Navegando por Palavras-chave "tacrolimus"

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    Análise prospectiva do perfil de segurança do estudo de conversão planejada do regime imunossupressor com base no sirolimo introduzido 3 meses após transplante renal, em comparação com um regime contínuo com base no tacrolimo em pacientes com novo transpl
    (Universidade Federal de São Paulo (UNIFESP), 2016-06-30) Felix, Maria Julia Pereira [UNIFESP]; Silva Junior, Helio Tedesco Silva Junior [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    The safety and tolerability of immunosuppressive regimens derive from complex interactions of factors including known drug-related off-target adverse events, drug doses/concentrations and combinations, demography and time after transplantation. This study investigated regimen-associated and time-dependent incidences of adverse events (AE) and serious adverse events (SAE) in kidney transplant recipients (KTR). This was a prospective study enrolling 119 low immunological risk KTR who received tacrolimus (TAC), mycophenolate sodium (MPS) and prednisone and were randomized at 3 months to be converted (n=60) or not (n=59) from TAC to SRL and followed till month 24. Before conversion, the cumulative incidence of AE was 98%, being 25% SAE. Gastrointestinal (66%) and Infection (58%) were the most frequent disorders. The incidences of TAC or MPS dose reductions due to AE were 1.7% and 12%, respectively. After conversion, the cumulative incidence of AE and SAE were 100% and 27% in the SRL group and 98% and 30% in the TAC group, respectively. The most common disorders were gastrointestinal (70% vs. 54% p=0.23) and infection (77% vs. 73%, p=0.79) in SRL and TAC, respectively. The incidence of aphthous ulcer (28 vs. 0%, p=0.00), sinusitis (10 vs. 0%, p=0.01), dermatitis (15 vs. 3%, p=0.03) and dyslipidemia (35 vs. 14%, p=0.02) were higher in SRL compared to TAC. COX regression analysis showed higher relative risk for Gastrointestinal (HR: 1.9, 1.2?3.01 95 %CI, p=0.05) and Skin and Subcutaneous tissue (HR: 2.5, 1.1?4.1 95 %CI, p=0.02) in SRL compared to TAC. AE-related dose reduction occurred in 18% with SRL and in 3% with TAC while MPS dose reduction occurred in 12% of patients receiving SRL and in 10% in TAC. The incidence, type and severity of AE are associated with time after transplantation and the immunosuppression. Nevertheless, careful drug dose adjustments were associated with low rates of early treatment discontinuation.
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    Association of the PPP3CA c.249G>A variant with clinical outcomes of tacrolimus-based therapy in kidney transplant recipients
    (Dove Medical Press Ltd, 2017) Salgado, Patricia C.; Genvigir, Fabiana D. V.; Felipe, Claudia Rosso [UNIFESP]; Tedesco-Silva Junior, Hélio [UNIFESP]; Pestana, Jose Osmar Medina [UNIFESP]; Doi, Sonia Q.; Hirata, Mario H.; Hirata, Rosario D. C.
    Background: The effects of genetic variants related to the pharmacodynamic mechanisms of immunosuppressive drugs on their therapeutic efficacy and safety have been poorly explored. This study was performed to investigate the influence of the PPP3CA c.249G>A variant on the clinical outcomes of kidney transplant recipients. Patients and methods: A total of 148 Brazilian patients received tacrolimus (TAC)-based immunosuppressive therapy for 90 days post-kidney transplantation. The PPP3CA rs3730251 (c.249G>A) polymorphism was determined by real-time polymerase chain reaction. Single nucleotide polymorphism (SNP) data for CYP3A5 rs776746 (CYP3A5*3C
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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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    Circadian and time-dependent variability in tacrolimus pharmacokinetics
    (Blackwell Publishing, 2007-04-01) Park, Sung-In; Felipe, Claudia R.; Pinheiro-Machado, Paula G.; Garcia, Riberto; Tedesco-Silva, Helio; Medina-Pestana, Jose O.; Universidade Federal de São Paulo (UNIFESP)
