Drug Interaction Potentiation
Conditions
Keywords
tacrolimus, everolimus, pharmacokinetics, drug interaction
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.
Interventions
DRUGEverolimus
Everolimus: 1 mg orally every 12 hours from post-operation day 1 to achieve trough concentrations of 3-8 ng/mL
DRUGMycophenolate 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)
DRUGTacrolimus
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
DRUGMethylprednisolone
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
DRUGPrednisolone
Prednisolone: 20 mg orally once a day from post-operation day 8 to post-operation week 4, then titrated gradually
Sponsors
National Taiwan University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic profiles | 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. |
Secondary
| Measure | Time frame |
|---|---|
| Acute rejection | Within the first 2 weeks post-transplantation |
Countries
Taiwan
Outcome results
None listed