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

• 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: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

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

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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 ]

Eligibility Criteria

• 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

Contacts and Locations

Locations

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

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01392469
• Other Study ID Numbers: CQTI571A2102; 2010-021344-17 ( EudraCT Number )
• First Posted: July 12, 2011
• Results First Posted: June 21, 2021
• Last Update Posted: June 21, 2021
• Last Verified: June 2021

• 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:

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