Adequacy of Initial Everolimus Dose, With and Without Calcineurin Inhibitors, in Kidney Transplant Recipients

Felipe, Cláudia Rosso; Ferreira, Alexandra; Bessa, Adrieli; Abait, Tamiris; Perez, Juliana Dinéia; Casarini, Dulce Elena; Medina-Pestana, José; Tedesco, H.

doi:10.1097/ftd.0000000000000464

Cited by 3 publications

(5 citation statements)

References 28 publications

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“…In a study to identify the optimal dose of EVR associated with CNI, Felipe et al . showed that there was a significant proportion of patients with EVR concentrations below 3 ng/ml during the first week after renal transplantation . The r‐ATG/EVR group had 14 episodes of first BPAR, 50% occurred within the first 30 days post‐transplantation and 65% of the patients had EVR below 4 ng/ml.…”

Section: Discussionmentioning

confidence: 99%

Prospective randomized study comparing everolimus and mycophenolate sodium inde novokidney transplant recipients from expanded criteria deceased donor

et al. 2019

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Summary The optimal immunosuppressive regimen for recipients of expanded criteria donor (ECD) kidneys has not been identified. In this single‐center study, 171 recipients of ECD kidney transplants were randomized to receive antithymocyte globulin induction, and delayed introduction of reduced dose tacrolimus, prednisone and everolimus (r‐ATG/EVR, n = 88), or mycophenolate (r‐ATG/MPS, n = 83). No cytomegalovirus (CMV) pharmacological prophylaxis was used. The primary endpoint was the incidence of CMV infection/disease at 12 months. Secondary endpoints included treatment failure [first biopsy‐proven acute rejection (BPAR), graft loss, or death] and safety. Patients treated with EVR showed a 89% risk reduction (13.6 vs. 71.6%; HR 0.11, 95% CI 0.06–0.220, P < 0.001) in the incidence of first CMV infection/disease. Incidences of BPAR (16% vs. 5%, P = 0.021), graft loss (11% vs. 1%, P = 0.008), death (10% vs. 1%, P = 0.013), and treatment discontinuation (40% vs. 28%, P = 0.12) were higher in the r‐ATG/EVR, leading to premature study termination. Mean glomerular filtration rate was lower in r‐ATG/EVR (31.8 ± 18.8 vs. 42.6 ± 14.9, P < 0.001). In recipients of ECD kidney transplants receiving no CMV pharmacological prophylaxis, the use of everolimus was associated with higher treatment failure compared with mycophenolate despite the significant reduction in the incidence of CMV infection/disease (ClinicalTrials.gov.NCT01895049).

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Section: Discussionmentioning

confidence: 99%

Prospective randomized study comparing everolimus and mycophenolate sodium inde novokidney transplant recipients from expanded criteria deceased donor

et al. 2019

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“…A study in de novo kidney transplant recipients suggest that the everolimus initial dose should consider which of the calcineurin inhibitors is administered. If administered with cyclosporine, the recommended starting dose is 0.75 mg twice daily, while in combination with tacrolimus, the recommended starting dose should be 1.5 mg twice daily to reach trough levels of 3–8 mg/L 44 . Further, the everolimus dose should initially be reduced by half in patients with mild and moderate hepatic impairment based on Child‐Pugh classification 22 .…”

Section: Resultsmentioning

confidence: 99%

“…If administered with cyclosporine, the recommended starting dose is 0.75 mg twice daily, while in combination with tacrolimus, the recommended starting dose should be 1.5 mg twice daily to reach trough levels of 3-8 mg/L. 44 Further, the everolimus dose should initially be reduced by half in patients with mild and moderate hepatic impairment based on Child-Pugh classification. 22 Although there are a number of other factors that could contribute to the individualization of everolimus dosing, specific dose adjustment recommendations are not available.…”

Section: Pharmacokinetic/pharmacodynamics (Pk/pd) Target and Dosage I...mentioning

confidence: 99%

Pharmacokinetic principles of dose adjustment ofmTORinhibitors in solid organ transplanted patients

Hartinger

Ryšánek

Slanař

et al. 2022

Clinical Pharmacy Therapeu

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Section: Introductionmentioning

confidence: 99%

“…Although everolimus can be utilized after renal transplantation to reduce nephrotoxicity induced by tacrolimus [ 1 , 2 , 3 ], the blood concentrations of everolimus are not influenced by tacrolimus but are affected by cyclosporine [ 10 , 16 , 17 , 18 ]. Therefore, the dose of everolimus that achieves equivalent exposure is 1.5- or 2-fold higher in the presence of tacrolimus than in the presence of cyclosporine [ 11 , 17 , 18 ]. Accordingly, when everolimus is administered in combination with cyclosporine, the influence of genetic polymorphisms, such as polymorphisms in NR1I2 or ABCB1 , on everolimus pharmacokinetics cannot be sufficiently assessed.…”

Section: Introductionmentioning

confidence: 99%

Effects of NR1I2 and ABCB1 Genetic Polymorphisms on Everolimus Pharmacokinetics in Japanese Renal Transplant Patients

Yagishita

Kagaya

Saito

et al. 2022

IJMS

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The purpose of this study was to evaluate the effects of NR1I2 (7635G>A and 8055C>T) and ABCB1 (1236C>T, 2677G>T/A, and 3435C>T) genetic polymorphisms on everolimus pharmacokinetics in 98 Japanese renal transplant patients. On day 15 after everolimus administration, blood samples were collected just prior to and 1, 2, 3, 4, 6, 9, and 12 h after administration. The dose-adjusted area under the blood concentration–time curve (AUC0-12) of everolimus was significantly lower in patients with the NR1I2 8055C/C genotype than in those with other genotypes (p = 0.022) and was significantly higher in male patients than female patients (p = 0.045). Significant correlations between the dose-adjusted AUC0-12 of everolimus and age (p = 0.001), aspartate transaminase (p = 0.001), and alanine transaminase (p = 0.005) were found. In multivariate analysis, aging (p = 0.008) and higher alanine transaminase levels (p = 0.032) were independently predictive of a higher dose-adjusted everolimus AUC0-12. Aging and hepatic dysfunction in patients may need to be considered when evaluating dose reductions in everolimus. In renal transplant patients, management using everolimus blood concentrations after administration may be more important than analysis of NR1I2 8055C>T polymorphism before administration.

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Adequacy of Initial Everolimus Dose, With and Without Calcineurin Inhibitors, in Kidney Transplant Recipients

Abstract: 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.

Cited by 3 publications

References 28 publications

Prospective randomized study comparing everolimus and mycophenolate sodium inde novokidney transplant recipients from expanded criteria deceased donor

Prospective randomized study comparing everolimus and mycophenolate sodium inde novokidney transplant recipients from expanded criteria deceased donor

Pharmacokinetic principles of dose adjustment ofmTORinhibitors in solid organ transplanted patients

Effects of NR1I2 and ABCB1 Genetic Polymorphisms on Everolimus Pharmacokinetics in Japanese Renal Transplant Patients

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