Navegando por Palavras-chave "everolimus"

Agora exibindo 1 - 8 de 8
  • Nenhuma Miniatura disponível
    Item
    Somente Metadadados
    Adequacy of Initial Everolimus Dose, With and Without Calcineurin Inhibitors, in Kidney Transplant Recipients
    (Lippincott Williams & Wilkins, 2018) Felipe, Claudia [UNIFESP]; Ferreira, Alexandra [UNIFESP]; Bessa, Adrieli [UNIFESP]; Abait, Tamiris [UNIFESP]; Perez, Juliana D. [UNIFESP]; Casarini, Dulce Elena [UNIFESP]; Medina-Pestana, Jose [UNIFESP]; Tedesco, Helio [UNIFESP]
    Background: This study investigates the adequacy of initial everolimus (EVR) dose, with and without calcineurin inhibitors (CNI), in kidney transplant recipients. Methods: This retrospective cohort analysis involved data from 305 kidney transplant recipients participating in 3 randomized trials receiving reduced dose cyclosporin A (CsA) combined with EVR 0.75 mg BID (CSA/EVR0.75, N = 32) or 1.5 mg BID (CSA/EVR1.5, N = 31), reduced dose tacrolimus (TAC) combined with EVR 1.5 mg BID (TAC(0.05)/EVR1.5, N = 83), standard dose TAC combined with EVR 1.5 mg BID (TAC(0.1)/EVR1.5,N = 93), and EVR 1.5 mg BID (EVR1.5, N = 66) with TAC introduction after day 5. The adequacy of the initial EVR dose, based on EVR whole blood trough between 3 and 8 ng/mL, was compared using first EVR blood concentrations obtained at day 3 after transplantation. Results: Recipient age, proportion of patients with diabetes mellitus, and proportion of grafts from living donors were different among the groups. Dose-corrected EVR concentrations were higher in patients receiving CsA than in those receiving TAC or no calcineurin inhibitors (6.7 +/- 5.9 versus 5.4 +/- 2.2 versus 2.4 +/- 0.8 versus 2.5 +/- 0.9 versus 2.2 +/- 0.7, P = 0.000). No differences were observed comparing dose adjusted EVR concentrations combined with TAC or alone (P = 0.073). The proportion of patients with EVR concentration below <3 ng/mL was lower when EVR was combined with CsA (25 versus 3 versus 43 versus 33 versus 50%, P = 0.000). Later introduction of TAC did not influence EVR concentrations. There were no differences in mean CsA concentrations comparing patients receiving EVR 0.75 or 1.5 mg BID (240 +/- 143 versus 213 +/- 105 ng/mL). On the other hand, mean TAC concentrations were higher according to the initial TAC dose regimen (6.4 +/- 3.9 versus 9.8 +/- 5.9 ng/mL). Conclusions: In de novo kidney transplant recipients, the choice of the initial dose of EVR should consider the type of calcineurin inhibitor to reach target EVR concentration within the first week in a higher proportion of patients, maximizing the efficacy/toxicity profile.
  • Nenhuma Miniatura disponível
    Item
    Somente Metadadados
    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.
  • Nenhuma Miniatura disponível
    Item
    Somente Metadadados
    FTY720 and everolimus in de novo renal transplant patients at risk for delayed graft function: results of an exploratory one-yr multicenter study
    (Wiley-Blackwell, 2009-09-01) Tedesco-Silva, H. [UNIFESP]; Lorber, M. I.; Foster, C. E.; Sollinger, H. W.; Mendez, R.; Carvalho, D. B.; Shapiro, R.; Rajagopalan, P. R.; Mayer, H.; Slade, J.; Kahan, B. D.; FTY720A2202 Clinical Study Grp; Universidade Federal de São Paulo (UNIFESP); Yale Univ; UCI Med Ctr; Univ Wisconsin; Natl Inst Transplantat; Hosp Geral Bonsucesso; Univ Pittsburgh; Med Univ S Carolina; Novartis Pharma AG; Novartis Pharmaceut; Univ Texas Med Sch
    This exploratory, multicenter, open-label study evaluated the efficacy and safety of FTY720, as a part of an immunosuppressive regimen, in combination with everolimus and steroids in de novo renal transplant recipients at increased risk of delayed graft function (DGF). Patients received FTY720 (5 mg) and everolimus (4 mg) 2-12 h pre-transplantation, followed by 2.5 mg/d FTY720 and concentration-controlled everolimus (4-8 ng/mL) post-transplant for 12 months. Induction therapy was prohibited. After enrollment of 56 of the planned 200 patients between 2000 and 2002, the recruitment was terminated. the primary endpoint, rate of graft loss, or death at three months was 15.4% and the biopsy-confirmed acute rejection was 42.3%. Death or graft loss at 12 months in the DGF and non-DGF arms was 36.0% and 25.9%, respectively. the mean estimated creatinine clearance at three months was 63 and 55 mL/min in the non-DGF and DGF groups, respectively, while at 12 months it was 56 mL/min in both the groups. Although there was no comparator arm, the results from this exploratory study (compared with data from other phases II and III trials) indicated no apparent benefits of FTY720-based regimens for prevention of acute rejection and preservation of renal function in renal transplant recipients at high risk of DGF.
