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

NCT ID: NCT02077556

Last Updated: 2019-07-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 14 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-04-30
• Study Completion Date: 2019-01-15

Brief Summary

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

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.

Conditions

Drug Interaction Potentiation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Everolimus

Everolimus/Tacrolimus/Methylprednisolone \& Prednisolone

Group Type: EXPERIMENTAL

Everolimus

Intervention Type: DRUG

Everolimus: 1 mg orally every 12 hours from post-operation day 1 to achieve trough concentrations of 3-8 ng/mL

Tacrolimus

Intervention Type: DRUG

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

Methylprednisolone

Intervention Type: DRUG

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

Prednisolone

Intervention Type: DRUG

Prednisolone: 20 mg orally once a day from post-operation day 8 to post-operation week 4, then titrated gradually

Mycophenolate mofetil

Mycophenolate mofetil/Tacrolimus/ Methylprednisolone \& Prednisolone

Group Type: ACTIVE_COMPARATOR

Mycophenolate mofetil

Intervention Type: DRUG

Mycophenolate mofetil: 10-15 mg/kg orally every 12 hours from post-operation day 1 (decrease 50% dose if white blood cell \< 4000/mcL)

Tacrolimus

Intervention Type: DRUG

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

Methylprednisolone

Intervention Type: DRUG

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

Prednisolone

Intervention Type: DRUG

Prednisolone: 20 mg orally once a day from post-operation day 8 to post-operation week 4, then titrated gradually

Interventions

Everolimus

Everolimus: 1 mg orally every 12 hours from post-operation day 1 to achieve trough concentrations of 3-8 ng/mL

Intervention Type: 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)

Intervention Type: 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

Intervention Type: 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

Intervention Type: DRUG

Prednisolone

Prednisolone: 20 mg orally once a day from post-operation day 8 to post-operation week 4, then titrated gradually

Intervention Type: DRUG

Other Intervention Names

Certican; CellCept; Prograf; Solu-Medrol; Predonine

Eligibility Criteria

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

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Taiwan University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Meng-Kun Tsai

Role: PRINCIPAL_INVESTIGATOR

National Taiwan University Hospital

Locations

National Taiwan University Hospital

Taipei, , Taiwan

Countries

Taiwan

Other Identifiers

201312011MINA

Identifier Type: -

Identifier Source: org_study_id