Pharmacokinetics of Apixaban in Nephrotic Syndrome

NCT ID: NCT02599532

Last Updated: 2019-07-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-04-30
• Study Completion Date: 2019-06-28

Brief Summary

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

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.

Conditions

Nephrotic Syndrome; Proteinuria

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

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.

Group Type: OTHER

apixaban

Intervention Type: DRUG

Study subjects will be given a single-dose of apixaban 10 mg.

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.

Group Type: OTHER

apixaban

Intervention Type: DRUG

Study subjects will be given a single-dose of apixaban 10 mg.

Interventions

apixaban

Study subjects will be given a single-dose of apixaban 10 mg.

Intervention Type: DRUG

Other Intervention Names

Eliquis

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 79 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

North Carolina Translational and Clinical Sciences Institute

OTHER

Sponsor Role: collaborator

University of North Carolina, Chapel Hill

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Daniel Crona, PharmD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of North Carolina, Chapel Hill

Vimal Derebail, MD, MPH

Role: STUDY_DIRECTOR

University of North Carolina, Chapel Hill

Locations

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Countries

United States

Other Identifiers

550KR161709

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

14-1455

Identifier Type: -

Identifier Source: org_study_id