  • Nenhuma Miniatura disponível
    Item
    Somente Metadadados
    Long-Term Follow-Up of De Novo Use of mTOR and Calcineurin Inhibitors After Kidney Transplantation
    (Lippincott Williams & Wilkins, 2016) de Paula, Mayara Ivani [UNIFESP]; Medina-Pestana, Jose Osmar [UNIFESP]; Ferreira, Alexandra Nicolau [UNIFESP]; Cristelli, Marina Pontello [UNIFESP]; Franco, Marcello Fabiano [UNIFESP]; Aguiar, Wilson Ferreira [UNIFESP]; Tedesco-Silva, Helio [UNIFESP]; Felipe, Claudia Rosso [UNIFESP]
    Background:Long-term efficacy and safety of de novo use of the mammalian target of rapamycin inhibitors (mTORi) have been evaluated primarily using registry data.Methods:This was a pooled retrospective analysis of data obtained from 10 prospective randomized trials in de novo kidney transplant recipients (n = 581) receiving calcineurin inhibitors (CNIs) combined with sirolimus (n = 329), everolimus (n = 128), or antimetabolites (n = 124).Results:There were no differences in patient (84.5 versus 80.9 versus 89.7%, P = 0.996), graft (65.4 versus 59.5 versus 73.1%, P = 0.868), and biopsy-confirmed acute rejection-free (78.1 versus 77.3 versus 79.0%, P = 0.976) survivals, respectively. The incidence of cytomegalovirus infection was lower (6 versus 3 versus 11%, P = 0.024) but treatment discontinuation was higher among patients receiving mTORi (66.0 versus 47.7 versus 31.5%, P < 0.001), respectively. At 5 years, median estimated glomerular filtration rate (49.6 versus 43.9 versus 53.2 mL/min, P = 0.006) was lower and the proportion of patients with proteinuria (53 versus 40 versus 23%, P < 0.001) was higher among patients receiving mTORi, respectively.Conclusions:The efficacy of de novo use of mTORi is comparable with that of antimetabolites in kidney transplant recipients receiving calcineurin inhibitor. Apart from the lower cytomegalovirus infection rate, the safety profile is unfavorable, showing higher treatment discontinuation rates and higher incidence of proteinuria.
  • Nenhuma Miniatura disponível
    Item
    Somente Metadadados
    Long-Term Follow-Up of De Novo Use of mTOR and Calcineurin Inhibitors After Kidney Transplantation
    (Lippincott Williams & Wilkins, 2016) de Paula, Mayara Ivani [UNIFESP]; Medina-Pestana, Jose Osmar [UNIFESP]; Ferreira, Alexandra Nicolau [UNIFESP]; Cristelli, Marina Pontello [UNIFESP]; Franco, Marcello Fabiano [UNIFESP]; Aguiar, Wilson Ferreira [UNIFESP]; Tedesco-Silva, Helio [UNIFESP]; Felipe, Claudia Rosso [UNIFESP]
    Background:Long-term efficacy and safety of de novo use of the mammalian target of rapamycin inhibitors (mTORi) have been evaluated primarily using registry data.Methods:This was a pooled retrospective analysis of data obtained from 10 prospective randomized trials in de novo kidney transplant recipients (n = 581) receiving calcineurin inhibitors (CNIs) combined with sirolimus (n = 329), everolimus (n = 128), or antimetabolites (n = 124).Results:There were no differences in patient (84.5 versus 80.9 versus 89.7%, P = 0.996), graft (65.4 versus 59.5 versus 73.1%, P = 0.868), and biopsy-confirmed acute rejection-free (78.1 versus 77.3 versus 79.0%, P = 0.976) survivals, respectively. The incidence of cytomegalovirus infection was lower (6 versus 3 versus 11%, P = 0.024) but treatment discontinuation was higher among patients receiving mTORi (66.0 versus 47.7 versus 31.5%, P < 0.001), respectively. At 5 years, median estimated glomerular filtration rate (49.6 versus 43.9 versus 53.2 mL/min, P = 0.006) was lower and the proportion of patients with proteinuria (53 versus 40 versus 23%, P < 0.001) was higher among patients receiving mTORi, respectively.Conclusions:The efficacy of de novo use of mTORi is comparable with that of antimetabolites in kidney transplant recipients receiving calcineurin inhibitor. Apart from the lower cytomegalovirus infection rate, the safety profile is unfavorable, showing higher treatment discontinuation rates and higher incidence of proteinuria.
