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NCT02688387

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

Completed Phase 1 Results posted Last updated 22 January 2019
What this trial tests

Phase 1 trial testing FDC (ambrisentan 10 mg-tadalafil 40 mg) single dose in Hypertension, Pulmonary in 112 participants. Completed in 4 August 2017.

Timeline
18 March 2016
Primary endpoint
4 August 2017
4 August 2017

Quick facts

Lead sponsorGlaxoSmithKline
PhasePhase 1
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designcrossover
Maskingnone
Primary purposetreatment
Enrollment112
Start date18 March 2016
Primary completion4 August 2017
Estimated completion4 August 2017
Sites1 location across United Kingdom

Drugs / interventions tested

Conditions studied

Sponsor

GlaxoSmithKline — full company profile →

Who can join

Adults 18 to 60, any sex, with Hypertension, Pulmonary. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Maximum Observed Concentration (Cmax) of Ambrisentan and Tadalafil in FDC (Ambrisentan 10 mg + Tadalafil 40 mg) and Montherapies (Ambrisentan 10 mg & Tadalafil 40 mg) - Part 1 Primary · Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose

Cmax is defined as the maximum (or peak) plasma concentration that the drug achieves, after the drug has been administered. Blood samples were collected at the indicated time points for analysis of ambrisentan and tadafil. The analysis was done under fasting condition post single dose. There is no formal hypotheses tested for Part 1 of the study. The analysis was performed on Pharmacokinetic (PK) parameter population, which included all participants who provided PK parameter data.

Ambrisentan, Cmax
GroupValue95% CI
Part 1,Treatment F1766.29± 18.2
Part 1,Treatment F2685.33± 20.5
Part 1,Treatment F3738.49± 22.1
Part 1,Treatment F4722.57± 27.7
Part 1, Treatment R755.37± 28.9
Tadalafil, Cmax
GroupValue95% CI
Part 1,Treatment F1581.41± 27.6
Part 1,Treatment F2595.47± 22.3
Part 1,Treatment F3588.11± 24.5
Part 1,Treatment F4590.36± 21.4
Part 1, Treatment R567.62± 18.0
Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to Infinite (Inf) Time, AUC (0-inf) of Ambrisentan and Tadalafil in FDC (Ambrisentan 10 mg + Tadalafil 40 mg) and Montherapies (Ambrisentan 10 mg & Tadalafil 40 mg) - Part 1 Primary · Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose

AUC (0- inf), is defined as area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for ambrisentan and tadafil. Blood samples were collected at the indicated time-points. The analysis was done under fasting condition post single dose. There is no formal hypothesis tested for Part 1 of the study.

Ambrisentan, (AUC 0 - inf)
GroupValue95% CI
Part 1,Treatment F15566.06± 23.8
Part 1,Treatment F25556.44± 25.9
Part 1,Treatment F35788.91± 25.8
Part 1,Treatment F46007.57± 23.7
Part 1, Treatment R5746.73± 20.8
Tadalafil, (AUC 0 - inf)
GroupValue95% CI
Part 1,Treatment F113408.30± 41.3
Part 1,Treatment F214415.47± 41.8
Part 1,Treatment F314545.28± 38.4
Part 1,Treatment F414418.35± 37.8
Part 1, Treatment R13955.85± 36.2
AUC From Time of Dose to Last Measurable Concentration (AUC [0-t]), in FDC, (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fasting- Part 1 Primary · Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose

AUC (0-t), was defined as, the AUC measured from the time of dose to the last measurable concentration. Blood samples of 2.7 mL and 2 mL, were collected for ambrisentan and tadafil respectively. The plasma samples at Part 1, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours. The analysis was done under fasting condition post single dose. The PK Parameter Population was used for analysis. There is no formal hypotheses tested for Part 1 of the study.

