Navegando por Palavras-chave "mycophenolate mofetil"

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    Calcineurin Inhibitor Minimization in the Symphony Study: Observational Results 3 Years after Transplantation
    (Wiley-Blackwell, 2009-08-01) Ekberg, H.; Bernasconi, C.; Tedesco-Silva Junior, Hélio [UNIFESP]; Vitko, S.; Hugo, C.; Demirbas, A.; Reyes Acevedo, R.; Grinyo, J.; Frei, U.; Vanrenterghem, Y.; Daloze, P.; Halloran, P. F.; Lund Univ; F Hoffmann La Roche Ltd; Universidade Federal de São Paulo (UNIFESP); IKEM; FAU Erlangen Nurnberg; Akdeniz Univ; Hosp Miguel Hidalgo; Ciutat Univ Bellvitge; Charite Virchow Klinikum; Katholieke Univ Leuven; CHUM Montreal; Univ Alberta
    The Symphony study showed that at 1 year posttransplant, a regimen based on daclizumab induction, 2 g mycophenolate mofetil (MMF), low-dose tacrolimus and steroids resulted in better renal function and lower acute rejection and graft loss rates compared with three other regimens: two with low-doses of cyclosporine or sirolimus instead of tacrolimus and one with no induction and standard cyclosporine dosage. This is an observational follow-up for 2 additional years with the same endpoints as the core study. Overall, 958 patients participated in the follow-up. During the study, many patients changed their immunosuppressive regimen (e.g. switched from sirolimus to tacrolimus), but the vast majority (95%) remained on MMF. During the follow-up, renal function remained stable (mean change: -0.6 ml/min), and rates of death, graft loss and acute rejection were low (all about 1% per year). the MMF and low-dose tacrolimus arm continued to have the highest GFR (68.6 +/- 23.8 ml/min vs. 65.9 +/- 26.2 ml/min in the standard-dose cyclosporine, 64.0 +/- 23.1 ml/min in the low-dose cyclosporine and 65.3 +/- 26.2 ml/min in the low-dose sirolimus arm), but the difference with the other arms was not significant (p = 0.17 in an overall test and 0.077, 0.039 and 0.11, respectively, in pair-wise tests). the MMF and low-dose tacrolimus arm also had the highest graft survival rate, but with reduced differences between groups over time, and the least acute rejection rate. in the Symphony study, the largest ever prospective study in de novo kidney transplantation, over 3 years, daclizumab induction, MMF, steroids and low-dose tacrolimus proved highly efficacious, without the negative effects on renal function commonly reported for standard CNI regimens.
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    FTY720 versus mycophenolate mofetil in de novo renal transplantation: Six-month results of a double-blind study
    (Lippincott Williams & Wilkins, 2007-10-15) Tedesco-Silva, Helio; Szakaly, Peter; Shoker, Ahmed; Sommerer, Claudia; Yoshimura, Norio; Schena, Francesco Paolo; Cremer, Malika; Hmissi, Abdel; Mayer, Hartmut; Lang, Philippe; FTY720 2218 Clinical Study Grp; Universidade Federal de São Paulo (UNIFESP); Med Univ Pecs; Royal Univ Hosp; Univ Heidelberg; Kyoto Prefectural Univ Med; Univ Bari; Novartis Pharma AG; Univ Paris 07
    Background. FTY720 is a novel immunomodulator that was developed to produce optimal graft protection with improved safety and tolerability. Phase II studies have demonstrated the efficacy of FTY720 up to the doses of 2.5 mg with full-dose cyclosporine (FDC).Methods. This multicenter, double-blind, Phase IIb, randomized study evaluated the safety and efficacy of 5 mg FTY720 (n=87; Group 1) vs. 2.5 mg FTY720 (n=90; Group 2) vs. mycophenolate mofetil (MMF; n=94; Group 3) in de novo renal transplant patients receiving FDC and prednisone.Results. the primary efficacy endpoint was the occurrence of treated biopsy-proven acute rejection, graft loss, death, or premature study discontinuation (composite endpoint) within 6 months. the primary endpoint was superior in Group 1 (24%) and statistically noninferior in Group 2 compared to Group 3 (24.1% vs. 29.2% vs. 39.4%; P=0.025 and 0.0039, respectively). FTY720 plus FDC was generally well tolerated, with a similar incidence of adverse events across all groups. FTY720 was associated with higher incidence of bradycardia (Group 1: 26.4%, P=0.0002 and Group 2: 15.6%, P=0.046, vs. Group 3: 6.4%), respiratory disorders (Group 1: 40.2%, not significant [P=NS] and Group 2: 34.4%, P= NS vs. Group 3: 28.7%). One macular edema occurred in Group 2. Lower creatinine clearances were observed with FTY720 versus MMF (Group 1: 52.4 ml/min, P=NS and Group 2:51.7 ml/min, P=0.039 vs. Group 3:62.5 ml/min).Conclusions. Although FTY720 with FDC provided adequate protection from acute rejection the safety profile was less favorable for adverse events than current standard immunosuppression in de novo renal transplant patients.
