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Pharmacokinetic Effects of QTI571 on Sildenafil and Bosentan in Pulmonary Arterial Hypertension Participants

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ClinicalTrials.gov Identifier: NCT01392469
Recruitment Status : Completed
First Posted : July 12, 2011
Results First Posted : June 21, 2021
Last Update Posted : June 21, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.

Condition or disease Intervention/treatment Phase
Pulmonary Arterial Hypertension Drug: Imatinib Drug: Sildenafil Drug: Bosentan Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Non-Randomized, Multiple Dose, Three Treatment Period, Open-Label, Single Sequence, Single Group Study to Evaluate the Pharmacokinetic Effect of Two Doses of QTI571 (Imatinib) on the Co-administered Drugs Sildenafil and Bosentan in Pulmonary Arterial Hypertension (PAH) Patients
Actual Study Start Date : April 20, 2011
Actual Primary Completion Date : October 25, 2012
Actual Study Completion Date : October 25, 2012


Arm Intervention/treatment
Experimental: Imatinib + Bosentan + Sildenafil
Participants received treatment with bosentan 125 milligrams (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.
Drug: Imatinib
Film coated tablets, oral administration
Other Name: QTI571

Drug: Sildenafil
Oral Administration

Drug: Bosentan
Oral Administration




Primary Outcome Measures :
  1. Geometric Mean Ratio of Dose Normalized Area Under the Curve From Time Zero to Tau (AUCtau) for Bosentan Before and After Imatinib Administrations [ 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 ]
    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).

  2. Geometric Mean Ratio of Dose Normalized AUCtau for Sildenafil Before and After Imatinib Administrations [ 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 ]
    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).

  3. Geometric Mean Ratio of Dose Normalized Maximum Plasma Concentration (Cmax) for Bosentan Before and After Imatinib Administrations [ 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 ]
    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).

  4. Geometric Mean Ratio of Dose Normalized Cmax for Sildenafil Before and After Imatinib Administrations [ 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 ]
    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 Outcome Measures :
  1. Number of Participants With At Least One or More Adverse Events (AEs) [ Time Frame: 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.

  2. 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 ]
  3. 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 ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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/exclusion criteria may apply


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01392469


Locations
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United States, Florida
Novartis Investigative Site
Tampa, Florida, United States, 33606
Novartis Investigative Site
Weston, Florida, United States, 33331
United States, New York
Novartis Investigative Site
Mineola, New York, United States, 11501
Australia, New South Wales
Novartis Investigative Site
Darlinghurst, New South Wales, Australia, 2010
Belgium
Novartis Investigative Site
Bruxelles, Belgium, 1070
Novartis Investigative Site
Leuven, Belgium, 3000
Germany
Novartis Investigative Site
Berlin, Germany, 12683
Novartis Investigative Site
Hannover, Germany, 30625
Italy
Novartis Investigative Site
Roma, RM, Italy, 00161
Lithuania
Novartis Investigative Site
Vilnius, Lithuania, LT-08661
United Kingdom
Novartis Investigative Site
London, United Kingdom, NW3 2PR
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01392469    
Other Study ID Numbers: CQTI571A2102
2010-021344-17 ( EudraCT Number )
First Posted: July 12, 2011    Key Record Dates
Results First Posted: June 21, 2021
Last Update Posted: June 21, 2021
Last Verified: June 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Pulmonary Arterial Hypertension
Pulmonary Vascular Resistance
Imatinib
Bosentan
Sildenafil
Additional relevant MeSH terms:
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Pulmonary Arterial Hypertension
Familial Primary Pulmonary Hypertension
Hypertension
Vascular Diseases
Cardiovascular Diseases
Hypertension, Pulmonary
Lung Diseases
Respiratory Tract Diseases
Imatinib Mesylate
Bosentan
Sildenafil Citrate
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Urological Agents
Antihypertensive Agents
Endothelin Receptor Antagonists