    Tacrolimus (TAC) is considered a critical dose drug. the purpose of our study was to investigate circadian and time-dependent changes in TAC pharmacokinetics over the first year after kidney transplantation. Pharmacokinetic (PK) studies were performed in 26 recipients of first living donor kidney transplants at day 7 after morning (a.m.) and evening (p.m.) doses of TAC. Additional serial PK studies were carried out in nine patients at month 6 (M6) and month 12 (M12). Blood samples were collected before 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 h after TAC administration. Demographics, TAC and adjunctive immunosuppressive doses, hematology, and biochemistry were recorded in each PK study. Mean age was 37 years, body mass index 23 kg/m(2), 58% males, and 85% Caucasian. Higher AUC (231.4 vs. 220 ng.h/mL, P = 0.06) and C-max (34.1 +/- 12.6 vs. 24.4 +/- 9.8 ng/mL, P < 0.001), and lower T-max (1.6 +/- 0.8 vs. 2.7 +/- 2.0 h, P = 0.05) values were observed comparing a.m. and p.m. administrations. Comparing D7, M6 and M12, there was a significant increase in dose-normalized AUC (31.4 +/- 22.2 vs. 50.1 +/- 33 vs. 39.2 +/- 24.4 ng.h/mL/mg, P = 0.005), C-max (4.4 +/- 2.4 vs. 7.8 +/- 3.5 vs. 6.0 +/- 3.3 ng/mL/mg, P < 0.001) and T-max (1.6 +/- 1.1 vs. 1.7 +/- 0.4 vs. 1.8 +/- 0.8 h, P = 0.006), respectively. Over the first year the intraindividual variability of dose-normalized AUC, C-max and C-0 were 82%, 72%, and 90%, respectively. No significant changes were observed comparing inter-individual variability of dose-normalized AUC (21%, 24%, 33%), C-max (46%, 45%, 55%), C-0 (49%, 83%, 81%) at D7, M6 and M12, respectively. We observed a good correlation between a.m. and p.m. TAC AUC (r(2) = 0.90) and C-0 (r(2) = 0.88). Tacrolimus pharmacokinetics display circadian variation suggesting a slower and delayed absorption phase at nighttime. Tacrolimus also showed time-dependent PK changes, suggesting an improvement in absorption during the first 6 months. Despite circadian variation we observed good correlations between a.m. and p.m. TAC AUC (r(2) = 0.90) and C-0 (r(2) = 0.88) and between C-0 and total daily TAC exposure (a.m. + p.m. AUC) suggesting that trough-guided therapeutic monitoring is still a reliable and simple strategy to optimize the clinical use of TAC.
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    Efficacy of Sotrastaurin Plus Tacrolimus After de Novo Kidney Transplantation: Randomized, Phase II Trial Results
    (Wiley-Blackwell, 2013-07-01) Russ, G. R.; Tedesco-Silva Junior, Hélio [UNIFESP]; Kuypers, D. R.; Cohney, S.; Langer, R. M.; Witzke, O.; Eris, J.; Sommerer, C.; von Zur-Muehlen, B.; Woodle, E. S.; Gill, J.; Ng, J.; Klupp, J.; Chodoff, L.; Budde, K.; Univ Adelaide; Universidade Federal de São Paulo (UNIFESP); Katholieke Univ Leuven Hosp; Royal Melbourne Hosp; Semmelweis Univ; Univ Duisburg Essen; Royal Prince Alfred Hosp; Univ Heidelberg Hosp; Uppsala Univ; Univ Cincinnati; St Pauls Hosp; Novartis Pharmaceut; Novartis Pharma AG; Charite
    Sotrastaurin, a novel immunosuppressant, blocks early T cell activation through protein kinase C inhibition. Efficacy and safety of sotrastaurin with tacrolimus were assessed in a dose-ranging non-inferiority study in renal transplant recipients. A total of 298 patients were randomized 1:1:1:1 to receive sotrastaurin 100 (n=77; discontinued in December 2011) or 200mg (n=73) b.i.d. plus standard tacrolimus (sTAC; 5-12ng/mL), sotrastaurin 300mg (n=75) b.i.d. plus reduced tacrolimus (rTAC; 2-5ng/mL) or enteric-coated mycophenolic acid (MPA) plus sTAC (n=73); all patients received basiliximab and corticosteroids. Composite efficacy failure (treated biopsy-proven acute rejectiongrade IA, graft loss, death or loss to follow up) rates at Month 12 were 18.8%, 12.4%, 10.9% and 14.0% for the sotrastaurin 100, 200 and 300mg, and MPA groups, respectively. the median estimated glomerular filtration rates were 55.7, 53.3, 64.9 and 59.2mL/min, respectively. Mean heart rates were faster with higher sotrastaurin doses and discontinuations due to adverse events and gastrointestinal adverse events were more common. Fewer patients in the sotrastaurin groups experienced leukopenia than in the MPA group (1.3-5.5% vs. 16.5%). Sotrastaurin 200 and 300mg had comparable efficacy to MPA in prevention of rejection with no significant difference in renal function between the groups.
