Apixaban Pharmacokinetics in Bariatric Patients (APB)
Condition: Bariatric Surgery; Obesity
Study type: Interventional
Phase: Phase 4

Summary: 
      The Center for Bariatric Surgery is interested in conducting a pharmacokinetic study of
      apixaban (an oral anticoagulant with FDA approval for use of venous thrombo embolism (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).

      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).

      Primary outcome variable.

      To determine the durability or change in pharmacokinetics and pharmacodynamics of apixaban in
      patients with a body mass index (BMI) of 35 kg/m2 or greater following one of two bariatric
      surgical procedures (pre-operative versus post-operative vertical sleeve gastrectomy or
      Roux-en-Y gastric bypass patients).

      Secondary outcome variables.

        1. To compare/contrast the pharmacokinetics and pharmacodynamics of apixaban in bariatric
           surgical patients who have undergone RYGB vs. VSG.

        2. To determine how the pharmacokinetics of the drug may differ when there is significant
           post-operative surgical weight loss (>40% estimated excess body weight) 12 to 18 months
           following surgery versus those patients who have suboptimal weight loss following
           bariatric surgery (< 40% of estimated excess body weight).
    

Detailed description: 
      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.
    

Intervention name(s): Apixaban
Intervention type(s): Drug
Intervention description(s): New Oral Anticoagulants (NOACs) are currently available for prophylaxis against venous thromboembolism in patients undergoing total hip or knee replacement surgery.
Other intervention name(s): Eliquis
Intervention MeSH terms: Apixaban
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science