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Pharmacokinetics of Apixaban in Nephrotic Syndrome

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02599532
Recruitment Status : Completed
First Posted : November 6, 2015
Last Update Posted : July 24, 2019
Sponsor:
Collaborator:
North Carolina Translational and Clinical Sciences Institute
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

Brief Summary:
This study is to investigate the pharmacokinetics and pharmacodynamics of apixaban in nephrotic syndrome.

Condition or disease Intervention/treatment Phase
Nephrotic Syndrome Proteinuria Drug: apixaban Phase 1

Detailed Description:

Nephrotic syndrome (NS) is characterized by proteinuria and hypoalbuminemia, and patients with nephrotic syndrome are known to be hypercoaguable with increased incidence of venous thromboembolism necessitating anticoagulation. While classically warfarin has been used as an anticoagulant in NS, newer oral anticoagulants, such as apixaban, are increasingly used to treat venous thromboembolism (VTE) in the general population. It is unknown how hypoalbuminemia and proteinuria affect the pharmacokinetics and pharmacodynamics of apixaban.

This will be a parallel arm, single-dose pilot study of the pharmacokinetics of apixaban in adults with nephrotic syndrome. Goal enrollment of twenty subjects with non-diabetic nephropathy who have nephrotic-range proteinuria, defined as >3.5g/24 hours or UPC >3.5 and ten healthy control subjects without nephrotic syndrome. Each subject will be administered a single dose of apixaban 10 mg. Plasma drug concentration level and plasma anti-Xa activity levels will be measured at 0, 0.5, 1, 3, 4, 6, 8, 24 hours after drug administration in order to determine the maximum plasma concentration of apixaban, area under the curve, and half-life of apixaban in the setting of hypoalbuminemia and proteinuria due to nephrotic syndrome. Apixaban levels will be measured via liquid-chromatography spectrometry mass. Additionally, thrombin generation will be measured at 0, 3, 6, and 24 hours.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Pharmacokinetics of Apixaban in Nephrotic Syndrome
Actual Study Start Date : April 30, 2017
Actual Primary Completion Date : June 28, 2019
Actual Study Completion Date : June 28, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Apixaban

Arm Intervention/treatment
Nephrotic syndrome
Subjects with nephrotic syndrome will receive a single dose of apixaban 10 mg and will subsequently have blood drawn at 0, 0.5, 1, 3, 4, 6, 8, 24 hours after drug administration.
Drug: apixaban
Study subjects will be given a single-dose of apixaban 10 mg.
Other Name: Eliquis

Non-nephrotic syndrome
Subjects without nephrotic syndrome will receive a single dose of apixaban 10 mg and will subsequently have blood drawn at 0, 0.5, 1, 3, 4, 6, 8, 24 hours after drug administration.
Drug: apixaban
Study subjects will be given a single-dose of apixaban 10 mg.
Other Name: Eliquis




Primary Outcome Measures :
  1. Area under the concentration versus time curve after single dose (AUC) of apixaban [ Time Frame: Predose; 0.5, 1, 3, 4, 6, and 8 hours (hr) postdose on Day 1; 24 hours postdose on Day 2 ]

Secondary Outcome Measures :
  1. Mean terminal phase plasma half-life (t½) [ Time Frame: Predose; 0.5, 1, 3, 4, 6, and 8 hours postdose on Day 1; 24 hours postdose on Day 2 ]
  2. Apparent oral clearance (CL/F) [ Time Frame: Predose; 0.5, 1, 3, 4, 6, and 8 hours postdose on Day 1; 24 hours postdose on Day 2 ]
  3. Maximum observed drug concentration in plasma after single dose administration (Cmax) [ Time Frame: Predose; 0.5, 1, 3, 4, 6, and 8 hours postdose on Day 1; 24 hours postdose on Day 2 ]
  4. Thrombin Generation Assay [ Time Frame: Predose; 3 and 6 hours postdose on Day 1; 24 hours postdose on Day 2 ]
  5. Anti-Xa activity [ Time Frame: Predose; 0.5, 1, 3, 4, 6, and 8 hours postdose on Day 1; 24 hours postdose on Day 2 ]

Other Outcome Measures:
  1. Proportion of germline variants in genes involved in apixaban metabolism and clearance [ Time Frame: DNA extracted from whole blood specimens will be genotyped at the conclusion of enrollment, approximately 12 months. ]
    Explore the relationship between variant genes responsible for apixaban metabolism and clearance (CYP3A4/5, CYP1A2, CYP2J2, ABCB1, and ABCG2) and drug exposure as measured by AUC. Genotyping analyses will be performed at conclusion of study and appropriate conventional statistical analyses will be employed to assess all genotype-phenotype associations.



