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A Pharmacokinetic Drug-Drug Interaction (DDI) Study Between Sitaxsentan And Sildenafil, And Between Sitaxsentan And Tadalafil After Multiple Doses

This study has been terminated.
(Safety Issue: The trial was prematurely terminated on Dec 9, 2010, due to safety concerns, specifically new emerging evidence of hepatic injury.)
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT01244620
First received: November 15, 2010
Last updated: January 18, 2012
Last verified: January 2011
History of Changes
  Purpose

Sitaxsentan has a low drug-drug interaction potential and it did not have a clinically relevant effect on pharmacokinetics of sildenafil (a CYP3A sensitive substrate and PDE5 inhibitor).

Tadalafil did not have clinically relevant effect on pharmacokinetics of bosentan and ambrisentan. Based on overall clinical drug-drug interaction profiles, and in vitro CYP enzymes and transporter data, a clinically relevant drug-drug interaction between sitaxsentan and tadalafil is not expected. Sildenafil is not expected to affect sitaxsentan pharmacokinetics (PK), as sitaxsentan is a substrate of CYP3A4 and CYP2C9, where sildenafil did not show clinically relevant effect on PK of substrates of CYP3A4 and CYP2C9.


Condition Intervention Phase
Pulmonary Arterial Hypertension
 Drug: sitaxentan
Drug: tadalafil
Drug: sitaxsentan
Drug: sildenafil
 Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1, Open Label, Randomized, Four Period, Crossover, Multiple Dose Study To Assess The Pharmacokinetic Interaction Between Sitaxsentan and Tadalafil and The Effect Of Sildenafil On Sitaxsentan PK In Healthy Subjects

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Time to Reach Maximum Observed Plasma Concentration (Tmax) [ Time Frame: Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) ] [ Designated as safety issue: No ]
  • Trough Plasma Concentrations (Ctrough) [ Time Frame: Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) ] [ Designated as safety issue: No ]
    Minimum or "trough"concentrations

  • Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) ] [ Designated as safety issue: No ]
  • Area Under the Curve of the 24 Hour Dosing Interval (AUC24) [ Time Frame: Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) ] [ Designated as safety issue: No ]
  • Apparent Oral Clearance (CL/F) [ Time Frame: Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) ] [ Designated as safety issue: No ]
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

  • Volume of Distribution at Steady State (Vss) [ Time Frame: Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) ] [ Designated as safety issue: No ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state.


Secondary Outcome Measures:
  • Plasma Decay Half-Life (t1/2) [ Time Frame: Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) ] [ Designated as safety issue: No ]
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.


Enrollment: 16
Study Start Date: November 2010
Study Completion Date: December 2010
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment A
sitaxsentan 100 mg QD for 6 days (Treatment A)
 Drug: sitaxentan
sitaxsentan 100 mg QD for 6 days
Other Name: Thelin
Experimental: Treatment B
tadalafil 40 mg QD for 6 days
 Drug: tadalafil
tadalafil 40 mg QD for 6 days
Experimental: Treatment C
sitaxsentan 100 mg QD co-administered with tadalafil 40 mg QD for 6 days
 Drug: sitaxsentan
sitaxsentan 100 mg QD for 6 days
Drug: tadalafil
tadalafil 40 mg QD for 6 days
Experimental: Treatment D
sitaxsentan 100 mg QD co-administered with sildenafil 20 mg TID for 6 days
 Drug: sitaxsentan
sitaxentan 100 mg QD for 6 days
Drug: sildenafil
sildenafil 20 mg TID for 6 days

  Eligibility

Ages Eligible for Study:   21 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy male subjects and women of non-child bearing potential between the ages of 21 and 55 years, inclusive. Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead ECG and clinical laboratory tests.
  • Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >45 kg (99 lbs).
  • An informed consent document signed and dated by the subject or a legally acceptable representative.
  • Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Exclusion Criteria:

  • Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing) or clinical findings at Screening.
  • A positive urine drug screen.
  • Subjects with hepatic dysfunction, defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >1.5 times the upper limit of the normal range at Screening. A retest may be done if AST and/or ALT within 1.5- to 2- times the upper limit of the normal range at Screening, and the average of the first and repeated test values should be used to decide the eligibility.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01244620

Locations
Singapore
Pfizer Investigational Site
Singapore, Singapore, 188770
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
To obtain contact information for a study center near you, click here.  This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01244620     History of Changes
Other Study ID Numbers: B1321056
Study First Received: November 15, 2010
Results First Received: January 18, 2012
Last Updated: January 18, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Pfizer:
A pharmacokinetic drug-drug interaction study between sitaxsentan and tadalafil and between sitaxsentan and sildenafil at the steady-state

Additional relevant MeSH terms:
Hypertension, Pulmonary
Hypertension
Lung Diseases
Respiratory Tract Diseases
Vascular Diseases
Cardiovascular Diseases
Sildenafil
Tadalafil
 Vasodilator Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on June 18, 2013