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    Gingival Overgrowth Among Patients Medicated With Cyclosporin A and Tacrolimus Undergoing Renal Transplantation: A Prospective Study
    (Amer Acad Periodontology, 2011-02-01) Paixao, Caroline G.; Sekiguchi, Ricardo T.; Saraiva, Luciana; Pannuti, Claudio M.; Silva, Hello T. [UNIFESP]; Medina-Pestana, Jose O. [UNIFESP]; Romito, Giuseppe A.; Universidade de São Paulo (USP); Universidade Federal de São Paulo (UNIFESP)
    Background: the aim of this study is to make a longitudinal evaluation of the incidence and severity of gingival overgrowth (GO) induced by immunosuppressive agents, such as tacrolimus (Tcr) and cyclosporin A (CsA), in the absence of calcium channel blockers in patients undergoing renal transplantation (RT).Methods: This longitudinal study is conducted in 49 patients with RT who were divided into a CsA group (n = 25) and Tcr group (n = 24). the individuals were assessed at four time intervals: before transplant and 30, 90, and 180 days after RTs. Demographic data and periodontal clinical parameters (plaque index, cemento-enamel junction to the gingival margin, probing depth, clinical attachment level, bleeding on probing [BOP], and GO) were collected at all time intervals.Results: the mean GO index was significantly lower in the Tcr group compared to the CsA group after 30 (P = 0.03), 90 (P = 0.004), and 180 (P = 0.01) days of immunosuppressive therapy. One hundred eighty days after RTs, a clinically significant GO was observed in 20.0% of individuals in the CsA group and 8.3% of individuals in the Tcr group. However, this difference was not statistically significant (P = 0.41). There was a reduction in periodontal clinical parameters regarding the time of immunosuppressive therapy for PI and BOP (P<0.001) in both groups.Conclusion: Although there was no statistical difference in the incidences of clinically significant GO after 180 days of immunosuppressive therapy, it was observed that GO occurred later in the Tcr group, and the severity of GO in this group was lower than in patients who used CsA. J Periodontol 2011;82:251-258.
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    The impact of ethnic miscegenation on tacrolimus clinical pharmacokinetics and therapeutic drug monitoring
    (Blackwell Munksgaard, 2002-08-01) Felipe, C. R.; Silva, H. T.; Machado, P. G.; Garcia, R.; Moreira, SRD; Pestana, J. O.; Universidade Federal de São Paulo (UNIFESP)
    The impact of ethnic miscegenation on tacrolimus clinical pharmacokinetics and therapeutic drug monitoring. We sought to determine the influence of ethnic miscegenation on tacrolimus pharmacokinetics and trough concentrations during the first 6 months after transplantation.Methods: Tacrolimus concentrations were measured in blood samples obtained from 22 transplant recipients during the first week of transplant, within pharmacokinetic profiles, and throughout the first 6 months post-transplant, using the Pro Tac II ELISA method. Pharmacokinetic parameters and between- and within-subject blood concentration variability were compared stratifying the total population in two distinct ethnic groups of white (W) and non-white (NW) patients, according to a stringent criterion.Results: Between-subject variability in dose-adjusted concentrations during dosing interval varied from 38.8 to 69.5%. Compared with W patients, NW patients showed higher variability in blood tacrolimus concentrations during dosing interval (37.40 +/- 5.64 vs. 56.95 +/- 11.49, p < 0.001) and lower drug exposures (AUC: 229.4 +/- 55.5 vs. 66.9 +/- 67.1 ng x h/mL, p=0.036). the correlation coefficients (r(2)) between C-0, C-12 or C-max and AUC were 0.83, 0.91 and 0.5, respectively. An equation derived from early time concentrations (C-0, C-1.5 and C-4) accounted for 94% of the variability observed in AUC. Compared with W patients, a higher proportion of tacrolimus blood determinations during the first week were below 10 νg/mL in NW patients (24% vs. 62%, p=0.028). Tacrolimus absorption increased from week 1-4 (1.1 +/- 0.53 vs. 1.73 +/- 0.97 νg/mL/mg, p < 0.0001) but was still showed high between- (41.6-70.4%) and within-subject (18.2-32.5%) variability, regardless of ethnicity, after stabilization.Conclusion: Non-white patients show higher tacrolimus variability and lower drug exposures after transplantation compared with W patients. Therefore, higher initial tacrolimus doses and intensive monitoring are recommended when administering tacrolimus-based immunosupressive therapy to NW patients of this transplant population.
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    Influence of ABCC2, CYP2C8, and CYP2J2 Polymorphisms on Tacrolimus and Mycophenolate Sodium-Based Treatment in Brazilian Kidney Transplant Recipients
    (Wiley, 2017) Genvigir, Fabiana D. V.; Nishikawa, Alvaro M.; Felipe, Claudia R. [UNIFESP]; Tedesco-Silva, Helio, Jr. [UNIFESP]; Oliveira, Nagilla [UNIFESP]; Salazar, Antony B. C.; Medina-Pestana, Jose O. [UNIFESP]; Doi, Sonia Q.; Hirata, Mario H.; Hirata, Rosario D. C.
