Navegando por Palavras-chave "mycophenolic acid"

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    Chronopharmacokinetics of Mycophenolic Acid and Its Glucuronide and Acyl Glucuronide Metabolites in Kidney Transplant Recipients Converted From Cyclosporine to Everolimus
    (Lippincott Williams & Wilkins, 2012-12-01) Tedesco-Silva, Helio [UNIFESP]; Felipe, Claudia Rosso [UNIFESP]; Slade, Alan; Schmouder, Robert L.; Medina Pestana, Jose Osmar [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Novartis Inst Biomed Res; Novartis Pharmaceut
    Background: the influence of the conversion from cyclosporine (CsA) to everolimus (EVR) on the chronopharmacokinetics of mycophenolic acid (MPA) and its glucuronide (MPAG) and acyl glucuronide (acyl-MPAG) metabolites in patients receiving enteric-coated mycophenolate sodium (EC-MPS) has not been studied.Methods: We evaluated daytime and nighttime steady-state MPA, MPAG, and acyl-MPAG pharmacokinetics in 24 stable kidney transplant recipients while receiving cyclosporine and 28 days after conversion from CsA to EVR. the effect of concomitant treatment and the circadian difference on AUC(t,ss) and C-max,C-ss were assessed using a linear mixed model.Results: After conversion from CsA to EVR, MPA AUC(t,ss) was 43% higher (29% daytime and 58% during nighttime), whereas MPAG AUC(t,ss) was 33% lower (35% daytime and 30% during nighttime) and acyl-MPAG AUC(t,ss) was 31% lower (36% during daytime and 26% nighttime). Compared with daytime, MPA AUC(t,ss) was 25% lower (32% with CsA and 17% with EVR), MPAG AUC(t,ss) was 24% lower (26% with CsA and 21% with EVR), and acyl-MPAG AUCt, ss was 26% lower (32% with CsA and 21% with EVR) during nighttime. After conversion from CsA to EVR, MPAG: MPA and acyl-MPAG: MPA AUC(t,ss) ratios were 50% lower but were not different during daytime compared with nighttime EC-MPS administration. There was no correlation between CsA or EVR concentrations with MPA, MPAG, and acyl-MPAG exposures during daytime and nighttime. At least 1 adverse event was reported in 70.8% of patients receiving EC-MPS and CsA and in 91.7% receiving EC-MPS and EVR.Conclusion: in stable kidney transplant recipients receiving EC-MPS and steroids, exposures to MPA, MPAG, and acyl-MPAG were lower during nighttime compared with daytime, both with CsA or EVR. This circadian effect on MPA exposure did not correlate with CsA or EVR concentrations or with altered MPAG and acyl-MPAG formation.
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    Enteric-coated mycophenolate sodium provides higher mycophenolic acid predose levels compared with mycophenolate mofetil: Implications for therapeutic drug monitoring
    (Lippincott Williams & Wilkins, 2007-06-01) Budde, Klemens; Tedesco-Silva, Helio; Pestana, Jose Medina; Glander, Petra; Neumayer, Hans-H.; Felipe, Claudia Rosso; Machado, Paula Pinheiro; Sechaud, Romain; Schmouder, Robert; Charite Univ Med Berlin; Universidade Federal de São Paulo (UNIFESP); Novartis Pharma; Novartis Pharmaceut Corp
    The delayed release of mycophenolic acid (MPA) from enteric-coated mycopbenolate sodium (EC-MPS) may lead to different MPA predose (CO) levels compared with mycopbenolate mofetil (MMF). A post hoc analysis was performed on MPA morning predose values assessed in 88 maintenance renal transplant patients from three studies converted from MMF (1000 mg twice a day) to equimolar EC-MPS (720 mg twice a day) or vice versa, both in combination with cyclosporine. the median MPA predose level was approximately 30% higher when patients received EGMPS (2.40 mu g/mL; range, 0.49-39.30 mu g/mL) compared with MMF (1.83 mu g/mL; range, < 0.1-12.80 mu g/mL). Rare cases (3.0%) of high MPA CO levels 15 mu g/mL or greater were observed with EGMPS consistent with a very prolonged release of MPA from this formulation. Both EGMPS and MMF exhibited a poor correlation between MPA CO levels and exposure as assessed by MPA area under the curve. Physicians targeting a certain MPA predose level have to be aware of the higher morning CO levels with EGMPS, whereas the overall MPA exposure is not different to MMF.