  • Nenhuma Miniatura disponível
    Item
    Somente Metadadados
    Pharmacokinetics and Long-TermSafety and Tolerability of Everolimus in Renal Transplant Recipients Converted From Cyclosporine
    (Lippincott Williams & Wilkins, 2016) Felipe, Claudia R. [UNIFESP]; Oliveira, Nagilla I. [UNIFESP]; Hannun, Pedro G. [UNIFESP]; de Paula, Mayara Ivani [UNIFESP]; Tedesco-Silva, Helio [UNIFESP]; Medina-Pestana, Jose O. [UNIFESP]
    Background:Conversion from cyclosporine (CsA) to everolimus (EVR) in kidney transplant recipients receiving mycophenolate sodium (MPS) and corticosteroids has been used to reduce CsA associated toxicities. Nevertheless, exposures produced by the initial EVR dose, the steady state pharmacokinetic and long-term safety and tolerability have not been explored in detail.Methods:Twenty-four stable kidney transplant recipients receiving CSA, MPS, and corticosteroids were converted from CSA to EVR. The initial EVR dose was 3 mg BID. Weekly monitoring of EVR blood concentrations was followed by a full 12 hour pharmacokinetic profile 28 days after conversion. Therapeutic drug monitoring, safety, and tolerability were analyzed during 5 years of follow-up.Results:The study population was relatively young (mean of 42 years) with a predominance of males (62%) and White (67%) recipients of kidneys from living (54%) or deceased (46%) donors. Mean time of the conversion was 61 months after transplantation. In the first 7 patients, the initial EVR dose of 3 mg BID resulted in mean EVR trough blood concentration of 14.7 3.7 ng/mL at day 7. The initial EVR dose was then reduced to 2 mg BID for the following 17 patients. Four weeks after conversion, mean EVR dose was 1.7 +/- 0.5 mg BID (7 patients were receiving 1 mg BID and 17 were receiving 2 mg BID) resulting in mean EVR trough blood concentration of 4.0 +/- 1.4 ng/mL. Whereas mean maximum concentration (13.4 +/- 2.8 versus 22.9 +/- 7.4 ng/mL, P = 0.003) and mean apparent clearance (232 +/- 79 versus 366 +/- 173 mL/min, P = 0.016) were higher, mean area under the curve (78.2 +/- 22.1 versus 102.5 +/- 38.5 ng.h/mL, P = 0.067) and mean C-0 (3.7 +/- 1.3 versus 4.1 +/- 1.5 ng/mL, P = 0.852) were no different comparing patients receiving 1 mg and 2 mg EVR BID. Mean inter-subject variability of area under the curve, trough concentration, and maximum concentration was 38%, 36%, and 38%. EVR treatment was discontinued in 29% of patients due to proteinuria (N = 2), pneumonia (N = 2), dyslipidemia (N = 2), and anemia (N = 1) and MPS dose was reduced in 58% of patients.Conclusions:The initial 3 mg BID dose produced high EVR trough blood concentrations. The 2 mg BID dose appears to be the appropriate initial dose to provide therapeutic concentrations but still requires initial intensive therapeutic monitoring to achieve and maintain blood concentrations within the therapeutic target concentration. The combination of EVR and full dose MPS has limited long-term tolerability and safety.
