Pulmonary Arterial Hypertension
Conditions
Keywords
Pulmonary Arterial Hypertension, Pulmonary Vascular Resistance, Imatinib, Bosentan, Sildenafil
Brief summary
The purpose of this study was to investigate the effects of QTI571 (imatinib) on pharmacokinetics of bosentan and sildenafil at steady state when co-administered to participants with pulmonary arterial hypertension.
Interventions
DRUGImatinib
Film coated tablets, oral administration
DRUGSildenafil
Oral Administration
DRUGBosentan
Oral Administration
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with Pulmonary arterial hypertension (PAH) in World Health Organization (WHO) Diagnostic Group 1, with pulmonary vascular resistance \> 800 dyne\*sec\*cm\^-5, * On stable doses of bosentan and sildenafil
Exclusion criteria
* Other diagnosis of PAH in World Health Organization (WHO) Diagnostic Group 1 such as congenital large or small unrepaired systemic to pulmonary shunts, portal hypertension, Human Immunodeficiency Virus (HIV) infection, glycogen storage disease, Gaucher's disease, hereditary hemorrhagic teleangiectasia, hemoglobinopathies, myeloproliferative disorders, veno-occlusive pulmonary disease * Significant lung diseases not related to PAH * Significant cardiovascular system disorders, hematological system disorders, liver insufficiency * Significant diseases in other organ system. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Geometric Mean Ratio of Dose Normalized Area Under the Curve From Time Zero to Tau (AUCtau) for Bosentan Before and After Imatinib Administrations | Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose | AUCtau was the area under the curve calculated to the end of the dosing interval, tau. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of bosentan was performed on dose normalized AUCtau of bosentan. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals were then back-transformed to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference). |
| Geometric Mean Ratio of Dose Normalized AUCtau for Sildenafil Before and After Imatinib Administrations | Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose | AUCtau was the area under the curve calculated to the end of the dosing interval, tau. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of sildenafil was performed on dose normalized AUCtau of sildenafil. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals were then back-transformed to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference). |
| Geometric Mean Ratio of Dose Normalized Maximum Plasma Concentration (Cmax) for Bosentan Before and After Imatinib Administrations | Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose | Cmax was the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after dose administration. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of bosentan was performed on dose normalized Cmax of bosentan. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals were then back-transformed to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference). |
| Geometric Mean Ratio of Dose Normalized Cmax for Sildenafil Before and After Imatinib Administrations | Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose | Cmax was the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after dose administration. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of sildenafil was performed on dose normalized Cmax of sildenafil. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals was then back-transformed to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dose Normalized Cmax of Imatinib and CGP74588 (Active Metabolite of Imatinib) | Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose | — |
| Dose Normalized AUCtau of Imatinib and CGP74588 (Active Metabolite of Imatinib) | Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose | — |
| Number of Participants With At Least One or More Adverse Events (AEs) | From time of first administration of study drug until end of study (up to approximately 18 months) | An adverse event was the appearance or worsening of any undesirable sign, symptom, or medical condition that occurred after starting the study drug even if the event was not considered to be related to study drug. Number of participants with AEs were reported by treatment period. |
Countries
Australia, Belgium, Germany, Italy, Lithuania, United Kingdom, United States
Participant flow
Recruitment details
Participants with pulmonary arterial hypertension (PAH) were enrolled in the study at 8 investigation sites worldwide from 20 April 2011 to 25 October 2012.
Participants by arm
| Arm | Count |
|---|---|
| Imatinib+ Bosentan+ Sildenafil Participants received treatment with bosentan 125 mg twice daily and sildenafil thrice daily for 8 days in treatment period 1. Participants were on the same sildenafil dose level (20, 40, 50 or 60 mg) they had been at study entry which was well tolerated in conjunction with bosentan. Following treatment period 1, the participants received concomitant treatment of oral imatinib 200 mg daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 2. Following treatment period 2, the participants received concomitant treatment of oral imatinib 400 mg daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 3. | 21 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Imatinib+ Bosentan+ Sildenafil |
|---|---|
| Age, Continuous | 54.4 years STANDARD_DEVIATION 13.44 |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 19 | 0 / 18 | 0 / 21 |
| other Total, other adverse events | 10 / 21 | 9 / 19 | 16 / 18 | 19 / 21 |
| serious Total, serious adverse events | 0 / 21 | 2 / 19 | 1 / 18 | 2 / 21 |
Outcome results
Primary
Geometric Mean Ratio of Dose Normalized Area Under the Curve From Time Zero to Tau (AUCtau) for Bosentan Before and After Imatinib Administrations
AUCtau was the area under the curve calculated to the end of the dosing interval, tau. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of bosentan was performed on dose normalized AUCtau of bosentan. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals were then back-transformed to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference).