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    How Delayed Graft Function Impacts Exposure to Mycophenolic Acid in Patients After Renal Transplantation
    (Lippincott Williams & Wilkins, 2011-04-01) van Gelder, Teun; Silva, Helio Tedesco [UNIFESP]; Fijter, Hans de; Budde, Klemens; Kuypers, Dirk; Mamelok, Richard D.; Armstrong, Victor W.; Oellerich, Michael; Erasmus MC; Universidade Federal de São Paulo (UNIFESP); Leiden Univ; Charite; Leuven Univ; Mamelok Consulting; Univ Gottingen
    Introduction: Mycophenolic acid (MPA) plasma concentrations are highly variable on standard-dose mycophenolate mofetil therapy. At creatinine clearances below 25 mL/min, MPA clearance increases as a result of a higher nonprotein-bound fraction. Patients with delayed graft function (DGF) after renal transplantation are exposed to low total MPA concentrations, when risk of rejection is highest. This study investigated the influence of DGF on MPA exposure and on clinical outcome.Methods: Adult renal transplantation patients treated with mycophenolate mofetil, corticosteroids, and either microemulsified cyclosporine (n = 459) or tacrolimus (n = 371) participated in a randomized controlled trial (the Fixed-Dose Concentration-Controlled [FDCC] Study). Abbreviated MPA areas under the curve (AUCs) were obtained on Day 3, Day 10, Week 4, and Month 3, to calculate MPA AUC((0-12)). Free MPA AUC values were available for a subgroup of patients (n = 269).Results: the overall incidence of DGF was 187 of 830 (23%) and did not differ between cyclosporine-treated (24%) and tacrolimus-(21%) treated patients. the incidence of biopsy-proven acute rejection at 12 months was significantly higher in patients with DGF (13.8% versus 21.4%). Patients with DGF had significantly lower dose-corrected MPA AUC on Day 3 and Day 10. Free MPA fraction and dose-corrected free MPA AUC were significantly higher in patients with DGF, from Day 3 until Month 3. the total number of patients with at least one opportunistic infection was significantly higher in patients with DGF (33.2%) compared with patients without DGF (25.8%) (P = 0.048). Patients with DGF developing opportunistic infections did not have higher total MPA AUC nor higher free MPA AUC compared with those without opportunistic infections.Conclusion: Patients with DGF have significantly lower dose-corrected MPA AUC in the first month after renal transplantation, presumably as a result of enhanced MPA clearance on account of the elevated MPA free fraction. Because patients with DGF have a higher rate of acute rejection and lower MPA exposure, higher dosing of mycophenolate mofetil in such patients may improve outcome. However, the already increased incidence of opportunistic infections in patients with DGF is a concern.
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    Mycophenolate mofetil substitution for cyclosporine A in renal transplant recipients with chronic progressive allograft dysfunction: the creeping creatinine study
    (Lippincott Williams & Wilkins, 2005-02-27) Dudley, C.; Pohanka, E.; Riad, H.; Dedochova, J.; Wijngaard, P.; Sutter, C.; Silva, H. T.; Mycophenolate Mofetil Creep; Southmead Gen Hosp; Univ Vienna; Manchester Royal Infirm; Internal Clin FNsP; F Hoffman La Roche Ltd; Universidade Federal de São Paulo (UNIFESP)
    Background. This study determined whether cyclosporine A (CsA)-treated renal allograft recipients with deteriorating renal function (creeping creatinine) secondary to chronic allograft nephropathy (CAN) benefit from the addition of mycophenolate mofetil (MMF) to their immunosuppressive regimen, followed by withdrawal of CsA.Methods. in a controlled, open, multicenter study, CsA-treated renal allograft recipients with progressively deteriorating renal function were randomized to have their CsA discontinued with the concomitant addition of MMF to their regimen (group A) or to continue treatment with CsA (group B). the primary endpoint was the response rate over the 6-month period after withdrawal of CsA in group A or the equivalent time in group B. Response was defined as a stabilization or reduction of serum creatinine (SCr), as evidenced by a flattening or positive slope of the 1/SCr plot and no graft loss. Secondary endpoints included the incidence of acute rejection, graft and patient survival, and changes in selected metabolic parameters.Results. the response rate in the primary intent-to-treat population (n = 122) was 58% (36/62) in group A versus 32% (19/60) in group B (P= 0.0060). the corresponding percentages of responders in the per-protocol population (n = 107) were 60% (36/60) and 26% (12/47), respectively (P=0.0008). There were no acute rejections in group A during the study period. Patients in this group also experienced a significant decrease in total cholesterol.Conclusions. in patients with progressively deteriorating renal function secondary to CAN, addition of MMF followed by withdrawal of CsA results in a significant improvement in transplant function without the risk of acute rejection.