Ambrisentan, (AUC 0- t)
GroupValue95% CI
Part 1,Treatment F15418.03± 22.9
Part 1,Treatment F25434.88± 25.3
Part 1,Treatment F35655.75± 25.5
Part 1,Treatment F45858.18± 22.9
Part 1, Treatment R5605.58± 20.2
Tadalafil, (AUC 0- t)
GroupValue95% CI
Part 1,Treatment F112469.86± 37.1
Part 1,Treatment F213307.95± 37.4
Part 1,Treatment F313376.86± 34.8
Part 1,Treatment F413238.89± 33.4
Part 1, Treatment R12805.01± 32.2
Cmax of Ambrisentan and Tadalafil in FDC (Ambrisentan 10 mg + Tadalafil 40 mg) and Montherapies (Ambrisentan 10 mg & Tadalafil 40 mg) - Part 2 Primary · Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose

Cmax is defined as the maximum (or peak) plasma concentration that the drug achieves, after the drug has been administered. Blood samples were collected at the indicated time-points, of Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose. The analysis was done under fasting condition post single dose. There is no formal hypotheses tested for Part 2 of the study. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

Ambrisentan, (n=21,20,20,20)
GroupValue95% CI
Part 2, Treatment R710.90± 28.2
Part 2, Treatment FG1720.79± 21.1
Part 2, Treatment FG2748.63± 22.9
Part 2, Treatment FG3726.15± 31.4
Tadalafil, (n=20,20,20,20)
GroupValue95% CI
Part 2, Treatment R537.80± 27.6
Part 2, Treatment FG1561.60± 28.4
Part 2, Treatment FG2550.78± 28.6
Part 2, Treatment FG3553.31± 20.5
AUC (0 - Inf) for FDC, (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fasting- Part 2 Primary · Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose

AUC (0- inf), is defined as area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for ambrisentan and tadafil. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 2, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis, was done under fasting condition post single dose. PK parameter Populatio was used for analysis. There is no formal hypotheses tested for Part 2 of the study. Only those pa

Ambrisentan, AUC (0-inf) (n=21,20,20,20)
GroupValue95% CI
Part 2, Treatment R6029.19± 29.6
Part 2, Treatment FG16179.41± 27.2
Part 2, Treatment FG26189.22± 29.5
Part 2, Treatment FG36201.40± 25.7
Tadalafil, AUC ( 0 - inf) (n=20,20,20,20)
GroupValue95% CI
Part 2, Treatment R14006.59± 46.7
Part 2, Treatment FG114443.86± 44.8
Part 2, Treatment FG214502.37± 40.5
Part 2, Treatment FG314457.33± 40.5
AUC (0-t) for FDC, (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fasting- Part 2 Primary · Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose

AUC (0-t), was defined as, the AUC measured from the time of dose to the last measurable concentration. Blood samples of 2.7 mL and 2 mL, were collected for ambrisentan and tadafil respectively. The plasma samples for Part 2, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours. The analysis was done under fasting condition post single dose. PK parameter Population was used for analysis. There is no formal hypotheses tested for Part 2 of the study. Only those participants available at the specified time points were analyzed (represented by n=

Ambrisentan, (n=21,20,20,20)
GroupValue95% CI
Part 2, Treatment R5893.74± 29.4
Part 2, Treatment FG16016.62± 27.1
Part 2, Treatment FG26051.83± 29.6
Part 2, Treatment FG36015.11± 25.9
Tadalafil, (n=20,20,20,20)
GroupValue95% CI
Part 2, Treatment R12832.91± 39.6
Part 2, Treatment FG113149.19± 37.5
Part 2, Treatment FG213305.50± 35.2
Part 2, Treatment FG313275.08± 33.3
Cmax for Ambrisentan and Tadalafil, Following Candidate FDC (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fed and Fasted Conditions-Part 3A Primary · Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose

Cmax is defined as the maximum (or peak) plasma concentration that the drug achieves, after the drug has been administered. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3A, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis was done under fed and fasting condition post single dose. PK parameter population was used.