    STUDY OBJECTIVE To investigate the influence of single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP2C8, CYP2J2, and UGT2B7) and transporters (ABCC2 and ABCG2) on dose and dose-adjusted trough blood concentrations (C:D ratio), clinical outcomes, and occurrence of adverse events of tacrolimus and mycophenolate sodium in Brazilian kidney transplant recipients. DESIGN Pharmacogenetic analysis of patients enrolled in a previously published study. PATIENTS One hundred forty-eight adult kidney transplant recipients treated with tacrolimus, enteric-coated mycophenolate sodium, and prednisone for 90 days posttransplantation. MEASUREMENTS AND MAIN RESULTS ABCC2 c.-24C>T and c.3972C>T, ABCG2 c.421C>A, CYP2C8*3, CYP2J2 c.-76G>T, and UGT2B7 c.372A>G SNPs were determined by real-time polymerase chain reaction. The CYP3A5*3C SNP data were used to eliminate the confounding effect of this variant on the results. ABCC2 c.3972T allele carriers showed higher tacrolimus C:D values than did carriers of the c.3972CC genotype. The CYP2C8*3 variant was also associated with slightly higher tacrolimus C:D values and higher estimated glomerular filtration rate but only in CYP3A5-nonexpressing patients (CYP3A5*3C/*3C carriers). None of the SNPs were associated with mycophenolate sodium dose or episodes of biopsy-confirmed acute rejection or delayed graft function. The CYP2J2 c.-76T allele was associated with increased risk for treatment-induced nausea and/or vomiting (OR: 5.30, 95% confidence interval 1.49-18.79, p<0.05). CONCLUSION The ABCC2 c.3972C>T polymorphism affected tacrolimus C:D in Brazilian kidney transplant recipients. Further, CYP2C8*3 and CYP2J2 c.-76G>T SNPs influenced the renal function of these patients and the occurrence of adverse events during treatment with tacrolimus and mycophenolate sodium.
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    Influence of the CYP3A4/5 genetic score and ABCB1 polymorphisms on tacrolimus exposure and renal function in Brazilian kidney transplant patients
    (Lippincott Williams & Wilkins, 2016) Genvigir, Fabiana D. V.; Salgado, Patricia C.; Felipe, Claudia Rosso [UNIFESP]; Luo, Elena Y. F.; Alves, Camila; Cerda, Alvaro; Tedesco-Silva Junior, Hélio [UNIFESP]; Pestana, Jose Osmar Medina [UNIFESP]; Oliveira, Nagilla Ione de [UNIFESP]; Rodrigues, Alice C.; Doi, Sonia Q.; Hirata, Mario H.; Hirata, Rosario D. C.
    BackgroundPolymorphisms in genes encoding transport proteins and metabolizing enzymes involved in tacrolimus (TAC) disposition may be important sources of individual variability during treatment.ObjectiveThe aim of this study was to investigate the effect of combined CYP3A4 and CYP3A5 variants, using a CYP3A4/5 genetic score, and ABCB1 polymorphisms on therapeutic TAC monitoring and their relationship with clinical outcomes.Material and methodsBrazilian kidney transplant recipients (n=151), who received TAC over 3 months after transplantation, were genotyped for CYP3A4 rs2242480 (g.20230G>A), CYP3A5 rs15524 (g.31611C>T) and rs776746 (g.6986A>G), ABCB1 rs1128503 (c.1236C>T), rs1045642 (c.3435C>T), and rs2032582 (c.2677G>T/A) polymorphisms.ResultsFrequencies of CYP3A4 g.20230A, CYP3A5 g.31611C, and g.6986A were 0.37, 0.26, and 0.28, respectively. These alleles were associated with TAC rapid metabolization and were used for CYP3A4/5 genetic score construction. A higher CYP3A4/5 genetic score was associated with higher TAC dose and lower concentrations for dose administered (Co/D, P<0.05). Ninety days after transplantation, the presence of two or more rapid metabolization alleles contributed toward 27.7% of Co/D variability and was associated with a lower estimated glomerular filtration rate values (P<0.05). For ABCB1, the frequencies of c.1236T, c.3435T, and c.2677T/A alleles were 0.42, 0.42, and 0.33/0.04. At 30 days after transplantation, patients carrying ABCB1 c.1236TT+c.3435TT+(c.2677TT+TA) genotypes had higher TAC Co/D than those with common or heterozygous genotypes (P<0.05).ConclusionThe results show the impact of the CYP3A4/5 genetic score on TAC exposure and renal function in Brazilian patients. Furthermore, ABCB1 polymorphisms, in a combined analysis, influenced TAC Co/D at 30 days after transplantation.
