Drug Interaction Study of Apixaban With Cyclosporine and Tacrolimus

Life- and graft-threatening complications in solid organ transplant patients have been
greatly reduced due to the potent immunosuppressive agents like calcineurin inhibitors (CNI)
that include cyclosporine and tacrolimus. Venous thromboembolism (clots in legs or lungs) in
transplant recipients is often difficult to manage due to polypharmacy and potential for drug
interactions. More than 90% of renal transplant (RT) recipients are maintained on a CNI-based
immunosuppressive regimen. Cyclosporine is an inhibitor of many metabolic pathways including
cytochrome P450 (CYP) 3A4, permeability glycoprotein (P-gp) and, breast cancer resistance
protein (BCRP). Tacrolimus shares some of the distributive and metabolic pathways of
cyclosporine. Apixaban is a combined substrate of CYP3A4, P-gp and, BCRP and thus has the
potential for drug interactions with cyclosporine and tacrolimus. Apixaban levels that are
too high or too low could be a problem for transplant patients. The purpose of this study is
to determine what happens to apixaban blood levels when given in combination with
cyclosporine or tacrolimus.

Inclusion Criteria:

1. Be a healthy male or female between ages 18-55 (inclusive) at the screening visit

2. Have a body mass index (BMI) ≥ 19 and ≤ 33 (inclusive)

3. Be a female subject, subject

1. Can be of childbearing potential and must demonstrate a urine β-hCG level
consistent with the non-pregnancy state and agree to use an acceptable method of
birth control throughout the study.

2. Can be of non-childbearing potential.

4. Be a nonsmoker for at least approximately 6 months

5. Have serum creatinine level < 1.5 mg/dL

6. Have a prothrombin time (PT) and activated partial thromboplastin time (PTT) level
below the upper limit of normal

7. Have platelet count within normal limits

8. Be willing to refrain from the use of anticoagulants and antiplatelet medications
including aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) during the entire
period of study participation

9. Be willing to comply with trial restrictions

Exclusion Criteria:

1. Has a history of clinically significant endocrine, gastrointestinal, cardiovascular,
hematological, hepatic, immunological, renal, respiratory, genitourinary or major
neurological (including stroke and chronic seizures), dermatologic or psychiatric
abnormalities or diseases

2. Has history of cancer (excluding treated cutaneous squamous or basal cell carcinoma of
>3 years previous)

3. Has history of venous or arterial thromboembolic disease

4. Has a history of a major bleeding event (defined as: (i) symptomatic bleeding in a
critical area or organ, such as intracranial, intraspinal, intraocular,
retroperitoneal, intra-articular or pericardial, or intramuscular with compartment
syndrome, and/or (ii) a fall in hemoglobin level of 2 g/dL or more, or leading to
transfusion of two or more units of whole blood or red cells) within 6 months prior to
screening visit

5. Has had major surgery within 6 months prior to screening visit

6. Is unable to refrain from or anticipates the use of any medication, including
prescription and non-prescription drugs or herbal remedies for 2 weeks prior to trial
start date until the post-trial visit

7. Is unable to refrain from using any drugs or substance known to be inhibitors or
inducers of cytochrome P450 (CYP) enzymes including grapefruit products for 2 weeks
prior to dosing and throughout the study, until the post-trial visit

8. Has a history of illicit drug abuse within six months prior to screening visit

9. Pregnant or lactating

10. Consumes greater than 3 glasses of alcoholic beverages per day and cannot refrain from
alcohol for the duration of the trial

11. Has a history of significant multiple and/or severe allergies (e.g. food, drug), or
has had an anaphylactic reaction or significant intolerability to prescription or
non-prescription drugs or food

12. Has known anaphylactic or severe systemic reactions to any components of study drugs
(including apixaban, cyclosporine or tacrolimus) or contraindication to the
administration of study drugs

13. Has moderate or severe hepatic disease or other clinically relevant bleeding risk

14. Has positive history for hepatitis B surface antigen, hepatitis C or HIV

15. Use of any drugs or products which at the discretion of the investigator would
increase bleeding risk

16. Is considered inappropriate for participation by the investigator for any reason