  • Nenhuma Miniatura disponível
    Item
    Somente Metadadados
    Pharmacokinetics and Long-TermSafety and Tolerability of Everolimus in Renal Transplant Recipients Converted From Cyclosporine
    (Lippincott Williams & Wilkins, 2016) Felipe, Claudia R. [UNIFESP]; Oliveira, Nagilla I. [UNIFESP]; Hannun, Pedro G. [UNIFESP]; de Paula, Mayara Ivani [UNIFESP]; Tedesco-Silva, Helio [UNIFESP]; Medina-Pestana, Jose O. [UNIFESP]
    Background:Conversion from cyclosporine (CsA) to everolimus (EVR) in kidney transplant recipients receiving mycophenolate sodium (MPS) and corticosteroids has been used to reduce CsA associated toxicities. Nevertheless, exposures produced by the initial EVR dose, the steady state pharmacokinetic and long-term safety and tolerability have not been explored in detail.Methods:Twenty-four stable kidney transplant recipients receiving CSA, MPS, and corticosteroids were converted from CSA to EVR. The initial EVR dose was 3 mg BID. Weekly monitoring of EVR blood concentrations was followed by a full 12 hour pharmacokinetic profile 28 days after conversion. Therapeutic drug monitoring, safety, and tolerability were analyzed during 5 years of follow-up.Results:The study population was relatively young (mean of 42 years) with a predominance of males (62%) and White (67%) recipients of kidneys from living (54%) or deceased (46%) donors. Mean time of the conversion was 61 months after transplantation. In the first 7 patients, the initial EVR dose of 3 mg BID resulted in mean EVR trough blood concentration of 14.7 3.7 ng/mL at day 7. The initial EVR dose was then reduced to 2 mg BID for the following 17 patients. Four weeks after conversion, mean EVR dose was 1.7 +/- 0.5 mg BID (7 patients were receiving 1 mg BID and 17 were receiving 2 mg BID) resulting in mean EVR trough blood concentration of 4.0 +/- 1.4 ng/mL. Whereas mean maximum concentration (13.4 +/- 2.8 versus 22.9 +/- 7.4 ng/mL, P = 0.003) and mean apparent clearance (232 +/- 79 versus 366 +/- 173 mL/min, P = 0.016) were higher, mean area under the curve (78.2 +/- 22.1 versus 102.5 +/- 38.5 ng.h/mL, P = 0.067) and mean C-0 (3.7 +/- 1.3 versus 4.1 +/- 1.5 ng/mL, P = 0.852) were no different comparing patients receiving 1 mg and 2 mg EVR BID. Mean inter-subject variability of area under the curve, trough concentration, and maximum concentration was 38%, 36%, and 38%. EVR treatment was discontinued in 29% of patients due to proteinuria (N = 2), pneumonia (N = 2), dyslipidemia (N = 2), and anemia (N = 1) and MPS dose was reduced in 58% of patients.Conclusions:The initial 3 mg BID dose produced high EVR trough blood concentrations. The 2 mg BID dose appears to be the appropriate initial dose to provide therapeutic concentrations but still requires initial intensive therapeutic monitoring to achieve and maintain blood concentrations within the therapeutic target concentration. The combination of EVR and full dose MPS has limited long-term tolerability and safety.
  • Nenhuma Miniatura disponível
    Item
    Somente Metadadados
    Sotrastaurin in Calcineurin Inhibitor-Free Regimen Using Everolimus in de Novo Kidney Transplant Recipients
    (Wiley-Blackwell, 2013-07-01) Tedesco-Silva Junior, Hélio [UNIFESP]; Kho, M. M. L.; Hartmann, A.; Vitko, S.; Russ, G.; Rostaing, L.; Budde, K.; Campistol, J. M.; Eris, J.; Krishnan, I.; Gopalakrishnan, U.; Klupp, J.; Universidade Federal de São Paulo (UNIFESP); Erasmus Univ; Univ Oslo; Inst Clin & Expt Med; Royal Adelaide Hosp; CHU Rangueil; Charite; Univ Barcelona; Royal Prince Alfred Hosp; Novartis Pharma AG; Novartis Healthcare Pvt Ltd
    Sotrastaurin, a novel selective protein-kinase-C inhibitor, inhibits early T cell activation via a calcineurin-independent pathway. Efficacy and safety of sotrastaurin in a calcineurin inhibitorfree regimen were evaluated in this two-stage Phase II study of de novo kidney transplant recipients. Stage 1 randomized 131 patients (2:1) to sotrastaurin 300mg or cyclosporine A (CsA). Stage 2 randomized 180 patients (1:1:1) to sotrastaurin 300 or 200mg or CsA. All patients received basiliximab, everolimus (EVR) and prednisone. Primary endpoint was composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, death or lost to follow-up. Main safety assessment was estimated glomerular filtration rate (eGFR) by MDRD-4 at Month 12. Composite efficacy failure rates at 12 months were higher in sotrastaurin arms (Stage 1: 16.5% and 10.9% for sotrastaurin 300mg and CsA; Stage 2: 27.2%, 34.5% and 19.4% for sotrastaurin 200mg, 300mg and CsA). eGFR was significantly better in sotrastaurin groups versus CsA at most time points, except at 12 months. Gastrointestinal and cardiac adverse events were more frequent with sotrastaurin. Higher treatment discontinuation, deaths and graft losses occurred with sotrastaurin 300mg. Sotrastaurin combined with EVR showed higher efficacy failure rates and some improvement in renal allograft function compared to a CsA-based therapy.