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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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    Pharmacogenetics of calcineurin inhibitors in Brazilian renal transplant patients
    (Future Medicine Ltd, 2011-09-01) Santoro, Ana; Felipe, Claudia Rosso [UNIFESP]; Tedesco-Silva, Helio [UNIFESP]; Medina-Pestana, Jose O. [UNIFESP]; Struchiner, Claudio J.; Ojopi, Elida B.; Suarez-Kurtz, Guilherme; Inst Nacl Canc; Universidade Federal de São Paulo (UNIFESP); Fundacao Oswaldo Cruz; Universidade de São Paulo (USP)
    Aim: Polymorphisms in the CYP3A5 and ABCB1 genes have been investigated as modulators of the pharmacokinetics and clinical effects of cyclosporine (CSA) and tacrolimus (TAC) in European, North American and Asian populations, with controversial results. the extensive variation in worldwide frequency distribution of CYP3A5 and ABCB1 polymorphisms is a caveat against the extrapolation of these data to the heterogeneous and admixed Brazilian population. We investigated the effect of CYP3A5 and ABCB1 polymorphisms on CSA and TAC dose-adjusted trough concentration (C(0)/dose) in Brazilian renal transplant recipients, during the first 3 months post-transplantation. Materials & methods: Patients receiving CSA (n = 150) or TAC (n = 151) were genotyped for CYP3A5(star)3 (rs776746, 6986A>G), (star)6(rs10264272, 14690G>A) and (star) 7 (rs41303343, 27131-27132insT) and for ABCB1 1236C>T (rs1128503), 2677G>T/A (rs2032582) and 3435C>T (rs1045642) polymorphisms. We explored the effects of CYP3A5 and ABCB1 polymorphisms, clinical and demographical characteristics on CSA and TAC C(0)/dose under a two-step data ana-lysis strategy by fitting a longitudinal mixed-effects model to the data; first to select the important covariates under a univariate setting and then to fit the final multivariate model. Results: C(0)/dose of TAC was associated with the number of CYP3A5-defective alleles, in a gene-dose manner, throughout the observation period, whereas C0/dose of CSA was associated with body surface area and prednisone dosing. No other significant associations were detected. Conclusion: Individual adjustment of the initial TAC dose according to the CYP3A5 haplotypes comprising the CYP3A5(star)3, (star)6 and (star)7 defective alleles might prove beneficial to Brazilian renal transplant recipients and should be further investigated in prospective trials. Original submitted 5 April 2011; Revision submitted 4 May 2011
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    Planned Randomized Conversion From Tacrolimus to Sirolimus-Based Immunosuppressive Regimen in de Novo Kidney Transplant Recipients
    (Wiley-Blackwell, 2013-12-01) Tedesco-Silva Junior, Hélio [UNIFESP]; Felipe, Claudia Rosso [UNIFESP]; Garcia, V. D.; Neto, E. D.; Filho, M. A.; Contieri, F. L. C.; Carvalho, D. D. B. M. de; Pestana, Jose Osmar Medina [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Santa Casa de Misericordia; Universidade de São Paulo (USP); Inst Urol & Nefrol; Med Sch FAMERP HB FUNFARME; Hosp Univ Evangel Curitiba; Bonsucesso Gen Hosp
    Planned conversion from tacrolimus to sirolimus was evaluated in de novo kidney transplant recipients. in this multicenter, randomized, open-label study, 297 patients were initially treated with tacrolimus, mycophenolate sodium and prednisone. of the 283 patients reaching 3 months, 97 were converted to sirolimus (SRL), 107 were maintained on tacrolimus (TAC) and 79 were patients receiving TAC without criteria to undergo intervention at month 3 (TACex). the primary objective was to show superior estimated glomerular filtration rate (eGFR) in the SRL group at month 24. of the 258 patients who completed 24 months, 91 (94%) were in the SRL group, 101 (94%) in the TAC group and 66 (84%) in the TACex group. in the intention-to-treat population there were no differences in eGFR (66.225.3 vs. 70.7 +/- 25.1, p=0.817) or in the severity of chronic sclerosing lesions scores in 24-month protocol biopsies. Higher mean urinary protein-to-creatinine ratio (0.36 +/- 0.69 vs. 0.15 +/- 0.53, p=0.03) and higher incidence of treated acute rejection between months 3-24 (13.4% vs. 4.7%, p=0.047) were observed in SRL compared to TAC group. in this population planned conversion from TAC to SRL 3 months after kidney transplantation was not associated with improved renal function at 24 months.