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    Mycophenolate mofetil vs. sirolimus in kidney transplant recipients receiving tacrolimus-based immunosuppressive regimen
    (Blackwell Publishing, 2008-03-01) Sampaio, Edison L. [UNIFESP]; Pinheiro-Machado, Paula G. [UNIFESP]; Garcia, Riberto [UNIFESP]; Felipe, Claudia R. [UNIFESP]; Park, Sung I. [UNIFESP]; Casarini, Dulce E. [UNIFESP]; Moreira, Silvia [UNIFESP]; Franco, Marcello F. [UNIFESP]; Tedesco-Silva, Helio [UNIFESP]; Medina-Pestana, Jose O. [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Mycophenolate mofetil (MMF) and sirolimus (SRL) are effective immunosuppressive drugs with distinct safety profile.Methods: Kidney transplant recipients receiving tacrolimus (TAC)-based immunosuppressive regimen were randomized to receive fixed daily doses of MMF (2 g/d, n = 50) or SRL (one loading dose of 15 mg, 5 mg/d till day 7 and 2 mg/d thereafter, n = 50) without induction therapy.Results: No differences were observed in the incidence of the composite (biopsy-confirmed acute rejection, graft loss or death) end-point (18% vs. 16%, p = 1.000), biopsy confirmed acute rejection (12% vs. 14%, p = 1.000), one-yr patient (94% vs. 98%, p = 0.308), graft (92% vs. 98%, p = 0.168), and death-censored graft survival (98% vs. 100%, p = 0.317) comparing patients receiving MMF or SRL respectively. Patients receiving SRL showed worse safety outcomes, higher mean creatinine (1.6 +/- 0.5 mg/dL vs. 1.4 +/- 0.3 mg/dL, p = 0.007), higher proportion of patients with proteinuria (52.0% vs. 10.7%, p = 0.041), higher mean urinary protein concentrations (0.3 +/- 0.5 g/L vs. 0.1 +/- 0.2 g/L, p = 0.012), higher mean cholesterol concentration (217 mg/dL vs. 190 mg/dL, p = 0.030), and higher proportion of patients prematurely discontinued from randomized therapy (26% vs. 8%, p = 0.031).Conclusion: in patients receiving TAC, MMF produced similar efficacy but superior safety profile compared with SRL.
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    Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation
    (Lippincott Williams & Wilkins, 2006-12-27) Tedesco-Silva, Helio; Pescovitz, Mark D.; Cibrik, Diane; Rees, Michael A.; Mulgaonkar, Shamkant; Kahan, Barry D.; Gugliuzza, Kristene K.; Rajagopalan, P. R.; Esmeraldo, Ronaldo de M.; Lord, Helene; Salvadori, Maurizio; Slade, Jennifer M.; FTY720 Study Grp; Universidade Federal de São Paulo (UNIFESP); Indiana Univ; Univ Michigan; Univ Toledo; St Barnabas Hosp; Univ Texas; Med Univ S Carolina; Hosp Geral Fortaleza; Hop Maison Neuve Rosemont; Careggi Univ Hosp; Novartis Pharmaceut Corp
    Background. Phase 11 trials of FTY720, a novel immunomodulator, have shown promise in preventing rejection with both standard and reduced cyclosporine exposure. This study was designed to confirm those findings.Methods. This one-year, multicenter, randomized, phase III study in 696 de novo renal transplant patients compared FTY720 5 mg plus reduced-dose cyclosporine (RDC) or FTY720 2.5 mg plus full-dose cyclosporine (FDC) with mycophenolate mofetil (MMF) plus FDC. All patients received concomitant corticosteroid therapy without antibody induction. the primary efficacy composite endpoint was the incidence of first treated biopsy-proven acute rejection (treated BPAR), graft loss, death or premature study discontinuation at month 12.Results. FTY720 2.5 mg plus FDC was demonstrated to be non-inferior to MMF plus FDC as the primary efficacy endpoint (30.8% and 30.6%) was comparable. the FTY720 5 mg plus RDC treatment regimen was discontinued due to an increased incidence of acute rejection episodes (primary endpoint 43.3%). FTY720 was associated with significantly lower creatinine clearance with a mean difference at 12 months between FTY720 2.5 mg plus FDC and MMF plus FDC of 8 ml/min.Conclusions. While FTY720 2.5 mg plus FDC yielded similar efficacy to MMF plus FDC, the FTY720 5 mg plus RDC did not allow a 50% reduction in cyclosporine exposure. the associated lower creatinine clearance indicated that FTY720 combined with cyclosporine provided no benefit over standard care.
