Association of mycophenolic acid dose with efficacy and safety events in kidney transplant patients receiving tacrolimus: an analysis of the Mycophenolic acid Observational REnal transplant registry

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Abstract

Background Dose-finding studies for mycophenolic acid (MPA) in tacrolimus-treated kidney transplant patients are lacking.

Methods Data from 901 de novo kidney transplant recipients enrolled in the prospective, non-interventional Mycophenolic acid Observational REnal (MORE) transplant registry were analyzed according to baseline daily MPA dose (<2000, 2000 or >2000 mg).

Results The proportion of patients receiving 2000 and <2000 mg was 77.6% and 19.9% at baseline, 74.5% and 23.3% at month 1, 62.4% and 35.5% at month 3, 48.5% and 50.2% at month 6, and 44.1% and 55.2% at month 12. More patients were maintained on 2000 mg with enteric-coated mycophenolate sodium (EC-MPS) vs. mycophenolate mofetil (month 6, 52.7% vs. 43.0% [p = 0.02]; month 12, 47.3% vs. 39.4% [p = 0.08]). Multivariate modeling showed no significant effect of baseline MPA dose on 12-month risk of biopsy-proven acute rejection, graft loss or estimated GFR, or on safety events including MPA discontinuation other than a higher rate of gastrointestinal adverse events in patients with an initial MPA dose >2000 mg (p = 0.029) vs. 2000 mg.

Conclusions These findings suggest that an initial MPA dose of <2000 mg does not compromise 12-month efficacy in tacrolimus-treated kidney transplants, but controlled trials are required and the lower threshold for MPA dose remains to be defined.

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Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus.

F Vincenti, S Friman, E Scheuermann … (2007)

DIRECT (Diabetes Incidence after Renal Transplantation: Neoral C(2) Monitoring Versus Tacrolimus) was a 6-month, open-label, randomized, multicenter study which used American Diabetes Association/World Health Organization criteria to define glucose abnormalities. De novo renal transplant patients were randomized to cyclosporine microemulsion (CsA-ME, using C(2) monitoring) or tacrolimus, with mycophenolic acid, steroids and basiliximab. The intent-to-treat population comprised 682 patients (336 CsA-ME, 346 tacrolimus): 567 were nondiabetic at baseline. Demographics, diabetes risk factors and steroid doses were similar between treatment groups. The primary safety endpoint, new-onset diabetes after transplant (NODAT) or impaired fasting glucose (IFG) at 6 months, occurred in 73 CsA-ME patients (26.0%) and 96 tacrolimus patients (33.6%, p = 0.046). The primary efficacy endpoint, biopsy-proven acute rejection, graft loss or death at 6 months, occurred in 43 CsA-ME patients (12.8%) and 34 tacrolimus patients (9.8%, p = 0.211). Mean glomerular filtration rate (Cockcroft-Gault) was 63.6 +/- 20.7 mL/min/1.73 m(2) in the CsA-ME cohort and 65.9 +/- 23.1 mL/min/1.73 m(2) with tacrolimus (p = 0.285); mean serum creatinine was 139 +/- 58 and 133 +/- 57 mumol/L, respectively (p = 0.005). Blood pressure was similar between treatment groups at month 6, but total cholesterol, LDL-cholesterol and triglyceride levels were significantly higher with CsA than with tacrolimus (total cholesterol:HDL remained unchanged). The profile and incidence of adverse events were similar between treatments. The incidence of NODAT or IFG at 6 months post-transplant is significantly lower with CsA-ME than with tacrolimus without a significant difference in short-term outcome.

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Regression models and life‐tables (with discussions)

Cox D.R., DR Cox, R. Cox D. … (1972)

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A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation.