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    Prospective Randomized Trial Investigating the Influence of Pharmaceutical Care on the Intra-Individual Variability of Tacrolimus Concentrations Early After Kidney Transplant
    (Lippincott Williams & Wilkins, 2016) Bessa, Adrieli B. [UNIFESP]; Felipe, Claudia R. [UNIFESP]; Hannun, Pedro [UNIFESP]; Sayuri, Priscila [UNIFESP]; Felix, Maria Julia [UNIFESP]; Ruppel, Priscila [UNIFESP]; Ferreira, Alexandra N. [UNIFESP]; Cristelli, Marina P. [UNIFESP]; Viana, Laila [UNIFESP]; Mansur, Juliana F. [UNIFESP]; Basso, Geovana [UNIFESP]; Aguiar, Wilson Ferreira [UNIFESP]; Tedesco-Silva, Helio [UNIFESP]; Medina-Pestana, Jose [UNIFESP]
    Background:This study evaluated the influence of pharmaceutical care (PhC) in the intra-individual variability of dose-corrected whole blood tacrolimus (TAC) trough concentrations, adherence to immunosuppressive therapy and clinical outcomes.Methods:We randomized 128 kidney transplant recipients to receive PhC consisted of predefined instructions provided by a pharmacist (PhC group, n = 64) or standard nurse staff instructions (control group, n = 64) from day 3 to day 90 after kidney transplantation. The study was powered to detect at least 50% reduction in the coefficient of variation (%CV), calculated from 6 dose-corrected whole blood TAC trough concentrations, in the PhC group. Patient adherence was evaluated using Basel Assessment of Adherence to Immunosuppressive Medication Scale (BAASIS) questionnaire.Results:There was no difference in the %CV comparing PhC and control group (31.4% 12.3% versus 32.5% +/- 16.1%, P = 0.673). There were no differences in the proportion of patients showing TAC concentrations within predefined target concentrations in each study visit. There was no difference in the proportion of nonadherent patients at day 28 (17% versus 26%, P = 0.135) and day 90 (27% versus 25%, P = 0.457) based on BAASIS questionnaire answers, respectively. There were no differences in clinical outcomes.Conclusions:Universal PhC in addition to standard nurse staff instruction was not associated with reduced intra-individual variability of dose-corrected whole blood TAC trough concentrations or improved adherence.
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    Tacrolimus and quality of life after kidney transplantation - a multicenter study
    (Blackwell Publishing, 2006-07-01) Bohlke, M.; Rocha, M.; Gomes, R. H.; Marini, S. S.; Terhorst, L.; Barcellos, F. C.; Hallal, P. C.; Casarini, D.; Irigoyen, M. C.; Catholic Univ Pelotas; Fed Univ Pelotas; Universidade Federal de São Paulo (UNIFESP); Universidade de São Paulo (USP)
    Kidney transplantation is currently the treatment of choice for end-stage renal disease. Although new immunosuppressive drugs have been introduced into clinical practice, the effect of such medication on quality of life (QoL) in transplant recipients is still unclear. the present study analyzes the impact of tacrolimus-based immunosuppression on QoL in a representative sample of adult kidney transplant recipients from Rio Grande do Sul, a Brazilian southern state. This was a cross-sectional multicenter study which used the SF-36 Health Survey for measuring QoL. the effect of tacrolimus on QoL was adjusted for possible confounders using multiple linear regression. A total of 272 patients (from 11 different centers) were evaluated, 48 of them were treated with tacrolimus. Transplant patients in use of tacrolimus presented significant higher scores in the physical component summary of SF-36 than non-users (49.1 +/- 8.3 vs. 46.1 +/- 8.7; p = 0.03), and such difference was noted in the physical functioning and general health subscales (81.5 +/- 17.1 and 74.7 +/- 21.8; 74.6 +/- 22.3 and 67.1 +/- 22.3 for users and non-users of tacrolimus, respectively, p < 0.05). the effect of tacrolimus remained significant after adjustment for age, gender, skin color and time since transplantation (coeff.: 2.83; 95% CI: 0.05-5.6, p = 0.045). the association between tacrolimus-based immunosuppression and better perception of physical functioning and general health for renal transplant patients represents a significant finding as it may influence therapeutical decisions and contribute to maximize kidney transplantation benefits.
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    Tacrolimus in pancreas transplant: a focus on toxicity, diabetogenic effect and drug-drug interactions
    (Informa Healthcare, 2014-11-01) Rangel, Erika B. [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Albert Einstein Hosp
    Introduction: With further reduction in surgical complications and improvement in immunosuppressive protocols, pancreas transplant offers excellent outcomes for patients with diabetes. However, long-term survival of pancreas allograft is affected not only by rejection but also by immunosuppressive regimen toxicity.Areas covered: This article reviews the existing literature and knowledge of tacrolimus toxicity and focuses on its diabetogenic effect after pancreas transplant. Some clinically relevant drug-drug interactions with glucocorticoids and sirolimus are also highlighted. This review also summarizes the diabetogenic mechanisms of tacrolimus, the alternatives to minimize these effects, and the main differential diagnosis of hyperglycemia after pancreas transplant.Expert opinion: Tacrolimus is a potent calcineurin inhibitor, an important pathway that regulates pancreatic development. Tacrolimus can induce beta-cell apoptosis, decrease insulin exocytosis and reduce insulin gene transcription, which ultimately lead to impaired functional beta-cell mass after pancreas transplant. Furthermore, insulin resistance can exacerbate the diabetogenic effect of tacrolimus due to inhibition of insulin gene transcription and beta-cell proliferation. It is important to critically analyze the results of clinical studies and investigate new immunosuppressive drugs and/or novel drug combinations. It is equally important to comprehend and interpret experimental data. Therefore, minimization of side effects, based on safe approaches, can prolong pancreas allograft survival.
