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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Drug Interaction Potentiation

Intervention / Treatment
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* Drug: Everolimus
* Drug: Mycophenolate mofetil
* Drug: Tacrolimus
* Drug: Methylprednisolone
* Drug: Prednisolone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus<br>Everolimus/Tacrolimus/Methylprednisolone & Prednisolone | Drug: Everolimus<br>* Everolimus: 1 mg orally every 12 hours from post-operation day 1 to achieve trough concentrations of 3-8 ng/mL<br>* Other names: Certican;Drug: Tacrolimus<br>* 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<br>* Other names: Prograf;Drug: Methylprednisolone<br>* 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<br>* Other names: Solu-Medrol;Drug: Prednisolone<br>* Prednisolone: 20 mg orally once a day from post-operation day 8 to post-operation week 4, then titrated gradually<br>* Other names: Predonine;|
| Active Comparator: Mycophenolate mofetil<br>Mycophenolate mofetil/Tacrolimus/ Methylprednisolone & Prednisolone | Drug: Mycophenolate mofetil<br>* Mycophenolate mofetil: 10-15 mg/kg orally every 12 hours from post-operation day 1 (decrease 50% dose if white blood cell < 4000/mcL)<br>* Other names: CellCept;Drug: Tacrolimus<br>* 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<br>* Other names: Prograf;Drug: Methylprednisolone<br>* 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<br>* Other names: Solu-Medrol;Drug: Prednisolone<br>* Prednisolone: 20 mg orally once a day from post-operation day 8 to post-operation week 4, then titrated gradually<br>* Other names: Predonine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic profiles | 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 | Measure Description | Time Frame |
| --- | --- | --- |
| Acute rejection |  | Within the first 2 weeks post-transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tacrolimus, everolimus, pharmacokinetics, drug interaction