Effect of Everolimus on the Pharmacokinetics of Tacrolimus in Renal Transplant Patients

July 22, 2019 updated by: National Taiwan University Hospital

The Effect of Everolimus on the Pharmacokinetics of Tacrolimus in Renal Transplant Patients, and the Effect of ABCB1、CYP3A4、CYP3A5、PORGenetic Polymorphism on the Two Drugs

The purpose of this study is to understand the effects of everolimus on tacrolimus pharmacokinetics (pk) in patients receiving de novo kidney transplants.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Multidrug immunosuppression regimens have synergistic effects which allow the use of lower doses of individual agents. These regimens generally include calcineurin inhibitors (CNIs: cyclosporine or tacrolimus), mammalian target of rapamycin (mTOR) inhibitors (everolimus or sirolimus), and corticosteroids. CNIs and mTOR inhibitors are substrates for cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp); in addition, cyclosporine is a inhibitor of CYP3A4 and P-gp. Therefore, concomitant administration of those drugs may alter their serum levels.

It is remained to be evaluated whether the pharmacokinetics or clinical efficacy of tacrolimus will be affected when the regimens contain everolimus in clinical practice and the effect of ABCB1、CYP3A4、CYP3A5、POR genetic polymorphism on the two Drugs. Mycophenolate mofetil (MMF) has no effect on pharmacokinetics of tacrolimus; therefore, MMF is used as a control to understand the effects of everolimus on pharmacokinetics of tacrolimus in patients receiving de novo kidney transplants. The effect of ABCB1、CYP3A4、CYP3A5、POR genetic polymorphism on the two Drugs was also assessed.

Study Type

Interventional

Enrollment (Actual)

14

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Taiwan
      • Taipei, Taiwan
        • National Taiwan University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 63 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion criteria:

  • De novo kidney transplants
  • 20 - 65 years old
  • aspartate aminotransferase/alanine aminotransferase within 2 times the upper limit of normal range

Exclusion criteria:

  • Pregnancy
  • Tuberculosis
  • Hepatitis B or C carrier status
  • Human immunodeficiency virus-positive status
  • Retransplantation or multiorgan transplantation
  • History of rheumatoid arthritis
  • Use of drugs that might have enhanced or inhibited CYP3A4 or P-gp activity

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Everolimus
Everolimus/Tacrolimus/Methylprednisolone & Prednisolone
Drug: Everolimus
Everolimus: 1 mg orally every 12 hours from post-operation day 1 to achieve trough concentrations of 3-8 ng/mL
Other Names:
  • Certican
Drug: Tacrolimus
Tacrolimus: 0.05-0.075 mg/kg orally every 12 hours from post-operation day 1 to achieve trough concentrations of 8-12 ng/mL
Other Names:
  • Prograf
Drug: Methylprednisolone
Methylprednisolone: 50 mg iv every 6 hours on post-operation day 1, 40 mg iv every 6 hours on post-operation day 2, 30 mg iv every 6 hours on post-operation day 3, 20 mg iv every 6 hours on post-operation day 4, 20 mg iv every 8 hours on post-operation day 5, 20 mg iv every 12 hours on post-operation day 6, 20 mg iv on post-operation day 7
Other Names:
  • Solu-Medrol
Drug: Prednisolone
Prednisolone: 20 mg orally once a day from post-operation day 8 to post-operation week 4, then titrated gradually
Other Names:
  • Predonine
Active Comparator: Mycophenolate mofetil
Mycophenolate mofetil/Tacrolimus/ Methylprednisolone & Prednisolone
Drug: Tacrolimus
Tacrolimus: 0.05-0.075 mg/kg orally every 12 hours from post-operation day 1 to achieve trough concentrations of 8-12 ng/mL
Other Names:
  • Prograf
Drug: Methylprednisolone
Methylprednisolone: 50 mg iv every 6 hours on post-operation day 1, 40 mg iv every 6 hours on post-operation day 2, 30 mg iv every 6 hours on post-operation day 3, 20 mg iv every 6 hours on post-operation day 4, 20 mg iv every 8 hours on post-operation day 5, 20 mg iv every 12 hours on post-operation day 6, 20 mg iv on post-operation day 7
Other Names:
  • Solu-Medrol
Drug: Prednisolone
Prednisolone: 20 mg orally once a day from post-operation day 8 to post-operation week 4, then titrated gradually
Other Names:
  • Predonine
Drug: Mycophenolate mofetil
Mycophenolate mofetil: 10-15 mg/kg orally every 12 hours from post-operation day 1 (decrease 50% dose if white blood cell < 4000/mcL)
Other Names:
  • CellCept

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pharmacokinetic profiles
Time Frame: Post-operation day 8-10
Pharmacokinetic parameters include the maximum concentration, trough concentration, area under the whole-blood concentration-time curve between 0 and 12 hours, time to maximum concentration, volume of distribution at steady state, and clearance at steady state.
Post-operation day 8-10

Secondary Outcome Measures

Outcome Measure
Time Frame
Acute rejection
Time Frame: Within the first 2 weeks post-transplantation
Within the first 2 weeks post-transplantation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Taiwan University Hospital

Investigators

  • Principal Investigator: Meng-Kun Tsai, National Taiwan University Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2014

Primary Completion (Actual)

January 15, 2019

Study Completion (Actual)

January 15, 2019

Study Registration Dates

First Submitted

March 2, 2014

First Submitted That Met QC Criteria

March 2, 2014

First Posted (Estimate)

March 4, 2014

Study Record Updates

Last Update Posted (Actual)

July 24, 2019

Last Update Submitted That Met QC Criteria

July 22, 2019

Last Verified

July 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 201312011MINA

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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