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    Tacrolimus Ointment for Refractory Posterior Blepharitis
    (Taylor & Francis Inc, 2017) Sakassegawa-Naves, Fernando Eiji; Moraes Ricci, Helena Maria; Moscovici, Bernardo Kaplan [UNIFESP]; Miyamoto, Daniela Akemi; Chiacchio, Brenda Biagio; Holzchuh, Ricardo; Santo, Ruth Muyuki; Hida, Richard Yudi
    Purpose: This prospective, randomized, double-blind interventional case series was designed to evaluate the short-term efficacy of 0.03% tacrolimus ointment as a new therapeutic approach for refractory cases of posterior blepharitis.Methods: Forty eyes (20 patients) with posterior blepharitis refractory to previous treatment were randomized. Eighteen eyes (9 patients) were treated with 0.03% tacrolimus ointment and 20 eyes (10 patients) with placebo ointment twice daily. Patients were evaluated with a questionnaire and slit-lamp examination 14days and 28days after treatment, and symptoms and signs of blepharitis were compared to those observed at baseline.Results: We could observe statistical difference in the outcome measurements of meibomian gland secretion, conjunctival hyperemia, telangiectasia of inferior lid, Rose Bengal, and fluorescein scoring for the study group. As for the symptoms score, we observed statistical difference in the symptoms scoring for pruritus and dry eye sensation in the tacrolimus group.Conclusion: This study suggests that topical administration of 0.03% tacrolimus ointment can improve some symptoms and some ocular surface status in patients with refractory posterior blepharitis.
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    Tacrolimus Once Daily (ADVAGRAF) Versus Twice Daily (PROGRAF) in de Novo Renal Transplantation: A Randomized Phase III Study
    (Wiley-Blackwell, 2010-12-01) Kraemer, B. K.; Charpentier, B.; Backman, L.; Silva, H. Tedesco [UNIFESP]; Mondragon-Ramirez, G.; Cassuto-Viguier, E.; Mourad, G.; Sola, R.; Rigotti, P.; Ortuno Mirete, J.; Tacrolimus Prolonged Release Rena; Univ Heidelberg; Univ Paris Sud; Univ Uppsala Hosp; Sahlgrens Univ Hosp; Universidade Federal de São Paulo (UNIFESP); Inst Mexicano Transplantes; Serv Nephrol; Hop Lapeyronie; Fundacio Puigvert; Azienda Osped Padova; Hosp Ramon & Cajal
    This multicenter, 1:1-randomized, parallel-group, noninferiority study compared the efficacy and safety of twice-daily tacrolimus (Tacrolimus BID; Prograf) and once-daily tacrolimus prolonged release (Tacrolimus QD; Advagraf), combined with steroids and low-dose mycophenolate mofetil without antibody induction, in 667 de novo kidney transplant recipients. A double-blind, double-dummy 24-week period was followed by an open extension of up to 12 months posttransplant. Biopsy-proven acute rejection rate at 24 weeks (primary endpoint, per-protocol analysis) was 15.8% for Tacrolimus BID versus 20.4% for Tacrolimus QD (p = 0.182; treatment difference 4.5%, 95% confidence interval-1.8%, 10.9%, just outside the prespecified 10% noninferiority margin). Kaplan-Meier 12-month patient and graft survival rates were 97.5% and 92.8% for Tacrolimus BID and 96.9% and 91.5% for QD. Both treatment groups showed equally well-maintained renal function at 12 months (mean creatinine clearance approximately 67 mL/min) and similar adverse event profiles. Overall results obtained with either Tacrolimus QD or BID, without antibody induction, were good, supporting use of the once-daily formulation as an effective alternative to the established twice-daily formulation.
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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.