Time frame: Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
Population: Pharmacokinetics (PK) analysis set included all participants with data for at least one of the primary PK variables in at least one period and no major protocol deviations with impact on PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan + Sildenafil (Reference) | Geometric Mean Ratio of Dose Normalized Area Under the Curve From Time Zero to Tau (AUCtau) for Bosentan Before and After Imatinib Administrations | 93.3 hr*ng/mL/mg | Geometric Coefficient of Variation 49.9 |
| Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1) | Geometric Mean Ratio of Dose Normalized Area Under the Curve From Time Zero to Tau (AUCtau) for Bosentan Before and After Imatinib Administrations | 109 hr*ng/mL/mg | Geometric Coefficient of Variation 52 |
| Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 2) | Geometric Mean Ratio of Dose Normalized Area Under the Curve From Time Zero to Tau (AUCtau) for Bosentan Before and After Imatinib Administrations | 131 hr*ng/mL/mg | Geometric Coefficient of Variation 38 |
90% CI: [1.03, 1.33]
90% CI: [1.23, 1.59]
Primary
Geometric Mean Ratio of Dose Normalized AUCtau for Sildenafil Before and After Imatinib Administrations
AUCtau was the area under the curve calculated to the end of the dosing interval, tau. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of sildenafil was performed on dose normalized AUCtau of sildenafil. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals were then back-transformed to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference).
Time frame: Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
Population: PK analysis set included all participants with data for at least one of the primary PK variables in at least one period and no major protocol deviations with impact on PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan + Sildenafil (Reference) | Geometric Mean Ratio of Dose Normalized AUCtau for Sildenafil Before and After Imatinib Administrations | 7.22 hr*ng/mL/mg | Geometric Coefficient of Variation 60.6 |
| Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1) | Geometric Mean Ratio of Dose Normalized AUCtau for Sildenafil Before and After Imatinib Administrations | 9.82 hr*ng/mL/mg | Geometric Coefficient of Variation 42.5 |
| Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 2) | Geometric Mean Ratio of Dose Normalized AUCtau for Sildenafil Before and After Imatinib Administrations | 12.3 hr*ng/mL/mg | Geometric Coefficient of Variation 40.9 |
90% CI: [1.14, 1.62]
90% CI: [1.43, 2.03]
Primary
Geometric Mean Ratio of Dose Normalized Cmax for Sildenafil Before and After Imatinib Administrations
Cmax was the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after dose administration. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of sildenafil was performed on dose normalized Cmax of sildenafil. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals was then back-transformed to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference).
Time frame: Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
Population: PK analysis set included all participants with data for at least one of the primary PK variables in at least one period and no major protocol deviations with impact on PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan + Sildenafil (Reference) | Geometric Mean Ratio of Dose Normalized Cmax for Sildenafil Before and After Imatinib Administrations | 2.44 ng/mL/mg | Geometric Coefficient of Variation 68.6 |
| Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1) | Geometric Mean Ratio of Dose Normalized Cmax for Sildenafil Before and After Imatinib Administrations | 3.14 ng/mL/mg | Geometric Coefficient of Variation 52.4 |
| Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 2) | Geometric Mean Ratio of Dose Normalized Cmax for Sildenafil Before and After Imatinib Administrations | 3.81 ng/mL/mg | Geometric Coefficient of Variation 52.9 |
90% CI: [1.03, 1.61]
90% CI: [1.24, 1.95]
Primary
Geometric Mean Ratio of Dose Normalized Maximum Plasma Concentration (Cmax) for Bosentan Before and After Imatinib Administrations
Cmax was the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after dose administration. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of bosentan was performed on dose normalized Cmax of bosentan. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals were then back-transformed to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference).
