Pharmacokinetics of Apixaban in Nephrotic Syndrome

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.

- 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.