Ambrisentan, Cmax
GroupValue95% CI
Part 3A,Treatment X1550.02± 30.9
Part 3A,Treatment X2756.60± 24.1
Part 3A,Treatment R1515.61± 33.4
Part 3A,Treatment R2728.32± 29.8
Tadalafil, Cmax
GroupValue95% CI
Part 3A,Treatment X1525.10± 26.5
Part 3A,Treatment X2508.72± 24.9
Part 3A,Treatment R1533.67± 19.5
Part 3A,Treatment R2520.62± 21.1
AUC (0-inf) for Ambrisentan and Tadalafil, Following Candidate FDC (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fed and Fasted Conditions-3A Primary · Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose

AUC (0- inf), is defined as area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for ambrisentan and tadafil. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3A, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 48 and 72 hours post-dose. The analysis, was done under fed and fasting conditions post single dose. PK parameter population was used.

Ambrisentan, AUC (0-inf)
GroupValue95% CI
Part 3A,Treatment X16075.51± 26.1
Part 3A,Treatment X26231.48± 25.1
Part 3A,Treatment R15898.72± 27.7
Part 3A,Treatment R26155.60± 24.4
Tadalafil, AUC (0-inf)
GroupValue95% CI
Part 3A,Treatment X116086.66± 41.5
Part 3A,Treatment X214856.32± 40.0
Part 3A,Treatment R116596.18± 37.8
Part 3A,Treatment R214612.84± 41.5
AUC (0-t) for Ambrisentan and Tadalafil, Following Candidate FDC (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fed and Fasted Conditions-Part 3A Primary · Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose

AUC (0-t), was defined as, the AUC measured from the time of dose to the last measurable concentration. Blood samples of 2.7 mL and 2 mL, were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3A, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis was done under fed and fasting condition post single dose. PK parameter population was used.

Ambrisentan, AUC (0-t)
GroupValue95% CI
Part 3A,Treatment X15926.87± 25.7
Part 3A,Treatment X26090.74± 24.8
Part 3A,Treatment R15766.71± 27.4
Part 3A,Treatment R26012.51± 24.0
Tadalafil, AUC (0-t)
GroupValue95% CI
Part 3A,Treatment X114366.73± 33.7
Part 3A,Treatment X213320.79± 32.4
Part 3A,Treatment R114946.32± 31.1
Part 3A,Treatment R213114.00± 32.6
Cmax for Ambrisentan and Tadalafil, FDCs (Ambrisentan 5 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 5 mg & Tadalafil 40 mg) Under Fasted Conditions-3B Primary · Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose

Cmax is defined as the maximum (or peak) plasma concentration that the drug achieves, after the drug has been administered. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3B, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis was done under fasting condition post single dose.

Ambrisentan, Cmax
GroupValue95% CI
Part 3B,Treatment Y1375.87± 23.0
Part 3B,Treatment R3380.47± 26.2
Tadalafil, Cmax
GroupValue95% CI
Part 3B,Treatment Y1488.36± 19.7
Part 3B,Treatment R3511.80± 28.3
AUC (0-inf) for Ambrisentan and Tadalafil, FDCs (Ambrisentan 5 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 5 mg & Tadalafil 40 mg) Under Fasted Conditions-3B Primary · Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose

AUC (0- inf), is defined as area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for ambrisentan and tadafil. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3B, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36,48 and 72 hours post-dose. The analysis was done under fasting condition post single dose. PK Parameter Population was used for analysis.

Ambrisentan AUC (0-inf)
GroupValue95% CI
Part 3B,Treatment Y13397.51± 19.7
Part 3B,Treatment R33277.81± 20.8
Tadalafil, AUC (0-inf)
GroupValue95% CI
Part 3B,Treatment Y114724.34± 39.7
Part 3B,Treatment R314938.29± 40.7
AUC (0-t) for Ambrisentan and Tadalafil, FDCs (Ambrisentan 5 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 5 mg & Tadalafil 40 mg) Under Fasted Conditions-3B Primary · Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose

AUC (0-t), was defined as, the AUC measured from the time of dose to the last measurable concentration. Blood samples of 2.7 mL and 2 mL, were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3B, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis was done under fasting condition post single dose. PK parameter population was used for analysis.

