Apixaban Pharmacokinetics in Bariatric Patients (APB)

Obesity is now the leading health problem of the 21st century. Weight reduction by
conservative methods including diet and exercise has had poor success rates. There has been a
substantial increase in the use of bariatric surgery to provide sustained weight loss and
thus a reduction in the medical comorbidities that are associated with obesity. However,
because these procedures may alter the anatomical and physiological aspects of the
gastrointestinal system, there is a possibility of altered pharmacokinetics to medications
particularly when taken orally. Furthermore, patients typically lose anywhere from 50 to 75%
of their estimated excess body mass approximately one to two years following surgery. This
successful therapeutic outcome of the surgery may be causing long term changes in the
pharmacokinetics that are independent of any direct anatomical or physiologic changes induced
by the procedure.

Physicians and surgeons are very interested in oral anticoagulants for this special patient
population. To date, there is no approved dosing for the obese patient (especially when
considering surgical intervention such as bariatric surgery). VTE is one of the top two
causes of morbidity and mortality in the bariatric surgical patient. In the ninth edition of
the Antithrombotic Therapy and Prevention of Thrombosis guideline published by the American
College of Chest Physicians (1), it is reported that virtually all bariatric surgical
patients have at least a moderate risk of VTE, with many patients at high risk. (2) The
approach to VTE prophylaxis used by most bariatric surgeons today is a combination of
non-invasive and pharmacologic techniques, including sequential compression devices,
anti-embolic stockings, anticoagulation, and early ambulation. Traditionally VTE prophylaxis
has been accomplished with subcutaneous injection however with the introduction of new oral
anticoagulant medications many practitioners are using these anticoagulants without
demonstration of effectiveness in this population.

The Johns Hopkins Center for Bariatric Surgery is interested in conducting a pharmacokinetic
study of apixaban (an oral anticoagulant with FDA approval for use of VTE prophylaxis and
treatment) in the obese adult population to determine if bariatric surgery influences
apixaban exposure. More interesting would be to see how the dose may need to change pre- vs.
post-bariatric surgery (this will be important for physicians as more and more patients
undergo this procedure worldwide and many may require anticoagulation in their future
healthcare).

Specific Aim 1: To determine the pharmacokinetics of apixaban in obese patients scheduled to
have bariatric surgery with a body mass index (BMI) of 35 kg/m2 or greater.

Hypothesis 1a: Obese patients prior to bariatric surgical intervention, compared to normal
weight historical controls, will have a decrease in both Cmax and area under the curve (AUC)
when given a single dose of 5 mg of apixaban.

Specific Aim 2: To determine the pharmacokinetics of apixaban in the bariatric surgical
patient who has undergone Roux-en Y gastric bypass (RYGB) or Vertical Sleeve Gastrectomy
(VSG) at 1, 6, 12 and 18 months post-op.

Hypothesis 2a: Patients who have recently undergone RYGB surgery (1 month post-op) will have
a decrease in both the Cmax and AUC, relative to pre-op values, when given a single dose of 5
mg of apixaban.

Hypothesis 2b: Patients who have recently undergone VSG surgery (1 month post-op) will have a
decrease in both the Cmax and AUC, relative to pre-op values, when given a single dose of 5
mg of apixaban. The magnitude of the decrease in Cmax and AUC will be less than that seen in
RYGB patients.

Rationale: Anatomic alteration of the GI tract will immediately reduce absorption in all
post-operative bariatric patients. In RYGB patients, the attenuated small bowel and altered
bile acid composition will lead to decreased absorption of the drug, whereas in sleeve
gastrectomy patients prolonged gastric emptying may affect pharmacokinetics.

These findings will be important when considering the use of apixaban as an oral
anticoagulation option for perioperative VTE prophylaxis in the bariatric population, both in
the acute hospital setting and after discharge in patients requiring extended VTE prophylaxis
or treatment.

Hypothesis 2c: After undergoing bariatric surgery, patients at 6, 12, and 18 months post-op
will have an increase in Cmax and AUC, relative to pre-op values, when given a single dose of
5 mg of apixaban.

Hypothesis 2d: After undergoing RYGB, patients at 6, 12, and 18 months post-op will have a
greater increase in both Cmax and AUC, relative to pre-op values, than VSG patients relative
to pre-op values when given a single dose of 5 mg of apixaban.

Rationale: Patients who are 6 to 18 months post-bariatric surgery generally have a 30-40%
decrease in excess body weight. This decrease in body weight reduces volume of distribution
of drug, potentially affecting Cmax. Results of the published Phase 1 apixaban study found
that exposure to a dose of apixaban was inversely related to body weight. Therefore, the
investigators should expect higher plasma levels of apixaban in patients who are 6 to 18
months post-bariatric surgery when compared to pre-op values.

Findings of the Phase I study (3,4) An open-label, parallel-group, non-randomized,
single-dose study in healthy male and female subjects was conducted to assess the effects of
body weight on the pharmacokinetics of a single 10 mg dose of apixaban. Following screening,
patients were enrolled in one of three groups: low body weight (≤50kg, N=18), normal body
weight (65-85kg, N=18) or high body weight (≥120kg, N=19).

Compared to normal body weight:

- There was a 27% increase in Cmax and 20% increase in AUC in patients with low body
weight

- There was a 31% decrease in Cmax and 23% decrease in AUC in patients with high body
weight

The effect of RYGB vs. sleeve gastrectomy on long-term pharmacokinetics is difficult to
predict because of the opposing effects of greater weight loss with reduced absorption in the
RYGB patient.

These findings will be important when considering apixaban as an oral medication for
long-term post-op bariatric patients who may require anticoagulation for stroke, myocardial
infarction, atrial fibrillation or orthopedic procedures such as hip or knee replacements.
(5, 6)

Specific Aim 3: To measure the effect of apixaban on Factor Xa activity (chromogenic anti-Xa
activity assay) in bariatric surgical patients pre-operatively then at 1, 6, 12 and 18 months
post-operatively.

Hypothesis 3a: In spite of the changes in pharmacokinetics, the pharmacodynamics response
(measured with a chromogenic anti-Xa activity assay) will not differ by more than 10% in
comparing pre-surgical response to that at 1, 6, 12 and 18 months after surgery.

Rationale: The changes in pharmacokinetics should not lead to a different
concentration-response relationship in the chromogenic anti- Xa activity of individual
patients following dosing with apixaban 5 mg. Were there to be a significant change in
pharmacodynamics, other factors due to the altered anatomy or substantial weight loss would
need to be invoked to explain that altered relationship.

Inclusion Criteria:

- Men or women, 18 to 65 years old with a BMI of 35 kg/m2 or greater who will be
undergoing bariatric surgery (VSG and RYGB)

- Signed written informed consent

- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to
the start of study drug

- Women must not be breastfeeding

Exclusion Criteria:

- History of documented clotting/coagulation disorder

- History of cancer (within the last year)

- Any diagnosis requiring anti-coagulation

- History of hypersensitivity reaction to apixaban

- Active clinically significant bleeding

- Creatinine > 1.5 mg/dL

- Participants currently receiving any type of anticoagulation or blood thinning
medications, including heparin, low molecular weight heparins, Plavix, aspirin, NSAIDS

- Participant who is taking any of the excluded medications

- Combined P-glycoprotein and strong cytochrome P450 (CYP) 3A4 inhibitor

- Combined P-glycoprotein and moderate CYP 3A4 inhibitor

- Combined P-glycoprotein inducer and strong CYP 3A4 inducer

- Inducers of p-glycoprotein

- Strong inducers of CYP 3A4