Drug Interaction Study of Apixaban With Cyclosporine and Tacrolimus

NCT ID: NCT03083782

Last Updated: 2017-10-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-04-18
• Study Completion Date: 2017-06-30

Brief Summary

This study aims to evaluate the pharmacokinetics (PK) of apixaban when co-administered with cyclosporine and tacrolimus in healthy volunteers. The study participants will receive apixaban alone, cyclosporine followed by apixaban and tacrolimus followed by apixaban.

Detailed Description

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.

Conditions

Venous Thromboembolism; Pharmacokinetics; Healthy

Keywords

Apixaban; Cyclosporine; Tacrolimus; Cytochrome P450 CYP3A4; Permeability Glycoprotein P-gp; Breast cancer resistance protein BCRP; Factor Xa Inhibitors; Anticoagulants; Enzyme Inhibitors

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Treatment A: Apixaban alone

Oral apixaban will be administered in healthy volunteers to define baseline apixaban pharmacokinetics

Group Type: ACTIVE_COMPARATOR

Apixaban alone

Intervention Type: DRUG

A single dose of 10 mg apixaban administered orally at 0H on Day 1.

Treatment B: Cyclosporine with apixaban

Oral cyclosporine will be administered to steady state in healthy volunteers followed by a single oral dose of apixaban to define apixaban pharmacokinetics in the presence of cyclosporine

Group Type: EXPERIMENTAL

Cyclosporine

Intervention Type: DRUG

Once daily dose of 100 mg cyclosporine administered orally on Days 1 to 3.

Apixaban

Intervention Type: DRUG

A single dose of 10 mg apixaban administered orally on Day 3 immediately following cyclosporine

Treatment C: Tacrolimus with apixaban

Oral tacrolimus will be administered to steady state in healthy volunteers followed by a single oral dose of apixaban to define apixaban pharmacokinetics in the presence of tacrolimus

Group Type: EXPERIMENTAL

Tacrolimus

Intervention Type: DRUG

Once daily dose of 5 mg tacrolimus administered orally on Days 1 to 3.

Apixaban

Intervention Type: DRUG

A single dose of 10 mg apixaban administered orally on Day 3 immediately following tacrolimus

Interventions

Apixaban alone

A single dose of 10 mg apixaban administered orally at 0H on Day 1.

Intervention Type: DRUG

Cyclosporine

Once daily dose of 100 mg cyclosporine administered orally on Days 1 to 3.

Intervention Type: DRUG

Tacrolimus

Once daily dose of 5 mg tacrolimus administered orally on Days 1 to 3.

Intervention Type: DRUG

Apixaban

A single dose of 10 mg apixaban administered orally on Day 3 immediately following cyclosporine

Intervention Type: DRUG

Apixaban

A single dose of 10 mg apixaban administered orally on Day 3 immediately following tacrolimus

Intervention Type: DRUG

Other Intervention Names

ELIQUIS; NEORAL; PROGRAF; ELIQUIS; ELIQUIS

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Bristol-Myers Squibb

INDUSTRY

Sponsor Role: collaborator

Thomas Jefferson University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Walter K Kraft, M.D.

Role: PRINCIPAL_INVESTIGATOR

Thomas Jefferson University

Locations

Thomas Jefferson University

Philadelphia, Pennsylvania, United States

Countries

United States

Other Identifiers

BMS-CV185-567

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

10570

Identifier Type: -

Identifier Source: org_study_id