Ambrisentan, AUC (0-t)
GroupValue95% CI
Part 3B,Treatment Y13297.16± 19.8
Part 3B,Treatment R33190.51± 20.3
Tadalafil, AUC (0-t)
GroupValue95% CI
Part 3B,Treatment Y113119.89± 31.0
Part 3B,Treatment R313325.63± 35.0

Adverse events — posted to ClinicalTrials.gov

Time frame: All SAEs and AEs were collected from Day 1 to up to follow-up ( up to 165 days). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Part 1,Treatment F1
Serious: 0/21 (0%)
Deaths: 0/21
Part 1,Treatment F2
Serious: 0/23 (0%)
Deaths: 0/23
Part 1,Treatment F3
Serious: 0/23 (0%)
Deaths: 0/23
Part 1,Treatment F4
Serious: 0/22 (0%)
Deaths: 0/22
Part 1, Treatment R
Serious: 0/21 (0%)
Deaths: 0/21
Part 2, Treatment R
Serious: 0/21 (0%)
Deaths: 0/21
Part 2, Treatment FG1
Serious: 0/20 (0%)
Deaths: 0/20
Part 2, Treatment FG2
Serious: 0/20 (0%)
Deaths: 0/20
Part 2, Treatment FG3
Serious: 0/20 (0%)
Deaths: 0/20
Part 3A,Treatment X1
Serious: 0/32 (0%)
Deaths: 0/32
Part 3A,Treatment X2
Serious: 0/33 (0%)
Deaths: 0/33
Part 3A,Treatment R1
Serious: 0/32 (0%)
Deaths: 0/32
Part 3A,Treatment R2
Serious: 0/32 (0%)
Deaths: 0/32
Part 3B,Treatment Y1
Serious: 0/30 (0%)
Deaths: 0/30
Part 3B,Treatment Y2
Serious: 0/31 (0%)
Deaths: 0/31
Part 3B,Treatment R3
Serious: 0/32 (0%)
Deaths: 0/32
Part 3B,Treatment R4
Serious: 0/30 (0%)
Deaths: 0/30
Other adverse events (26 terms — click to expand)

ReactionSystemPart 1,Treatment F1Part 1,Treatment F2Part 1,Treatment F3Part 1,Treatment F4Part 1, Treatment RPart 2, Treatment RPart 2, Treatment FG1Part 2, Treatment FG2Part 2, Treatment FG3Part 3A,Treatment X1Part 3A,Treatment X2Part 3A,Treatment R1Part 3A,Treatment R2Part 3B,Treatment Y1Part 3B,Treatment Y2Part 3B,Treatment R3Part 3B,Treatment R4
HeadacheNervous system disorders
Back painMusculoskeletal and connective tissue disorders
NauseaGastrointestinal disorders
Pain in extremityMusculoskeletal and connective tissue disorders
Nasal congestionRespiratory, thoracic and mediastinal disorders
Musculoskeletal painMusculoskeletal and connective tissue disorders
PhotophobiaEye disorders
Eye painEye disorders
DizzinessNervous system disorders
EpistaxisRespiratory, thoracic and mediastinal disorders
Eye swellingEye disorders
FlushingVascular disorders
PalpitationsCardiac disorders
VomitingGastrointestinal disorders
Gastrooesophageal reflux diseaseGastrointestinal disorders
PriapismReproductive system and breast disorders
Limb discomfortMusculoskeletal and connective tissue disorders
Hot flushVascular disorders
FatigueGeneral disorders
Gait disturbanceGeneral disorders
Euphoric moodPsychiatric disorders
InsomniaPsychiatric disorders
Erection increasedReproductive system and breast disorders
Seasonal allergyImmune system disorders
Viral upper respiratory tract infectionInfections and infestations
PolydipsiaMetabolism and nutrition disorders

Data from ClinicalTrials.gov NCT02688387 adverse events section.

Sponsor's own description

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.

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Insights into Endothelin Receptors in Pulmonary Hypertension.
    Liu R, Yuan T, Wang R, Gong D, et al · · 2023 · cited 12× · PMID 37373355 · DOI 10.3390/ijms241210206
  2. A Phase I Study to Show the Relative Bioavailability and Bioequivalence of Fixed-Dose Combinations of Ambrisentan and Tadalafil in Healthy Subjects.
    Okour M, Puri A, Chen G, Port K, et al · · 2019 · cited 1× · PMID 31060740 · DOI 10.1016/j.clinthera.2019.04.007

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