Prophylactic use of mTOR inhibitors and other immunosuppressive agents in heart transplant patients

Santoni, Matteo; Massari, Francesco; Cascinu, Stefano

doi:10.1038/cmi.2014.27

Cited by 2 publications

(2 citation statements)

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“…[6] These results strengthen the possibility of equilibrium between efficient immunosuppressive drug therapy and preservation over the development of cancer, [25,26] thereby offering new therapeutic strategies for the treatment of malignancies in clinical practice. [27,28] However, drug–drug interaction between these drugs might exist as well, and studies on the influence of EVR on MPA pharmacokinetic parameters are limited and it requires further evaluation.…”

Section: Introductionmentioning

confidence: 99%

Influence of cyclosporine and everolimus on the main mycophenolate mofetil pharmacokinetic parameters

et al. 2017

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The objective of the present study was to assess the effect of cyclosporine (CsA) on the pharmacokinetic parameters of mycophenolic acid (MPA), an active mycophenolate mofetil (MMF) metabolite, and to compare with the effect of everolimus (EVR).Anonymized medical records of 404 kidney recipients were reviewed. The main MPA pharmacokinetic parameters (AUC(0–12) and Cmax) were evaluated.The patients treated with a higher mean dose of CsA displayed higher MPA AUC(0–12) exposure in the low-dose MMF group (1000 mg/day) (40.50 ± 10.97 vs 28.08 ± 11.03 h mg/L; rs = 0.497, P < 0.05), medium-dose MMF group (2000 mg/day) (43.00 ± 6.27 vs 28.85 ± 11.08 h mg/L; rs = 0.437, P < 0.01), and high-dose MMF group (3000 mg/day) (56.75 ± 16.78 vs 36.20 ± 3.70 h mg/L; rs = 0.608, P < 0.05).A positive correlation was also observed between the mean CsA dose and the MPA Cmax in the low-dose MMF group (Cmax 22.83 ± 10.82 vs 12.08 ± 5.59 mg/L; rs = 0.507, P < 0.05) and in the medium-dose MMF group (22.77 ± 8.86 vs 13.00 ± 6.82 mg/L; rs = 0.414, P < 0.01).The comparative analysis between 2 treatment arms (MMF + CsA and MMF + EVR) showed that MPA AUC(0–12) exposure was by 43% higher in the patients treated with a medium dose of MMF and EVR than in the patients treated with a medium dose of MMF and CsA.The data of the present study suggest a possible CsA versus EVR influence on MMF pharmacokinetics. Study results show that CsA has an impact on the main MPA pharmacokinetic parameters (AUC(0–12) and Cmax) in a CsA dose-related manner, while EVR mildly influence or does not affect MPA pharmacokinetic parameters. Low-dose CsA (lower than 180 mg/day) reduces MPA AUC(0–12) exposure under the therapeutic window and may lead to ineffective therapy, while a high-dose CsA (>240 mg/day) is related to greater than 10 mg/L MPA Cmax and increases the likelihood of adverse events.

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Section: Introductionmentioning

confidence: 99%

Influence of cyclosporine and everolimus on the main mycophenolate mofetil pharmacokinetic parameters

et al. 2017

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“…These results regarding mTOR inhibitors strengthen the possibility of an equilibrium between efficient immunosuppressive drug therapy and control over the development of cancer, thereby offering new therapeutic strategies for the treatment of malignancies in clinical practice. 30 , 31 …”

Section: Discussionmentioning

confidence: 99%

Analysis of malignancies in patients after heart transplantation with subsequent immunosuppressive therapy

Rivinius¹,

Helmschrott²,

Ruhparwar³

et al. 2014

DDDT

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ObjectiveThe aim of this study was to analyze the distribution of malignancies in patients after heart transplantation (HTX) and to evaluate the risk factors including immunosuppressive therapy with regard to the development of malignancies and survival. Special emphasis was placed on the effects of a mammalian target of rapamycin (mTOR) containing immunosuppressive regimen.MethodsA total of 381 patients (age ≥18 years) receiving HTX were included in the present analysis. All patients were followed-up at the University of Heidelberg Heart Center, Heidelberg, Germany. Data were retrieved from the Heidelberg Registry for Heart Transplantation being collected between 1989 and 2014. According to center standard, all patients received induction therapy with anti-thymocyte globulin guided by T-cell monitoring since 1994. The initial immunosuppressive regimen consisting of cyclosporine A (CsA) and azathioprine (AZA) was replaced by CsA and mycophenolate mofetil (MMF) in 2001 and by tacrolimus (TAC) and MMF in 2006. Additionally, mTOR inhibitors (everolimus/sirolimus) were applied since 2003.ResultsMean recipient age at HTX was 51.2±10.5 years and the mean follow-up period after HTX was 9.7±5.9 years. During follow-up, 130 patients developed a neoplasm (34.1% of total). Subgroup analysis revealed 58 patients with cutaneous malignancy only (15.2%), 56 patients with noncutaneous malignancy only (14.7%), and 16 patients with both cutaneous and noncutaneous malignancy (4.2%). Statistically significant risk factors associated with an increased risk of malignancy after HTX were older age (P<0.0001), male recipients (P=0.0008), dyslipidemia (P=0.0263), diabetes mellitus (P=0.0003), renal insufficiency (P=0.0247), and >1 treated rejection episode (TRE) in the first year after HTX (P=0.0091). Administration of CsA (P=0.0195), AZA (P=0.0008), or steroids (P=0.0018) for >1 year after HTX was associated with increased development of malignancy, whereas administration of MMF (P<0.0001) or mTOR inhibitors (P<0.0001) was associated with a lower risk for development of malignancy. Additionally, 5-year follow-up of cutaneous malignancy recurrence (P=0.0065) and noncutaneous malignancy mortality (P=0.0011) was significantly lower in patients receiving an mTOR inhibitor containing therapy after the development of a malignancy.ConclusionThis study highlights the complexity of risk factors including immunosuppression with regard to the development of malignancies after HTX. mTOR-inhibitor-based immunosuppression is associated with a better outcome after HTX, particularly in cases with noncutaneous malignancy.

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Prophylactic use of mTOR inhibitors and other immunosuppressive agents in heart transplant patients

Cited by 2 publications

References 8 publications

Influence of cyclosporine and everolimus on the main mycophenolate mofetil pharmacokinetic parameters

Influence of cyclosporine and everolimus on the main mycophenolate mofetil pharmacokinetic parameters

Analysis of malignancies in patients after heart transplantation with subsequent immunosuppressive therapy

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Prophylactic use of mTOR inhibitors and other immunosuppressive agents in heart transplant patients

Cited by 2 publications

References 8 publications

Influence of cyclosporine and everolimus on the main mycophenolate mofetil pharmacokinetic parameters

Influence of cyclosporine and everolimus on the main mycophenolate mofetil pharmacokinetic parameters

Analysis of malignancies in patients&nbsp;after&nbsp;heart transplantation with subsequent immunosuppressive therapy

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Analysis of malignancies in patients after heart transplantation with subsequent immunosuppressive therapy