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) (AUC-MPA)

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.

Study Overview

• Status: Completed
• Conditions: Renal Transplantation
• Intervention / Treatment: Drug: Mycophenolate sodium; Drug: Mycophenolate mofetil

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.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • Rio Grande do Sul
    • Porto Alegre, Rio Grande do Sul, Brazil, 90020090
      • Irmandade da Santa Casa de Misericórdia de Porto Alegre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SUPPORTIVE_CARE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Mycophenolate sodium; Arm1(Conversion):MPA AUC below 30mcg*h ml-1 - MPS+Calcineurin inhibitor+prednisone	Drug: Mycophenolate sodium; 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.
ACTIVE_COMPARATOR: Mycophenolate mofetil; Arm2(Maintained):MPA AUC between 30 to 60 mg*h ml-1 or above 60 mg - MMF+Calcineurin inhibitor+prednisone	Drug: Mycophenolate mofetil; Mycophenolate mofetil dose will be maintained or adjusted to keep 30 to 60 mg*h ml-1.

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

Collaborators and Investigators

• Sponsor: Irmandade Santa Casa de Misericórdia de Porto Alegre
• Collaborators: Novartis
• Investigators: Study Chair: Daniela Seelig, Physician, IRMANDADE DA SANTA CASA DE MISERICÓRIDA DE PORTO ALEGRE; Study Chair: Fabiano Klaus, Physician, IRMANDADE DA SANTA CASA DE MISERICÓRIDA DE PORTO ALEGRE; Study Director: Ronivan Dal Pra, Pharmacist, Irmandade da Santa Casa de Misericórdia de Porto Alegre; Study Director: Larissa Pacheco, Pharmacist, Irmandade da Santa Casa de Misericórdia de Porto Alegre; Study Director: Bruna Cardoso, Pharmacist, Irmandade da Santa Casa de Misericórdia de Porto Alegre; Study Director: Roger Kist, Trainee, Irmandade da Santa Casa de Misericórdia de Porto Alegre; Study Director: Helen Zanetti, Pharmacist, Irmandade da Santa Casa de Misericórdia de Porto Alegre

Publications and helpful links

General Publications

• Tett SE, Saint-Marcoux F, Staatz CE, Brunet M, Vinks AA, Miura M, Marquet P, Kuypers DR, van Gelder T, Cattaneo D. Mycophenolate, clinical pharmacokinetics, formulations, and methods for assessing drug exposure. Transplant Rev (Orlando). 2011 Apr;25(2):47-57. doi: 10.1016/j.trre.2010.06.001. Epub 2010 Dec 28.
• Grinyo JM, Ekberg H, Mamelok RD, Oppenheimer F, Sanchez-Plumed J, Gentil MA, Hernandez D, Kuypers DR, Brunet M. The pharmacokinetics of mycophenolate mofetil in renal transplant recipients receiving standard-dose or low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus: the Symphony pharmacokinetic substudy. Nephrol Dial Transplant. 2009 Jul;24(7):2269-76. doi: 10.1093/ndt/gfp162. Epub 2009 Apr 8.
• Sommerer C, Muller-Krebs S, Schaier M, Glander P, Budde K, Schwenger V, Mikus G, Zeier M. Pharmacokinetic and pharmacodynamic analysis of enteric-coated mycophenolate sodium: limited sampling strategies and clinical outcome in renal transplant patients. Br J Clin Pharmacol. 2010 Apr;69(4):346-57. doi: 10.1111/j.1365-2125.2009.03612.x.

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (ACTUAL): March 1, 2015
• Study Completion (ACTUAL): March 1, 2015

Study Registration Dates

• First Submitted: March 21, 2013
• First Submitted That Met QC Criteria: March 27, 2013
• First Posted (ESTIMATE): April 2, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): April 3, 2015
• Last Update Submitted That Met QC Criteria: April 1, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: mycophenolate mofetil; mycophenolic acid; Renal transplantation; mycophenolate sodium; area under the curve
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Mycophenolic Acid
• Other Study ID Numbers: CERL080; CERL080ABR08T (OTHER: NOVARTIS)