Time frame: Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
Population: PK analysis set included all participants with data for at least one of the primary PK variables in at least one period and no major protocol deviations with impact on PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan + Sildenafil (Reference) | Geometric Mean Ratio of Dose Normalized Maximum Plasma Concentration (Cmax) for Bosentan Before and After Imatinib Administrations | 21.9 ng/mL/mg | Geometric Coefficient of Variation 48.8 |
| Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1) | Geometric Mean Ratio of Dose Normalized Maximum Plasma Concentration (Cmax) for Bosentan Before and After Imatinib Administrations | 21.8 ng/mL/mg | Geometric Coefficient of Variation 60.3 |
| Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 2) | Geometric Mean Ratio of Dose Normalized Maximum Plasma Concentration (Cmax) for Bosentan Before and After Imatinib Administrations | 23.4 ng/mL/mg | Geometric Coefficient of Variation 44.7 |
90% CI: [0.82, 1.21]
90% CI: [0.88, 1.31]
Secondary
Dose Normalized AUCtau of Imatinib and CGP74588 (Active Metabolite of Imatinib)
Time frame: Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
Population: PK analysis set included all participants with data for at least one of the primary PK variables in at least one period and no major protocol deviations with impact on PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosentan + Sildenafil (Reference) | Dose Normalized AUCtau of Imatinib and CGP74588 (Active Metabolite of Imatinib) | Imatinib AUCtau/Dose | 90.9 hr*ng/mL/mg | Standard Deviation 49.3 |
| Bosentan + Sildenafil (Reference) | Dose Normalized AUCtau of Imatinib and CGP74588 (Active Metabolite of Imatinib) | CGP74588 AUCtau/Dose | 19.3 hr*ng/mL/mg | Standard Deviation 9.69 |
| Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1) | Dose Normalized AUCtau of Imatinib and CGP74588 (Active Metabolite of Imatinib) | Imatinib AUCtau/Dose | 88.4 hr*ng/mL/mg | Standard Deviation 36 |
| Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1) | Dose Normalized AUCtau of Imatinib and CGP74588 (Active Metabolite of Imatinib) | CGP74588 AUCtau/Dose | 20.6 hr*ng/mL/mg | Standard Deviation 9.07 |
Secondary
Dose Normalized Cmax of Imatinib and CGP74588 (Active Metabolite of Imatinib)
Time frame: Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
Population: PK analysis set included all participants with data for at least one of the primary PK variables in at least one period and no major protocol deviations with impact on PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosentan + Sildenafil (Reference) | Dose Normalized Cmax of Imatinib and CGP74588 (Active Metabolite of Imatinib) | Imatinib Cmax/Dose | 7.55 ng/ml/mg | Standard Deviation 4.18 |
| Bosentan + Sildenafil (Reference) | Dose Normalized Cmax of Imatinib and CGP74588 (Active Metabolite of Imatinib) | CGP74588 Cmax/Dose | 1.37 ng/ml/mg | Standard Deviation 0.538 |
| Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1) | Dose Normalized Cmax of Imatinib and CGP74588 (Active Metabolite of Imatinib) | Imatinib Cmax/Dose | 6.71 ng/ml/mg | Standard Deviation 3.39 |
| Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1) | Dose Normalized Cmax of Imatinib and CGP74588 (Active Metabolite of Imatinib) | CGP74588 Cmax/Dose | 1.39 ng/ml/mg | Standard Deviation 0.575 |
Secondary
Number of Participants With At Least One or More Adverse Events (AEs)
An adverse event was the appearance or worsening of any undesirable sign, symptom, or medical condition that occurred after starting the study drug even if the event was not considered to be related to study drug. Number of participants with AEs were reported by treatment period.
Time frame: From time of first administration of study drug until end of study (up to approximately 18 months)
Population: Safety analysis set included all participants enrolled and who received at least one dose of study drug (bosentan, sildenafil, or imatinib).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bosentan + Sildenafil (Reference) | Number of Participants With At Least One or More Adverse Events (AEs) | 10 Participants |
| Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1) | Number of Participants With At Least One or More Adverse Events (AEs) | 9 Participants |
| Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 2) | Number of Participants With At Least One or More Adverse Events (AEs) | 16 Participants |