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Ages Eligible for Study:   18 Years to 79 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • Inclusion Criteria:

    • Study subjects:

      • Between 18 and 79 years old
      • Confirmed diagnosis of Nephrotic Syndrome, with at least one of the following:

        • 1. Nephrotic-range proteinuria, defined as >3.5 g/24 hours or UPC >3.5 (confirmed within 1 month prior to scheduled study visit)
        • 2. Hypoalbuminemia, defined as <3 g/dL (confirmed within 1 month prior to scheduled study visit)
    • Control subjects:

      • Between 18 and 79 years old
      • Normal albumin levels (≥3.5 mg/dL)
      • No proteinuria (UPC <0.15)
  • Exclusion criteria:

    • Age <18 or ≥ 80 years old
    • SCr ≥ 1.5 AND weight ≤ 60kg (these subjects would receive a reduce dose of apixaban, per drug labeling)
    • On dialysis
    • Baseline prolonged PT/INR, PTT (as defined by greater than the upper limit of normal)

      • INR will be used as the primary lab value to evaluate bleeding risk (e.g. a patient presenting with an INR within normal limits, but prolonged PT or PTT, will not meet this exclusion criterion and will still be eligible for the study)
      • Reference Ranges

        • INR: >1.4
        • PT: >13.3 sec
        • aPTT: >37.7 sec
    • Platelets <100
    • History of GI bleed
    • History of intracranial bleed
    • History of stroke
    • Use of (but not limited to) the following medications within the past 14 days:

      • Inducers of CYP3A4 (e.g. rifampin, carbamazepine, phenytoin, St. John's wort, etc.)
      • Strong inhibitors of CYP3A4 (e.g. ketoconazole, ritonavir, clarithromycin, etc.)
      • Antiplatelet and/ or anticoagulant agents: heparin, aspirin* (see below), clopidogrel, prasugrel, NSAIDs, warfarin, rivaroxaban, dabigatran, edoxaban
      • Selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitors (SNRI)
    • Pregnancy/breastfeeding
    • Liver disease with impaired synthetic function (INR >1.4, total bilirubin >1.2)
    • Congestive heart failure

Special consideration for patients on aspirin: for patients on chronic low-dose aspirin therapy, we will allow a 7 day wash out period. This will only be allowed for patients who are taking aspirin as primary prophylaxis or for unclear indications. Patients who are on aspirin therapy for following indications will be excluded: primary prophylaxis of stroke due to atrial fibrillation, secondary prevention of stroke or myocardial infarction, history of coronary artery disease or peripheral vascular disease. For patients who meet the potential criteria for the 7-day wash out, their medical history will be reviewed by one of the clinician investigators to ensure that it is safe and appropriate to hold the agent.

Those subjects taking aspirin for the following reasons will be excluded:

  • Primary stroke prevention from atrial fibrillation
  • Secondary prevention due to prior stroke, heart attack or cardiac stent
  • Existing heart disease or peripheral vascular disease.

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): NCT02599532


Locations
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United States, North Carolina
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States, 27599
Sponsors and Collaborators
University of North Carolina, Chapel Hill
North Carolina Translational and Clinical Sciences Institute
Investigators
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Principal Investigator: Daniel Crona, PharmD, PhD University of North Carolina, Chapel Hill
Study Director: Vimal Derebail, MD, MPH University of North Carolina, Chapel Hill

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Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT02599532    
Other Study ID Numbers: 14-1455
550KR161709 ( Other Grant/Funding Number: NCTraCS )
First Posted: November 6, 2015    Key Record Dates
Last Update Posted: July 24, 2019
Last Verified: July 2019

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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 University of North Carolina, Chapel Hill:
Apixaban
Pharmacokinetics
Pharmacodynamics
Additional relevant MeSH terms:
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Proteinuria
Nephrotic Syndrome
Nephrosis
Syndrome
Disease
Pathologic Processes
Urination Disorders
Urologic Diseases
Urological Manifestations
Signs and Symptoms
Kidney Diseases
Apixaban
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants