Clinical trial NCT01822483: 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)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Renal Transplantation
Keywords: Renal transplantation
mycophenolic acid
mycophenolate mofetil
mycophenolate sodium
area under the curve
Lead sponsor: Irmandade Santa Casa de Misericórdia de Porto Alegre
Sponsor class: OTHER
Collaborators: name: Novartis
First posted: 2013-04-02
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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.

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.

Primary outcomes:
measure: Evaluate the frequency of renal transplants recipients taking mycophenolate mofetil (MMF) with MPA AUC below target level (30mcg*h ml-1).
timeFrame: Baseline
Secondary outcomes:
measure: Evaluate the association of MPA AUC in renal transplant recipients with donor specific antibodies (DSA);
timeFrame: Baseline; month 6.
measure: 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).
timeFrame: 6 months
measure: Evaluate the association of MPA AUC with renal function estimated by MDRD formula.
timeFrame: Baseline; day one; months 2, 4 and 6.
measure: Evaluate the MPA_AUC in renal transplant patients converted to mycophenolate sodium (MPS) with equivalent dose of mycophenolate mofetil (MMF).
timeFrame: Baseline, five days after day one, fourteen days after day one, months 2,4 and 6
measure: Evaluate the MPA_AUC in renal transplant patients maintained with mycophenolate mofetil (MMF).
timeFrame: baseline, months 2,4 and 6
Other outcomes:
Locations:
city: Porto Alegre
country: Brazil
facility: Irmandade Da Santa Casa de Misericórdia de Porto Alegre
state: Rio Grande do Sul
Study officials:
affiliation: IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
name: Valter Garcia, Physician
role: PRINCIPAL_INVESTIGATOR
affiliation: IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
name: Elizete Keitel, Physician
role: STUDY_CHAIR
affiliation: IRMANDADE DA SANTA CASA DE MISERICÓRIDA DE PORTO ALEGRE
name: Daniela Seelig, Physician
role: STUDY_CHAIR
affiliation: IRMANDADE DA SANTA CASA DE MISERICÓRIDA DE PORTO ALEGRE
name: Fabiano Klaus, Physician
role: STUDY_CHAIR
affiliation: IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
name: Ronivan Dal Pra, Pharmacist
role: STUDY_DIRECTOR
affiliation: IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
name: Larissa Pacheco, Pharmacist
role: STUDY_DIRECTOR
affiliation: IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
name: Bruna Cardoso, Pharmacist
role: STUDY_DIRECTOR
affiliation: IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
name: Roger Kist, Trainee
role: STUDY_DIRECTOR
affiliation: IRMANDADE DA SANTA CASA DE MISERICÓRDIA DE PORTO ALEGRE
name: Helen Zanetti, Pharmacist
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.