ACT: Drug Interaction Study of Apixaban With Cyclosporine and Tacrolimus

Sponsor

Thomas Jefferson University (Other)

Overall Status

Completed

CT.gov ID

NCT03083782

Collaborator

Bristol-Myers Squibb (Industry)

Enrollment

Location

Arms

2.4

Actual Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Venous Thromboembolism Pharmacokinetics Healthy	Drug: Apixaban alone Drug: Cyclosporine Drug: Tacrolimus Drug: Apixaban Drug: Apixaban	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

12 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

Intervention Model: Crossover AssignmentIntervention Model: Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

A Phase I, Open-Label, Crossover, Drug Interaction Study of Apixaban With Cyclosporine and Tacrolimus in Healthy Volunteers

Actual Study Start Date :

Apr 18, 2017

Actual Primary Completion Date :

Jun 5, 2017

Actual Study Completion Date :

Jun 30, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Treatment A: Apixaban alone Oral apixaban will be administered in healthy volunteers to define baseline apixaban pharmacokinetics	Drug: Apixaban alone A single dose of 10 mg apixaban administered orally at 0H on Day 1. Other Names: ELIQUIS
Experimental: 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	Drug: Cyclosporine Once daily dose of 100 mg cyclosporine administered orally on Days 1 to 3. Other Names: NEORAL Drug: Apixaban A single dose of 10 mg apixaban administered orally on Day 3 immediately following cyclosporine Other Names: ELIQUIS
Experimental: 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	Drug: Tacrolimus Once daily dose of 5 mg tacrolimus administered orally on Days 1 to 3. Other Names: PROGRAF Drug: Apixaban A single dose of 10 mg apixaban administered orally on Day 3 immediately following tacrolimus Other Names: ELIQUIS

Arm

Intervention/Treatment

Active Comparator: Treatment A: Apixaban alone

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

Drug: Apixaban alone

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

Other Names:

ELIQUIS

Experimental: 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

Drug: Cyclosporine

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

Other Names:

NEORAL

Drug: Apixaban

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

Other Names:

ELIQUIS

Experimental: 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

Drug: Tacrolimus

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

Other Names:

PROGRAF

Drug: Apixaban

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

Other Names:

ELIQUIS

Outcome Measures

Primary Outcome Measures

Apixaban area under the plasma concentration curve between 0 and 72 hours (AUC(0-72)). [Days 1-4 (Treatment A), Days 3-6 (Treatment B & C)]
Blood samples for Apixaban pharmacokinetics will be collected prior to apixaban administration at 0H, and then at 1, 2, 3, 4, 6, 12, 24, 48 and, 72 hours in each treatment arm.
Apixaban peak plasma concentration (Cmax) [Days 1-4 (Treatment A), Days 3-6 (Treatment B & C)]
Blood samples for Apixaban pharmacokinetics will be collected prior to apixaban administration at 0H, and then at 1, 2, 3, 4, 6, 12, 24, 48 and, 72 hours in each treatment arm.

Secondary Outcome Measures

Safety and tolerability of apixaban when co-administered with cyclosporine assessed by capturing adverse events and laboratory safety tests [Day 1-4 (Treatment A), Day 1-6 (Treatment B & C)]
Safety and tolerability of apixaban when co-administered with cyclosporine based on adverse events reports and the results of vital sign measurements, electrocardiogram, physical examinations, and clinical laboratory tests
Safety and tolerability of apixaban when co-administered with tacrolimus assessed by capturing adverse events and laboratory safety tests [Day 1-4 (Treatment A), Day 1-6 (Treatment B & C)]
Safety and tolerability of apixaban when co-administered with tacrolimus based on adverse events reports and the results of vital sign measurements, electrocardiogram, physical examinations, and clinical laboratory tests

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Be a healthy male or female between ages 18-55 (inclusive) at the screening visit
Have a body mass index (BMI) ≥ 19 and ≤ 33 (inclusive)
Be a female subject, subject
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.
Can be of non-childbearing potential.
Be a nonsmoker for at least approximately 6 months
Have serum creatinine level < 1.5 mg/dL
Have a prothrombin time (PT) and activated partial thromboplastin time (PTT) level below the upper limit of normal
Have platelet count within normal limits
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
Be willing to comply with trial restrictions

Exclusion Criteria:

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
Has history of cancer (excluding treated cutaneous squamous or basal cell carcinoma of

3 years previous)

Has history of venous or arterial thromboembolic disease
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
Has had major surgery within 6 months prior to screening visit
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
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
Has a history of illicit drug abuse within six months prior to screening visit
Pregnant or lactating
Consumes greater than 3 glasses of alcoholic beverages per day and cannot refrain from alcohol for the duration of the trial
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
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
Has moderate or severe hepatic disease or other clinically relevant bleeding risk
Has positive history for hepatitis B surface antigen, hepatitis C or HIV
Use of any drugs or products which at the discretion of the investigator would increase bleeding risk
Is considered inappropriate for participation by the investigator for any reason