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    Randomized crossover study to assess the inter- and intrasubject variability of morning mycophenolic acid concentrations from enteric-coated mycophenolate sodium and mycophenolate mofetil in stable renal transplant recipients
    (Wiley-Blackwell, 2010-07-01) Tedesco-Silva, Helio [UNIFESP]; Felipe, Claudia R. [UNIFESP]; Park, Sung I. [UNIFESP]; Pinheiro-Machado, Paula G. [UNIFESP]; Garcia, Riberto [UNIFESP]; Slade, Alan; Schmouder, Robert; Medina-Pestana, Jose O. [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Novartis Pharmaceut
    The delayed release of mycophenolic acid (MPA) from enteric-coated mycophenolate sodium (EC-MPS, myfortic (R)) may have an impact on the variability of MPA trough (C(0 h)) levels. A randomized, two-period crossover study was performed in 24 maintenance renal transplants to evaluate the inter- and intrasubject variability of MPA predose levels from EC-MPS and mycophenolate mofetil (MMF, CellCept (R)), both in combination with cyclosporine. Patients received EC-MPS (720 mg b.i.d.) and MMF (1000 mg b.i.d.) for a period of 21 d each. MPA plasma levels were measured over the final seven consecutive days at -1, 0, 1, 2, and 3 h after the morning MPA dose. Intersubject coefficients of variation (%CV) for MPA troughs were 47.5% (95% CI, 34.1-80.3) and 54.4% (40.0-86.8) for EC-MPS and MMF, respectively; intrasubject %CVs were 62.7% (55.1-72.9) and 42.8% (37.9-49.2). High MPA C(0 h) levels > 10 mu g/mL were rarely observed with both EC-MPS (1.8%) and MMF (0.6%). Mean MPA area under the curve (AUC)(0-3 h) was comparable between treatments, while MPA C(0 h) was on average 46% higher with EC-MPS. in conclusion, predose MPA trough level monitoring appears of limited value during EC-MPS and MMF therapy given the large intrasubject variability in MPA C(0 h) levels with both treatments.
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    Tacrolimus pharmacokinetic drug interactions: effect of prednisone, mycophenolic acid or sirolimus
    (Wiley-Blackwell, 2009-02-01) Park, Sung-In [UNIFESP]; Felipe, Claudia R. [UNIFESP]; Pinheiro-Machado, Paula G. [UNIFESP]; Garcia, Riberto [UNIFESP]; Fernandes, Fernanda B. [UNIFESP]; Casarini, Dulce E. [UNIFESP]; Tedesco-Silva, Helio [UNIFESP]; Medina-Pestana, Jose O. [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    This study was conducted to evaluate time-dependent pharmacokinetic changes and drug interactions over the first 6 months after transplantation in kidney transplant recipients receiving tacrolimus (TAC), prednisone (PRED) and mycophenolate mofetil (MMF) or sirolimus (SRL). Pharmacokinetic assessments were carried out at day 7 and months 1, 3, and 6 in kidney transplant recipients receiving TAC plus PRED with either MMF (2 g/day, n = 13) or SRL (15 mg loading dose, 5 mg for 7 days followed by 2 mg/day, n = 12). There were no differences in the main demographic characteristics or in mean PRED doses during the first 6 months after transplant. From day 7 to month 6, there was a 65% increase in TAC dose corrected exposure (dose corrected area under the curve; AUC) in patients receiving MMF (P = 0.005) and a 59% increase in TAC dose corrected exposure in patients receiving SRL (P = 0.008). From day 7 to month 6, there was a 72% increase in mycophenolate dose corrected exposure (P = 0.001) and a 65% increase in SRL dose corrected exposure (P = 0.008). TAC dose corrected exposure was 23% lower in patients receiving SRL compared with MMF (P = 0.012) on average over the study period. PRED dose reduction was associated with increase in TAC (in patients receiving SRL, P = 0.040) and mycophenolic acid (MPA) (P = 0.070) drug exposures. Tercile distribution of TAC drug exposure showed a positive correlation with mean SRL exposures (P = 0.016). Conversely, tercile distribution of SRL drug exposure showed a positive correlation with mean TAC exposures (P = 0.004). Time-dependent increases in TAC, MPA and SRL drug exposures occur up to 6 months after transplantation. Drug-to-drug interactions indicate that intense therapeutic drug monitoring is required to avoid under-or over-immunosuppression.