Pharmacokinetics of Apixaban in Nephrotic Syndrome

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

Study Overview

• Status: Completed
• Conditions: Proteinuria; Nephrotic Syndrome
• Intervention / Treatment: Drug: apixaban

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.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 77 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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 Names: Eliquis
Other: 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 Names: Eliquis

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of germline variants in genes involved in apixaban metabolism and clearance	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.	DNA extracted from whole blood specimens will be genotyped at the conclusion of enrollment, approximately 12 months.

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: North Carolina Translational and Clinical Sciences Institute
• Investigators: Principal Investigator: Daniel Crona, PharmD, PhD, University of North Carolina, Chapel Hill; Study Director: Vimal Derebail, MD, MPH, University of North Carolina, Chapel Hill

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2017
• Primary Completion (Actual): June 28, 2019
• Study Completion (Actual): June 28, 2019

Study Registration Dates

• First Submitted: November 4, 2015
• First Submitted That Met QC Criteria: November 5, 2015
• First Posted (Estimate): November 6, 2015

Study Record Updates

• Last Update Posted (Actual): July 24, 2019
• Last Update Submitted That Met QC Criteria: July 23, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Pharmacodynamics; Apixaban
• Additional Relevant MeSH Terms: Pathologic Processes; Kidney Diseases; Urologic Diseases; Urological Manifestations; Disease; Urination Disorders; Syndrome; Proteinuria; Nephrotic Syndrome; Nephrosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Apixaban
• Other Study ID Numbers: 14-1455; 550KR161709 (Other Grant/Funding Number: NCTraCS)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No