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    Time-Dependent and Immunosuppressive Drug-Associated Adverse Event Profiles in De Novo Kidney Transplant Recipients Converted from Tacrolimus to Sirolimus Regimens
    (Wiley-Blackwell, 2016) Felix, Maria Julia Pereira [UNIFESP]; Felipe, Claudia Rosso [UNIFESP]; Tedesco-Silva, Helio [UNIFESP]; Medina-Pestana, Jose Osmar [UNIFESP]
    Study ObjectiveTo evaluate the safety and tolerability of immunosuppressive drugs used in a planned randomized conversion from a calcineurin inhibitor, tacrolimus, to a mammalian target of rapamycin inhibitor, sirolimus, in de novo kidney transplant recipients. DesignProspective safety analysis of data from a prospective, randomized, open-label, controlled study. PatientsA total of 119 adult kidney transplant recipients who received tacrolimus (TAC), mycophenolate sodium (MPS), and prednisone between February 2008 and May 2010; after 3 months of this regimen, 60 of these patients were randomized to conversion from TAC to sirolimus (SRL/MPS group), and 59 patients continued with the TAC regimen (TAC/MPS group). Measurements and Main ResultsBoth groups were followed for 24 months after transplantation for immunosuppressive regimen-associated and time-dependent occurrences of adverse events (AEs) and serious adverse events (SAEs). Before conversion from TAC to SRL, the cumulative incidence of AEs was 98%; 25% were SAEs. Gastrointestinal AEs (66%) and infections (58%) were the most frequent AEs. The incidences of TAC and MPS dose reductions due to AEs were 1.7% and 12%, respectively. After conversion, no significant differences were noted in the SRL/MPS group versus the TAC/MPS group in the cumulative incidences of AEs (100% vs 98%) and SAEs (27% vs 30%). The most common AEs were gastrointestinal (70% vs 54%, p=0.23) and infection (77% vs 73%, p=0.79) in the SRL/MPS versus TAC/MPS groups. The incidence of aphthous ulcer (28% vs 0%, p=< 0.01), sinusitis (10% vs 0%, p=0.01), dermatitis (15% vs 3%, p=0.03), and dyslipidemia (35% vs 14%, p=0.02) were higher in the SRL/MPS group compared with the TAC/MPS group. Cox proportion regression analysis showed a higher relative risk for gastrointestinal (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.2-3.01, p<0.05) and skin and subcutaneous tissue (HR 2.5, 95% CI 1.1-4.1, p<0.05) AEs in the SRL/MPS group compared with the TAC/MPS group. AE-related dose reductions occurred in 18.3% of patients receiving SRL and 3.3% of patients receiving TAC. MPS dose reductions due to AEs occurred in 11.7% of patients receiving SRL and 13.6% of patients receiving TAC. ConclusionSRL/MPS treatment was associated with a time-dependent higher incidence of gastrointestinal and skin and subcutaneous tissue AEs, which occurred mainly during the first 6 months after conversion from TAC/MPS. Although the treatments with SRL or TAC after 3 months of transplantation showed different safety profiles, both regimens demonstrated adequate tolerability, with low rates of early discontinuation related to AEs.
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    Time-Dependent and Immunosuppressive Drug-Associated Adverse Event Profiles in De Novo Kidney Transplant Recipients Converted from Tacrolimus to Sirolimus Regimens
    (Wiley-Blackwell, 2016) Felix, Maria Julia Pereira [UNIFESP]; Felipe, Claudia Rosso [UNIFESP]; Tedesco-Silva, Helio [UNIFESP]; Medina-Pestana, Jose Osmar [UNIFESP]
    Study ObjectiveTo evaluate the safety and tolerability of immunosuppressive drugs used in a planned randomized conversion from a calcineurin inhibitor, tacrolimus, to a mammalian target of rapamycin inhibitor, sirolimus, in de novo kidney transplant recipients. DesignProspective safety analysis of data from a prospective, randomized, open-label, controlled study. PatientsA total of 119 adult kidney transplant recipients who received tacrolimus (TAC), mycophenolate sodium (MPS), and prednisone between February 2008 and May 2010; after 3 months of this regimen, 60 of these patients were randomized to conversion from TAC to sirolimus (SRL/MPS group), and 59 patients continued with the TAC regimen (TAC/MPS group). Measurements and Main ResultsBoth groups were followed for 24 months after transplantation for immunosuppressive regimen-associated and time-dependent occurrences of adverse events (AEs) and serious adverse events (SAEs). Before conversion from TAC to SRL, the cumulative incidence of AEs was 98%; 25% were SAEs. Gastrointestinal AEs (66%) and infections (58%) were the most frequent AEs. The incidences of TAC and MPS dose reductions due to AEs were 1.7% and 12%, respectively. After conversion, no significant differences were noted in the SRL/MPS group versus the TAC/MPS group in the cumulative incidences of AEs (100% vs 98%) and SAEs (27% vs 30%). The most common AEs were gastrointestinal (70% vs 54%, p=0.23) and infection (77% vs 73%, p=0.79) in the SRL/MPS versus TAC/MPS groups. The incidence of aphthous ulcer (28% vs 0%, p=< 0.01), sinusitis (10% vs 0%, p=0.01), dermatitis (15% vs 3%, p=0.03), and dyslipidemia (35% vs 14%, p=0.02) were higher in the SRL/MPS group compared with the TAC/MPS group. Cox proportion regression analysis showed a higher relative risk for gastrointestinal (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.2-3.01, p<0.05) and skin and subcutaneous tissue (HR 2.5, 95% CI 1.1-4.1, p<0.05) AEs in the SRL/MPS group compared with the TAC/MPS group. AE-related dose reductions occurred in 18.3% of patients receiving SRL and 3.3% of patients receiving TAC. MPS dose reductions due to AEs occurred in 11.7% of patients receiving SRL and 13.6% of patients receiving TAC. ConclusionSRL/MPS treatment was associated with a time-dependent higher incidence of gastrointestinal and skin and subcutaneous tissue AEs, which occurred mainly during the first 6 months after conversion from TAC/MPS. Although the treatments with SRL or TAC after 3 months of transplantation showed different safety profiles, both regimens demonstrated adequate tolerability, with low rates of early discontinuation related to AEs.