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

Pharmacokinetics Clinical Trial

— ACT-KLR  

Official title:

Pharmacokinetics of Apixaban and Tacrolimus or Cyclosporine in Kidney and Lung Transplant Recipients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04023760
• Other study ID #: 99861
• Status: Completed
• Phase: Phase 4
• Start date: June 26, 2019
• Est. completion date: March 30, 2020

Study information

• Verified date: April 2021
• Source: University of Saskatchewan
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Solid organ transplantation is a lifesaving option for many patients with end-stage organ disease. After transplant surgery, patients must take immunosuppressive therapy, which carries significant risk for drug-drug interactions and adverse medication-related events.

Transplant recipients are at an increased risk for co-morbidities traditionally managed with warfarin, such as venous thromboembolism and atrial fibrillation. Apixaban has the potential to provide safer and more effective treatment, without additional monitoring of the INR, but it has not been studied in conjunction with anti-rejection agents in this population. Apixaban is metabolized by CYP3A4 and P-gp and BCRP transporters. As part of their immunosuppressive therapy, solid organ transplant recipients are maintained on calcineurin inhibitors, which are weak CYP3A4 as well as potent P-gp and BCRP inhibitors. A study was recently undertaken to evaluate the potential drug-drug interaction between cyclosporine or tacrolimus and apixaban in healthy subjects (ClinicalTrials.gov Identifier: NCT03083782) . The results indicated that the change in apixaban exposure was not clinically relevant.

PK studies in healthy volunteers are a first step for determining the nature and extent of potential drug-drug interactions. However, follow-up studies in the actual patient populations are essential for ensuring safety and tolerability, and providing clinicians the confidence to use these combinations. The purpose of this study is to confirm the pharmacokinetic characteristics and safety of apixaban in combination with tacrolimus and cyclosporine in stable kidney and lung transplant recipients.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: March 30, 2020
• Est. primary completion date: March 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• Kidney Transplant
• Lung Transplant
• Pharmacokinetics

Intervention

Drug:
• Apixaban
Study subjects given a single-dose of apixaban 10 mg.

Locations

Country	Name	City	State
Canada	Saskatchewan Health Authority	Saskatoon	Saskatchewan

Sponsors (3)

Lead Sponsor	Collaborator
University of Saskatchewan	Lung Association of Saskatchewan, Saskatchewan Health Research Foundation

Country where clinical trial is conducted

Canada, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Differences in area under the plasma concentration curve between 0 and 72 hours AUC (0-72)) in kidney and lung transplant recipients	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
Other	Differences in peak plasma concentration (Cmax) hours between kidney and lung transplant recipients	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
Other	Differences in area under the plasma concentration curve between 0 and 72 hours AUC(0-72)) between transplant recipients and healthy subjects	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
Other	Differences in peak plasma concentration (Cmax) hours between transplant recipients and healthy subjects	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
Primary	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
Primary	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	Safety and tolerability of Apixaban when co-administered with cyclosporine assessed by capturing incidence of adverse events	Number of participants who experience an adverse events based on the results of laboratory safety tests and the results of vital sign measurements, physical examinations, and clinical laboratory tests	Days 1-4
Secondary	Safety and tolerability of Apixaban when co-administered with tacrolimus assessed by capturing incidence of adverse events	Number of participants who experience an adverse events based on the results of laboratory safety tests and the results of vital sign measurements, physical examinations, and clinical laboratory tests	Days 1-4