Drug Interaction Study of Apixaban With Cyclosporine and Tacrolimus

NCT03083782 | Completed Phase 1 FDA Drug

• 2 other identifiers: 10570BMS-CV185-567
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (2)

• Apixaban area under the plasma concentration curve between 0 and 72 hours (AUC(0-72)).

  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.

  Days 1-4 (Treatment A), Days 3-6 (Treatment B & C)

• Apixaban peak plasma concentration (Cmax)

  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.

  Days 1-4 (Treatment A), Days 3-6 (Treatment B & C)

Secondary Outcomes (2)

• 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 tacrolimus assessed by capturing adverse events and laboratory safety tests

  Day 1-4 (Treatment A), Day 1-6 (Treatment B & C)

Study Arms (3)

Treatment A: Apixaban alone

ACTIVE COMPARATOR

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

Drug: Apixaban alone

Treatment B: Cyclosporine with apixaban

EXPERIMENTAL

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; Drug: Apixaban

Treatment C: Tacrolimus with apixaban

EXPERIMENTAL

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; Drug: Apixaban

Interventions

Apixaban alone DRUG

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

Also known as: ELIQUIS

Treatment A: Apixaban alone

Cyclosporine DRUG

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

Also known as: NEORAL

Treatment B: Cyclosporine with apixaban

Tacrolimus DRUG

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

Also known as: PROGRAF

Treatment C: Tacrolimus with apixaban

Apixaban DRUG

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

Also known as: ELIQUIS

Treatment B: Cyclosporine with apixaban

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Thomas Jefferson University: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

Location

MeSH Terms

Conditions

Venous Thromboembolism

Interventions

apixaban; Cyclosporine; Tacrolimus

Condition Hierarchy (Ancestors)

Thromboembolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Macrolides; Lactones; Organic Chemicals

Study Officials

• Walter K Kraft, M.D.

  Thomas Jefferson University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Intervention Model: Crossover Assignment

Study Record Dates

• First Submitted: March 6, 2017
• First Posted: March 20, 2017
• Study Start: April 18, 2017
• Primary Completion: June 5, 2017
• Study Completion: June 30, 2017
• Last Updated: October 11, 2017

Record last verified: 2017-10

Data Sharing

• IPD Sharing: Will share

Locations

US (1)