of AMB. PK parameters were calculated by standard non-compartmental analysis.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [(AUC(0-inf)] After Administration of AMB Under Fasted Condition
Blood samples were collected at indicated time-points for PK analysis of AMB. PK parameters were calculated by standard non-compartmental analysis.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
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
Blood samples were collected at indicated time-points for PK analysis of AMB. PK parameters were calculated by standard non-compartmental analysis.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Apparent Terminal Phase Half-life (t1/2) After Administration of AMB Under Fasted Condition
Blood samples were collected at indicated time-points for PK analysis of AMB. PK parameters were calculated by standard non-compartmental analysis.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Number of Participants With Serious Adverse Events (SAEs) and Non-Serious Adverse Events (Non-SAEs >=2%)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Any untoward event resulting in death, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment were categorized as SAE.
Time frame: Up to 40 days
Number of Participants With Worst Case Vital Sign Results Relative to Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline
Vital signs were measured in semi-supine position after 5 minutes rest and included Systolic blood pressure (SBP), Diastolic blood pressure (DBP), Heart rate (HR). Data for number of participants with Post-Baseline worst case Vital Sign results relative to PCI Criteria relative to Baseline has been presented. Participants are counted in worst case category that their value changes to low, within range or high. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, are recorded in "Within Range or No Change" category. Participants are counted twice if values changed 'To Low' and 'To High', so the percentages are not added to 100%. Participants with missing baseline value are assumed as within range value. PCI ranges were: SBP \[lower: \<85, upper: \>160 millimeter of mercury (mmHg)\]; DBP (lower: \<40, upper: \>110 mmHg); HR (lower: \<45, upper: \>100 beats per minute). The value at Day 1 was considered as Baseline.
Time frame: Baseline (Day 1) and up to 40 days
Number of Participants With Worst Case Post-Baseline Abnormal Electrocardiogram (ECG) Findings
12-lead ECGs were recorded in semi-supine position after 5 minutes rest using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT and QT duration corrected for heart rate by Fridericia's formula (QTcF) intervals. Data for number of participants with abnormal clinically significant ECG findings for worst case post-Baseline has been presented. Clinically significant abnormal laboratory findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. The value at Day 1 was considered as Baseline.
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Time frame: Baseline (Day 1) and up to 40 days
Number of Participants With Worst Case Hematology Results Relative to PCI Criteria Post-Baseline Relative to Baseline
Blood samples were collected to analyze hemoglobin, hematocrit, lymphocytes, total neutrophils, platelet count, and white blood cell(WBC) counts. PCI ranges were hematocrit (high: \>0.54 proportion of red blood cells in blood and low: change from Baseline \<0.075); hemoglobin(high: \>180 grams per liter\[g/L\] and low: change from Baseline \<25 g/L); lymphocytes (low: \<0.8 Giga cells per liter\[GI/L\]); platelet count (low: \<100 GI/L and high: \>550 GI/L); neutrophil count (low: \<1.5 GI/L); WBC count (low: \<3 GI/L and high: \>20 GI/L). Participants were counted in worst-case category that their value changed to low, within range or no change, or high unless there was no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in ''To within Range or No Change' category. Participants were counted twice if participant had both values that changed 'To Low' and 'To High'. Baseline is defined as Day -1.
Time frame: Baseline (Day -1) and up to 40 days
Number of Participants With Worst Case Clinical Chemistry Results Relative to PCI Criteria Post-Baseline Relative to Baseline
Blood samples were collected to analyze PCI ranges for aspartate amino transferase (AST), alanine amino transferase (ALT), \& alkaline phosphatase (ALP) (high: \>=2 times (\*) upper limit of normal \[ULN\] International units per liter \[IU/L\]); bilirubin (high: \>=1.5 \* ULN micromoles per liter \[µmol/L\]); calcium (low: \<2 millimoles per liter \[mmol/L\] \& high: \>2.75 mmol/L); glucose (low: \<3 \& high: \>9 mmol/L); potassium (low: \<3 \& high: \>5.5 mmol/L); sodium (low: \<130 \& high: \>150 mmol/L) \& Blood Urea Nitrogen (BUN) (high: \>=2 \* ULN µmol/L). Participants were counted in worst-case category that their value changed to (low, within range or no change, or high) unless there was no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category. Participants were counted twice if participant had both values that changed 'To Low' \& 'To High'.
Time frame: Baseline (Day -1) and up to 40 days
Number of Participants With Worst Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline
Urine samples were collected for analysis of cellular casts, granular casts, hyaline casts and red blood cells. WBCs were counted as cells per high-power field (cells/HPF). Participants with worst case any increase in urinalysis results post-Baseline relative to Baseline has been presented. Baseline is defined as Day -1.
Time frame: Baseline (Day -1) and up to 40 days