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    Limited Sampling Strategies Drawn Within 3 Hours Postdose Poorly Predict Mycophenolic Acid Area-Under-the-Curve After Enteric-Coated Mycophenolate Sodium
    (Lippincott Williams & Wilkins, 2009-10-01) Winter, Brenda C. M. de; van Gelder, Teun; Mathot, Ron A. A.; Glander, Petra; Tedesco-Silva, Helio [UNIFESP]; Hilbrands, Luuk; Budde, Klemens; van Hest, Reinier M.; Erasmus Univ; Humboldt Univ; Universidade Federal de São Paulo (UNIFESP); Radboud Univ Nijmegen
    Previous studies predicted that limited sampling strategies (LSS) for estimation of mycophenolic acid (MPA) area-under-the-curve (AUC(0-12)) after ingestion of enteric-coated mycophenolate sodium (EC-MPS) using a clinically feasible sampling scheme may have poor predictive performance. Failure of LSS was thought to be due to the slow absorption of MPA causing late and variable times of maximum MPA concentration and variable predose concentrations. The aim of this study was to formally test the performance of LSS by developing and validating LSS for estimation of MPA AUC(0-12) after EC-MPS administration. Pharmacokinetic data from 109 renal transplant recipients collected during the maintenance period after transplantation were analysed retrospectively. LSS were developed separately for renal transplant patients who concurrently used cyclosporine (n = 79) and for patients not concurrently treated with cyclosporine (n = 30). Data were split into an index and a validation data set. For clinical feasibility reasons, a LSS could consist of a maximum of 3 sampling time points with the latest sample drawn 2 hours after drug administration. LSS with the latest sample drawn 3 hours after drug administration or even later were also tested. The validation of the developed LSS showed that MPA AUC(0-12) for patients concurrently treated with cyclosporine was best estimated by AUC(0-12) (mg.h.L(-1)) = 36.536 + 1.642 x C(0.5) + 0.569 x C(1.5) + 0.905 X C(2) (r(2) = 0.33, bias = -1.0 mg.h.L(-1), precision = 24 mg.h.L(-1)), whereas AUC(0-12) [mg.h.L(-1)] = 19.801 + 1.827 x C(0.5) + 1.111 x C(1) + 1.429 x C(2) was the best AUC(0-12) estimator for patients not cotreated with cyclosporine (r(2) = 0.31, bias = 0.4 mg.h.L(-1), precision = 14.5 mg.h.L(-1)). Both LSS showed poor precision and overestimation of AUC(0-12) values below the therapeutic window and underestimation of AUC(0-12) values above the therapeutic window of MPA. Using C(3) as latest sampling time point improved the fit slightly, but not satisfactory, with r(2) still <0.40 and precision still >14.0 mg.h.L(-1). Estimation of MPA AUC(0-12) with LSS for EC-MPS drawn within 2 or 3 hours postdose in renal transplant recipients in the maintenance period is likely to result in biased and imprecise results.
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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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    Safety profile comparing azathioprine and mycophenolate in kidney transplant recipients receiving tacrolimus and corticosteroids
    (Wiley-Blackwell, 2013-08-01) Cristelli, M. P. [UNIFESP]; Tedesco-Silva, H. [UNIFESP]; Medina-Pestana, J. O. [UNIFESP]; Franco, M. F. [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Background. Debate is increasing on whether mycophenolic acid (MPA) provides survival benefits comparable to azathioprine (AZA) after renal transplantation.Methods. This retrospective cohort study compared safety and efficacy of AZA (n = 662) vs. MPA (n = 267) in low- immunologicrisk kidney transplant recipients (KTR) receiving tacrolimus (TAC) and steroids between 1998 and 2007. Primary outcomes were treatment discontinuation and infection. Secondary endpoints included survival free from biopsy- proven acute rejection, graft loss, death, and renal function.Results. the 5- year survival free of treatment discontinuation was higher in the MPA compared to the AZA group (74.1% vs. 60.3%, P < 0.001). MPA was discontinued exclusively because of adverse events (16.4%), while AZA was discontinued primarily for lack of efficacy (21.2%). in univariable analysis, MPA was associated with higher incidence of total (561.5 vs. 667.5 episodes/1000 person- year, P < 0.001), bacterial (167 vs. 158 episodes/1000 person- years, P = 0.001), and viral infections (83.2 vs. 100.4 episodes/1000 personyears, P = 0.001), but this association was not confirmed in multivariable analysis. Over 29% of viral infections in the AZA group occurred after conversion to MPA. A high incidence of tuberculosis was observed (2.9 episodes/1000 person- years) with a higher incidence (but not a statistically significant difference) in the AZA group. No significant differences were found in patient survival (90% vs. 89%, P = 0.78) or graft survival (81% vs. 77.7%, P = 0.08), but infection accounted for > 50% of all deaths.Conclusion. the type of antimetabolite, AZA or MPA, was not independently associated with any safety or efficacy outcome 5 years after transplantation, suggesting that AZA is still a viable option for low- risk KTR receiving TAC and steroids.