Investigation Into the Therapeutic Dosage of Fondaparinux Sodium, a Medication Used to Prevent Blood Clots in Morbidly Obese Volunteers
Investigation Into the Therapeutic Dosage of Fondaparinux Sodium, a Medication Used to Prevent Blood Clots in Morbidly Obese Volunteers
Morbidly obese individuals are at high risk for potentially life threatening blood clots
 around the time of abdominal surgical procedures. Fondaparinux sodium (Arixtra) is an FDA-
 approved medication used in the prevention of deep venous thrombosis (DVT) at the time of
 orthopedic or abdominal surgery, as well as for the treatment of DVT and pulmonary embolism
 (PE). As with many medications, therapeutic dosages have not been fully investigated for the
 morbidly obese population. Our goal is to study the therapeutic blood levels, after 2
 different dosages of the medication are given to morbidly obese volunteers. We will recruit
 21 morbidly obese (Body Mass Index (BMI) > 35) individuals who are in the evaluation process
 for bariatric surgery. They will be divided into 7 groups: 3 participants with BMI 35 - 39.9,
 3 with a BMI of 40 - 49.9, 3 with a BMI of 50 - 59.9, 3 with a BMI > 60, 3 with a weight of
 100 - 149 KG, 3 with a weight of 150 - 199 KG and 3 with a weight of 200 - 249 KG.
 Participants will be administered two different doses of the medication with a 2-week
 interval in between, then blood will be drawn in various intervals throughout the next 48
 hours to see which dose provides the best therapeutic levels. Participants will be monitored
 closely for any side effects or complications.
Bariatric surgery carries a mortality rate of 0.5-1%, with PE found to be the most frequent
 postoperative complications and causes of death. Currently employed prophylactic methods
 include unfractionated or low molecular weight heparins in combination with mechanical calf
 compression. However, despite the implementation of these standard measures, the reported
 incidence of fatal PE has ranged from 0.2 to 0.64% accounting for between 30 to 50% of deaths
 after bariatric surgery.

 With a reported 40,000 bariatric surgical procedures in 2001, and the numbers growing rapidly
 every year, there is clearly a need for a more effective prophylaxis from DVT and PE. The
 pentasaccharide fondaparinux is an anti-thrombotic agent used in the prophylaxis of venous
 thromboembolism after orthopedic or abdominal surgery. Its clinical value has been
 established in multiple randomized double blind studies in high-risk major orthopedic surgery
 where it showed a 55% greater reduction in DVT episodes compared to enoxaparin (Lovenox®)
 Although fondaparinux has been administered in obese patients in clinical studies for
 prevention of venous thromboembolism after orthopedic surgery and preliminary results show no
 influence of ABW on the clinical outcome, the pharmacokinetic properties of the drug in the
 morbidly obese have not been investigated. Previously published fondaparinux pharmacokinetic
 studies excluded patients whose body weight was more than 30% of ideal, with the heaviest
 group being 77.2+/-10.1 Kg and with a BMI of 25.7+/2.6 Kg/m2. Similar studies on low
 molecular weight heparins, such as enoxaparin and dalteparin, showed predictable anti-Xa
 activity with weight-based dosing in the morbidly obese.

 There has been no study on the pharmacokinetics of this drug in the morbidly obese (BMI>35
 Kg/m2). It is clinically imperative to have a predictable anti-Xa level and a predictable DVT
 prophylactic effect in the morbidly obese whose body weight may vary by as much as 3 to 4
 fold higher compared to the average 70 Kg adult. This has become a critical issue in view of
 the large number of bariatric surgical operations being undertaken, which has increased 150%
 in the last two years.

 The purpose of this study is to assess the pharmacokinetic properties of fondaparinux in
 morbidly obese volunteers. This is a prospective crossover, randomized study with a 2-week
 washout period comparing two dosing regimens of fondaparinux in morbidly obese volunteers.
INCLUSION

 1. Age 19-65 years

 2. BMI 35-65 Kg/m2

 3. Pregnancy test Negative on day of study

 4. Past DVT/PE/MI These patients will not be excluded providing they are not on current
 therapy with anticoagulants, aspirin, or anti-platelet agents.

 EXCLUSION

 1. BP ≥ 160/90

 2. Temperature > 37.5 0C (99.5 0F)

 3. Nursing mothers Exclude if nursing

 4. Pregnancy test Positive on day of study

 5. Medications Anticoagulants, anti-platelet agents, aspirin, NSAIDs within a month of
 the study

 Past medical history

 1. cerebrovascular accident (including TIA within 6 months of the study)

 2. Diabetic retinopathy proven by fundoscopy

 3. History of inherited thrombotic/hypercoagulable defect

 4. Active peptic ulcer disease diagnosed by upper endoscopy

 5. Known bleeding disorder, thrombophilia

 6. History of heparin induced thrombocytopenia

 7. History of bacterial endocarditis

 8. Known hypersensitivity to fondaparinux

 9. Ulcerative colitis

 10. History of GI bleeding

 11. History of hematuria

 12. Recent surgery (last 3 months)

 13. Recent trauma (last 3 months)

 Laboratory values

 1. Platelet count ≤ 100,000 mm3

 2. Hemoglobin < 12 g/dL (women), or < 14 g/dL (men)

 3. Prothrombin time > 13 sec

 4. PTT > 35 sec

 5. ALT 3xULN and bilirubin 1.5xULN (>35% direct); or ALT 5xULN; or ALT 3xULN if
 associated with the appearance or worsening of hepatitis symptoms or rash

 6. Estimated urinary creatinine clearance ≤ 50 ml/min

 7. Hematuria on urine dipstick