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

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ClinicalTrials.gov Identifier: NCT01244620
Recruitment Status : Terminated (Safety Issue: The trial was prematurely terminated on Dec 9, 2010, due to safety concerns, specifically new emerging evidence of hepatic injury.)
First Posted : November 19, 2010
Results First Posted : February 22, 2012
Last Update Posted : February 22, 2012
Sponsor:
Information provided by (Responsible Party):

Study Description
Brief Summary:

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 or disease Intervention/treatment Phase
Pulmonary Arterial Hypertension Drug: sitaxentan Drug: tadalafil Drug: sitaxsentan Drug: sildenafil Phase 1

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (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
Study Start Date : November 2010
Primary Completion Date : December 2010
Study Completion Date : December 2010


Arms and Interventions

Arm Intervention/treatment
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


Outcome Measures

Primary Outcome Measures :
  1. 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) ]
  2. 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) ]
    Minimum or "trough"concentrations

  3. 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) ]
  4. 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) ]
  5. 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) ]
    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.

  6. 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) ]
    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 :
  1. 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) ]
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.


Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
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

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): 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:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01244620     History of Changes
Other Study ID Numbers: B1321056
First Posted: November 19, 2010    Key Record Dates
Results First Posted: February 22, 2012
Last Update Posted: February 22, 2012
Last Verified: January 2011

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
Familial Primary Pulmonary Hypertension
Vascular Diseases
Cardiovascular Diseases
Hypertension, Pulmonary
Lung Diseases
Respiratory Tract Diseases
Sildenafil Citrate
Tadalafil
Sitaxsentan
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents
Endothelin Receptor Antagonists