T van Gelder, L B Hilbrands, Y Vanrenterghem … (1999)

Adding a fixed dose of 1 g b.i.d. of mycophenolate mofetil (MMF) to an immunosuppressive regimen consisting of cyclosporine and prednisone results in a 50% reduction in the incidence of acute rejection after kidney transplantation. This study was designed to investigate the relationship between pharmacokinetic data (mycophenolic acid area under the curve; MPA AUC) and the prevention of rejection after kidney transplantation. A total of 154 adult recipients of a primary or secondary cadaveric kidney graft were randomly allocated, in this double-blind trial, to receive MMF treatment aimed at three predefined target MPA AUC values (16.1, 32.2, and 60.6 microg x hr/ml). During the first 6 months after transplantation, plasma samples for nine AUCs were collected. After analysis of the samples, a coded dose adjustment advice was generated using a Bayesian algorithm, maintaining the double blinding. Immunosuppressive therapy further consisted of cyclosporine and prednisone. The primary end point of this study was the occurrence of biopsy-proven acute rejection within the 6-month study period. A total of 150 patients were eligible for analysis. Although after day 21, the mean MMF dose was reduced, the mean MPA AUC gradually increased and target MPA AUC values were exceeded in all three groups. The incidences of biopsy-proven acute rejection in the low, intermediate, and high target MPA AUC groups were 14 of 51 (27.5%), 7 of 47 (14.9%), and 6 of 52 (11.5%), respectively. The incidences of premature withdrawal from the study due to adverse events in the three groups were 4 of 51 (7.8%), 11 of 47 (23.4%), and 23 of 52 (44.2%), respectively. Logistic regression analysis showed a highly statistically significant relationship between median ln(MPA AUC) and the occurrence of a biopsy-proven rejection (P<0.001). The logistic regression using median ln(Cpredose) was also statistically significant for this relationship (P=0.01), whereas it was not when using mean MMF dose (P=0.082). In contrast, the logistic regression using mean MMF dose for comparison of patients who successfully completed the study versus patients experiencing premature withdrawal due to adverse events was highly significant (P<0.001), whereas this was not significant when using median ln(Cpredose) (P=0.512) or median ln(MPA AUC) (P=0.434). MPA Cpredose and MPA AUC are significantly related to the incidence of biopsy-proven rejection after kidney transplantation, whereas MMF dose is significantly related to the occurrence of adverse events.

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Author and article information

Journal

Journal ID (nlm-ta): Clin Transplant

Journal ID (iso-abbrev): Clin Transplant

Journal ID (publisher-id): ctr

Title: Clinical Transplantation

Publisher: John Wiley & Sons, Ltd (Chichester, UK )

ISSN (Print): 0902-0063

ISSN (Electronic): 1399-0012

Publication date (Print): November 2012

Publication date (Electronic): 02 November 2012

Volume: 26

Issue: 6

Pages: E602-E611

Affiliations

[a ]Department of Transplant Surgery, Thomas Jefferson University Hospital Philadelphia, PA, USA

[b ]Department of Surgery, Montefiore Medical Center New York, NY, USA

[c ]Department of Medicine, Scott and White Memorial Hospital Temple, TX, USA

[d ]The Barry S. Levin, M.D. Department of Transplantation, California Pacific Medical Center San Francisco, CA, USA

[e ]Novartis Pharmaceuticals Corporation East Hanover, NJ, USA

[f ]Department of Urology, Charleston Area Medical Center Charleston, WV, USA

[g ]Department of Medicine, University of Colorado Medical Center Denver, CO, USA

Author notes

Corresponding author: Cataldo Doria, MD, PhD, Department of Transplant Surgery, Thomas Jefferson University Hospital, 1100 Walnut Street, Philadelphia, PA 19107-5563, USA. Tel.: 1 215 503 6308; fax: 1 215 503 1420; e-mail: cataldo.doria@ 123456jefferson.edu

Article

DOI: 10.1111/ctr.12035

PMC ID: 3556697

PubMed ID: 23121178

SO-VID: 76227280-97da-48d1-ac71-bdab1987534f

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Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

Association of mycophenolic acid dose with efficacy and safety events in kidney transplant patients receiving tacrolimus: an analysis of the Mycophenolic acid Observational REnal transplant registry

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Most cited references 32

Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus.

Regression models and life‐tables (with discussions)

A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation.

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