A Prospective Study to Investigate Mycophenolic Acid (MPA) Exposure Through Area Under the Curve (AUC) in Renal Transplants Recipients Treated With Mycophenolate Mofetil (MMF) and After Conversion to Mycophenolate Sodium (EC-MPS)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is investigate mycophenolic acid exposure through area under the curve in renal transplants recipients treated with mycophenolate mofetil and after conversion to mycophenolate sodium.

Detailed Description
-----------------
A growing body of evidence has shown that mycophenolate acid (MPA) exposure assessment and dosage adjustment are necessary in patients treated with mycophenolate mofetil (MMF), but there is still limited information about the dose-exposure-effect relationship of the enteric-coated mycophenolate sodium (EC-MPS) formulation that has quite different physicochemical properties (TETT et al., 2011). Pharmacokinetically guided exposure-controlled area under the concentration-time curve (AUC) approaches are helpful to limit interpatient variability of MPA exposure and to improve the clinical outcome of organ transplant recipients (TETT et al., 2011). MPA area under the concentration-time curve values between 30 and 60 μg h/mL in the early post-transplant period reduces the risk of acute rejections and seems to be appropriate in renal allograft recipients taking mycophenolate sodium (MPS) and calcineurin inhibitors (GRINYÓ et al., 2009; SOMMERER et al., 2010). Among the benefits of therapeutic drug monitoring of MPA are the evaluation of interaction between MPA and proton pump inhibitors and association of donor-specific antibodies reduction.

Official Title
-----------------
A Prospective Study to Investigate Mycophenolic Acid (MPA) Exposure Through Area Under the Curve (AUC) in Renal Transplants Recipients Treated With Mycophenolate Mofetil (MMF) and After Conversion to Mycophenolate Sodium (EC-MPS)

Conditions
-----------------
Renal Transplantation

Intervention / Treatment
-----------------
* Drug: Mycophenolate sodium
* Drug: Mycophenolate mofetil


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years at the time of screening; Subjects above the sixth month post renal transplant; Subjects receiving mycophenolate mofetil; Women of childbearing potential (CBP) with a negative pregnancy test at screening (urine or serum); Women of CBP and men with sexual partners of CBP must agree to use a medically acceptable method of contraception throughout the study. Exclusion Criteria: Subjects who, in the opinion of the investigator, are not able to complete the study; Recipients of multiple organ transplant (i.e., prior or concurrent transplantation of a non-renal allograft; Use of any investigational drug or treatment up to 4 weeks before enrollment; Subjects with a calculated GFR < 30ml/min (abbreviated MDRD formula); Subjects with a screening total white blood cell count (WBC) ≤ 2000/mm3, hemoglobin ≤ 10g/dL and platelet count ≤ 100000/mm3; TGO/AST, TGP/ALT and bilirubin with values three times higher that reference values; History of malignancy within 3 years enrollment other than adequately treated basal cell or squamous cell carcinoma of the skin; Subjects who are known to be human immunodeficiency virus (HIV), hepatitis B or hepatitis C; Chronic hepatic failure; Planned treatment with immunosuppressive therapies other than those described in the protocol; Recipients who required desensitization protocols.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mycophenolate sodium<br>Arm1(Conversion):MPA AUC below 30mcg*h ml-1 - MPS+Calcineurin inhibitor+prednisone | Drug: Mycophenolate sodium<br>* The conversion will be performed abruptly for all patients. Mycophenolate mofetil will be discontinued one day before the day of conversion (Day 1). Mycophenolate sodium will be introduced on day 1 with equivalent doses.<br>|
| Active Comparator: Mycophenolate mofetil<br>Arm2(Maintained):MPA AUC between 30 to 60 mg*h ml-1 or above 60 mg - MMF+Calcineurin inhibitor+prednisone | Drug: Mycophenolate mofetil<br>* Mycophenolate mofetil dose will be maintained or adjusted to keep 30 to 60 mg*h ml-1.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the frequency of renal transplants recipients taking mycophenolate mofetil (MMF) with MPA AUC below target level (30mcg*h ml-1). | Evaluate the frequency of renal transplants recipients taking mycophenolate mofetil (MMF) with MPA AUC below target level (30mcg*h ml-1). | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the association of MPA AUC in renal transplant recipients with donor specific antibodies (DSA); | Evaluate the association of MPA AUC in renal transplant recipients with donor specific antibodies (DSA); | Baseline; month 6. | 
| Evaluate the interaction between MMF or EC-MPS and the proton pump inhibitor omeprazole through the AUC in patients with MPA below target level (30mcg*h ml-1). | Evaluate the interaction between MMF or EC-MPS and the proton pump inhibitor omeprazole through the AUC in patients with MPA below target level (30mcg*h ml-1). | 6 months | 
| Evaluate the association of MPA AUC with renal function estimated by MDRD formula. | Evaluate the association of MPA AUC with renal function estimated by MDRD formula. | Baseline; day one; months 2, 4 and 6. | 
| Evaluate the MPA_AUC in renal transplant patients converted to mycophenolate sodium (MPS) with equivalent dose of mycophenolate mofetil (MMF). | Evaluate the MPA_AUC in renal transplant patients who were taking mycophenolate mofetil (MMF) and were converted to the use of mycophenolate sodium (MPS) by having the MPA concentration below the target level of 30 mcg*h ml-1. | Baseline, five days after day one, fourteen days after day one, months 2,4 and 6 | 
| Evaluate the MPA_AUC in renal transplant patients maintained with mycophenolate mofetil (MMF). | Evaluate the AUC_MPA in renal transplant patients maintained with mycophenolate mofetil(MMF) by having the MPA concentration between 30-60 mcg*h ml-1 | baseline, months 2,4 and 6 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Renal transplantation, mycophenolic acid, mycophenolate mofetil, mycophenolate sodium, area under the curve