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 Transplantation1

Gelder, Teun van; Hilbrands, Luuk B.; Vanrenterghem, Yves; Weimar, Willem; Fijter, Johan W. de; Squifflet, Jean; Hené, Ronald J.; Verpooten, Gert A.; Navarro, Mercidita T.; Hale, Mike; Nicholls, Andrew

doi:10.1097/00007890-199907270-00018

Cited by 491 publications

(357 citation statements)

References 8 publications

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“…6 The MPA AUC estimates in patients with chronic GVHD 6 were also higher than in patients who received MMF early after HCT to prevent acute GVHD 30 but closely similar to MPA AUC estimates in patients who received MMF to prevent rejection after kidney transplantation. 29 Although trough levels of MPA correlate poorly with the MPA AUC, 30,35 total MPA trough concentrations of 1 to 4 g/mL have been provisionally considered within the therapeutic range in kidney transplantation recipients. 22,36,37 Total MPA trough concentrations among patients taking MMF at 1 g orally twice daily in the current study approximated this therapeutic range.…”

Section: Discussionmentioning

confidence: 99%

“…Testing was done at 3 months after enrollment because the MPA AUC increases during the first 3 months after beginning treatment with MMF. [27][28][29] Total MPA and free MPA (ie, not bound to protein) concentrations were measured in the laboratory of Dr Pamala Jacobson at the University of Minnesota, using methods described previously. 30 Free MPA has biologic activity, whereas protein-bound MPA does not.…”

Section: Plasma Trough Concentrations Of Mpamentioning

confidence: 99%

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Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease

Martin

Storer

Rowley

et al. 2009

Blood

143

118

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We conducted a double-blind, randomized multicenter trial to determine whether the addition of mycophenolate mofetil (MMF) improves the efficacy of initial systemic treatment of chronic graft-versushost disease (GVHD). The primary endpoint was resolution of chronic GVHD and withdrawal of all systemic treatment within 2 years, without secondary treatment. Enrollment of 230 patients was planned, providing 90% power to observe a 20% difference in success rates between the 2 arms. The study was closed after 4 years because the interim estimated cumulative incidence of success for the primary endpoint was 23% among 74 patients in the MMF arm and 18% among 77 patients in the control arm, indicating a low probability of positive results for the primary endpoint after completing the study as originally planned. Analysis of secondary endpoints showed no evidence of benefit from adding MMF to the systemic regimen first used for treatment of chronic GVHD. The estimated hazard ratio of death was 1.99 (95% confidence interval, 0.9-4.3) among patients in the MMF arm compared with the control arm. MMF should not be added to the initial systemic treatment regimen for chronic GVHD. This trial was registered at www.clinicaltrials.gov

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Section: Discussionmentioning

confidence: 99%

Section: Plasma Trough Concentrations Of Mpamentioning

confidence: 99%

Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease

Martin

Storer

Rowley

et al. 2009

Blood

143

118

View full text Add to dashboard Cite

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“…There are large interindividual and intraindividual variations in MPA pharmacokinetic parameters [64]. As with CsA, there is mounting evidence that systemic exposure to MPA, as measured by the AUC, is correlated to clinical events [78]. However, trough MPA levels seem poorly correlated to the 12-h AUC of MPA, so that therapeutic drug-monitoring strategies for MMF will also have to be refined in the near future [64].…”

Section: Maintenance Therapymentioning

confidence: 99%

Immunosuppressive therapy after human lung transplantation

Knoop¹,

Haverich²,

Fischer³

2003

Eur Respir J

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numbers of lung transplantation (LTx) were performed with or without induction therapy with antilymphocyte antibodies, monoclonal anti-CD3 antibody or anti-interleukin-2-receptor monoclonal antibodies. It remains to be established if induction therapy after LTx is beneficial or deleterious for long-term graft and patient survival.The vast majority of lung transplant recipients receive a triple-drug maintenance regimen including a calcineurin inhibitor, a cell-cycle inhibitor and steroids. Equal proportions receive cyclosporin A (CsA) and tacrolimus (Tac). There is also a trend to prescribe mycophenolate mofetil (MMF) instead of azathioprine (Aza). Steroid withdrawal is uncommon even 5 yrs after transplantation.The superiority of Tac over CsA as a maintenance agent has not been established to date, and the administration of MMF instead of Aza in combination with CsA and steroids did not improve graft or patient survival in a recent international, prospective, randomised, controlled trial.Shift from cyclosporin A to tacrolimus has emerged as the first treatment step of refractory acute rejection followed by high-dose steroids or antilymphocyte agents, total lymphoid irradiation or photopheresis. The treatment of chronic rejection remains deceptive and includes varied strategies such as modification of the maintenance regimen, addition of inhaled immunosuppressants and/or total lymphoid irradiation and photopheresis. Eur Respir J 2004; 23: 159-171.

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“…A randomized MMF concentration-controlled trial (RCCT) showed a significant correlation between prevention of graft rejection and MPA plasma trough levels and MPA-area under the concentration-time curve (AUC 0ª24 h ) (10). A prospective study in renal transplant patients has been designed to maintain MPA trough and AUC 0ª24 h concentrations within a target range (11).…”

Section: Barten Et Almentioning

confidence: 99%

Pharmacodynamics of Mycophenolate Mofetil after Heart Transplantation: New Mechanisms of Action and Correlations with Histologic Severity of Graft Rejection

Barten

Gelder

Gummert

et al. 2002

American Journal of Transplantation

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The primary mechanism of action in vivo of mycophenolate mofetil (MMF) is believed to be inhibition of lymphocyte proliferation. We used novel assays of lymphocyte functions (pharmacodynamics, PD) in whole blood collected from rat heart allograft recipients treated with MMF to investigate the mechanisms of action of the active metabolite of MMF, mycophenolate acid (MPA) in vivo. Allograft recipients were treated orally once daily with 3 different doses of MMF. Seven days after transplantation, blood was collected 24 h after the penultimate dose and several timepoints after the last dose, after which grafts were removed for microscopic grading of rejection. Lymphocytes in whole blood samples were mitogen stimulated through calcium-dependent and -independent signaling pathways. Inhibition of PD was measured by lymphocyte proliferation and expression of several surface antigens on T cells, and was calculated as area under the time-inhibition of immune function effect curve (AUE 0ª24 h ). We found that inhibition of lymphocyte proliferation and antigen expression by MPA correlated highly with MMF-dose, MPA level and with the histologic severities of graft rejection (p ∞0.05). In summary, MPA suppressed lymphocyte proliferation and expression of T-cell surface antigens in whole blood collected from MMF-treated allograft recipients, thus demonstrating the multiple mechanisms of suppression of rejection on peripheral blood T cells after MMF treatment.

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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 Transplantation1

Abstract: 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.

Cited by 491 publications

References 8 publications

Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease

Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease

Immunosuppressive therapy after human lung transplantation

Pharmacodynamics of Mycophenolate Mofetil after Heart Transplantation: New Mechanisms of Action and Correlations with Histologic Severity of Graft Rejection

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