Drug Interaction Study of Apixaban With Cyclosporine or Tacrolimus in Transplant Recipients

NCT04023760 | Completed Phase 4

• 1 other identifier: 99861
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

This study aims to evaluate the pharmacokinetics (PK) of apixaban in kidney and lung transplant recipients stabilized on either cyclosporine or tacrolimus as part of their immunosuppressive therapy.

Conditions

Pharmacokinetics; Kidney Transplant; Lung Transplant

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 1-3

• 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 1-3

Secondary Outcomes (2)

• Safety and tolerability of Apixaban when co-administered with cyclosporine assessed by capturing incidence of adverse events

  Days 1-4

• Safety and tolerability of Apixaban when co-administered with tacrolimus assessed by capturing incidence of adverse events

  Days 1-4

Other Outcomes (4)

• Differences in area under the plasma concentration curve between 0 and 72 hours AUC (0-72)) in kidney and lung transplant recipients

  Days 1-3

• Differences in peak plasma concentration (Cmax) hours between kidney and lung transplant recipients

  Days 1-3

• Differences in area under the plasma concentration curve between 0 and 72 hours AUC(0-72)) between transplant recipients and healthy subjects

  Days 1-3

Study Arms (4)

Treatment group A: Cyclosporine in transplant recipients

EXPERIMENTAL

A single oral dose of 10 mg apixaban will be administered to kidney or lung transplant recipients stabilized on cyclosporine as part of their immunosuppressive regimen

Drug: Apixaban

Cyclosporine in healthy subjects

ACTIVE COMPARATOR

Results from Treatment group A will be compared to previously obtained data in healthy participants receiving a single dose of apixaban with a daily dose of 100 mg of cyclosporine at steady state concentration (Bashir et al. Clin Transl Sci. 2018 Jul 3. doi: 10.1111/cts.12580) Transplant recipients require continuous immunosuppression so it will not be possible to stop the cyclosporine or tacrolimus to serve as a control. As such PK plasma time curves will be compared to data in healthy volunteers.

Drug: Apixaban

Treatment group B: Tacrolimus in transplant recipients

EXPERIMENTAL

A single oral dose of 10 mg apixaban will be administered to kidney or lung transplant recipients stabilized on tacrolimus as part of their immunosuppressive regimen

Drug: Apixaban

Tacrolimus in healthy subjects

ACTIVE COMPARATOR

Results from Treatment group B will be compared to previously obtained data in healthy participants receiving a single dose of apixaban with a daily dose of 100 mg of tacrolimus at steady state concentration (Bashir et al. Clin Transl Sci. 2018 Jul 3. doi: 10.1111/cts.12580) Transplant recipients require continuous immunosuppression so it will not be possible to stop the cyclosporine or tacrolimus to serve as a control. As such PK plasma time curves will be compared to data in healthy volunteers.

Drug: Apixaban

Interventions

Apixaban DRUG

Study subjects given a single-dose of apixaban 10 mg.

Also known as: Eliquis

Cyclosporine in healthy subjects; Tacrolimus in healthy subjects; Treatment group A: Cyclosporine in transplant recipients; Treatment group B: Tacrolimus in transplant recipients

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Kidney or lung transplant patients followed as outpatients who are currently stabilized on immunosuppressive therapy with tacrolimus or cyclosporine
• Age 18 or older
• At least six months after transplantation
• Lack of transplant rejection within the last 12 weeks
• Creatinine clearance at least above 15ml/min as calculated by Cockroft-Gault formula
• Negative urine pregnancy test for female patients of childbearing potential
• Consent to the study
• Be a nonsmoker for at least approximately 6 months prior to the study
• Have a prothrombin time (PT) and activated partial thromboplastin time (PTT) level below the upper limit of normal
• Have a hemoglobin level of above at least 80g/L
• Be willing to refrain from the use of anticoagulants and antiplatelet medications including aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) for two weeks prior and during the entire period of study participation
• Be willing to avoid drinking grapefruit juice or consuming natural health products for two weeks prior and during the study period
• Be willing to avoid alcohol and cannabis for 48 hours before the study and for the entire duration of the study
• Be willing to comply with trial restrictions
• Be deemed safe to participate by the study physician

You may not qualify if:

• Patients on antiplatelet therapy for any cardiovascular treatment (such as clopidogrel, prasugrel, ticagrelor). Patients on prophylactic aspirin will be eligible otherwise.
• Patients not receiving tacrolimus or cyclosporine
• A history of an anaphylactic or severe systemic reactions to apixaban
• Any form of substance abuse or major untreated psychiatric disorder
• Pregnancy or lactation
• Tacrolimus or cyclosporine changes within the last two weeks
• Receiving concurrent therapy with warfarin, or are taking medications known to be strong inhibitors of both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) such as azole-antimycotics antifungals (e.g., ketoconazole, voriconazole.)
• Has congenitial or acquired coagulation disorders
• Has moderate or severe hepatic disease or other clinically relevant bleeding risk
• Use of any drugs or products which at the discretion of the investigator would increase bleeding risk
• Has any unstable medical condition that could interfere with the study
• Is considered inappropriate for participation by the investigator for any reason
• Clinically significant active bleeding, including gastrointestinal bleeding
• Lesions or conditions at increased risk of clinically significant bleeding, e.g., recent cerebral infarction (ischemic or hemorrhagic), active peptic ulcer disease with recent bleeding, patients with spontaneous or acquired impairment of hemostasis
• Patients who donate blood within 56 days of participating in the study

Sponsors & Collaborators

• University of Saskatchewan: lead
• Saskatchewan Health Research Foundation: collaborator
• Lung Association of Saskatchewan: collaborator

Study Sites (1)

Saskatchewan Health Authority

Saskatoon, Saskatchewan, Canada

Location

Related Publications (2)

• Bashir B, Stickle DF, Chervoneva I, Kraft WK. Drug-Drug Interaction Study of Apixaban with Cyclosporine and Tacrolimus in Healthy Volunteers. Clin Transl Sci. 2018 Nov;11(6):590-596. doi: 10.1111/cts.12580. Epub 2018 Jul 27.

  PMID: 29972633 BACKGROUND

• Mansell H, Shoker A, Alcorn J, Fenton ME, Tam JS, Semchuk W, Bashir B, Kraft WK, Yao S, Douketis JD. Pharmacokinetics of apixaban and tacrolimus or cyclosporine in kidney and lung transplant recipients. Clin Transl Sci. 2022 Jul;15(7):1687-1697. doi: 10.1111/cts.13284. Epub 2022 May 2.

  PMID: 35439353 DERIVED

MeSH Terms

Interventions

apixaban

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor, College of Pharmacy and Nutrition

Study Record Dates

• First Submitted: June 28, 2019
• First Posted: July 18, 2019
• Study Start: June 26, 2019
• Primary Completion: March 30, 2020
• Study Completion: March 30, 2020
• Last Updated: May 3, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will share

Locations

CA (1)