Optimal Dose and Target Trough Level in Cyclosporine and Tacrolimus Conversion in Renal Transplantation as Evaluated by Lymphocyte Drug Sensitivity and Pharmacokinetic Parameters

Takeuchi, Hirohito; Okuyama, Kiyoshi; Konno, Osamu; Jojima, Y.; Akashi, Isao; Nakamura, Yuki; Iwamoto, Hitoshi; Hama, K.; Iwahori, Tohru; Uchiyama, M; Ashizawa, T.; Matsuno, Naoto; Nagao, Toshiyasu; Hirano, Toshihiko; Oka, Kitaro

doi:10.1016/j.transproceed.2005.02.075

Cited by 23 publications

(13 citation statements)

References 4 publications

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“…In other treatment groups, the average of trough levels were 1.4 ng / mL for the 0.5 mg / kg group and 2.4 ng/ mL for the 1.0 mg / kg group. These blood levels seem to be quite reasonable compared to the human clinical setting, and this result also suggests the benefit of using the cynomolgus monkey renal transplant model and supports the theoretical background to employ 0.5 or 1.0 mg / kg of tacrolimus to discover a new agent that can reduce the blood level of tacrolimus (21).…”

Section: Discussionsupporting

confidence: 70%

Efficacy of Oral Treatment With Tacrolimus in the Renal Transplant Model in Cynomolgus Monkeys

Kinugasa¹,

Nagatomi²,

Ishikawa³

et al. 2008

J Pharmacol Sci

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Abstract. Many studies have examined the efficacy of tacrolimus in rats and dogs, but few have reported its evaluation in cynomolgus monkeys. The aim of this study was to clarify the efficacy of tacrolimus in a cynomolgus monkey renal transplant model based on the efficacy of various doses. Monkeys that had undergone renal transplant were treated with a vehicle or 0.5, 1.0, or 2.0 mg / kg of tacrolimus by oral administration. Tacrolimus administration prolonged animal survival in a dose-dependent manner, and the median survival time (MST) was 11, 21, and >90 days for the 0.5, 1.0, and 2.0 mg / kg tacrolimus groups, respectively. The MST of the vehicle group was 6 days. Histopathological analyses of all transplanted kidneys were also performed. Typical pathological findings of acute rejection were observed in both the vehicle and tacrolimus (0.5 and 1.0 mg / kg)-treated groups. Only limited mononuclear cell infiltration and hemorrhage were present in the tacrolimus (2.0 mg / kg)-treated group. In conclusion, 2.0 mg / kg was considered to be a therapeutic dose in this model, and 0.5 or 1.0 mg / kg could be used for a study when efficacy of a new compound is evaluated in a combination therapy with tacrolimus.

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Section: Discussionsupporting

confidence: 70%

Efficacy of Oral Treatment With Tacrolimus in the Renal Transplant Model in Cynomolgus Monkeys

Kinugasa¹,

Nagatomi²,

Ishikawa³

et al. 2008

J Pharmacol Sci

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“…CsA is a potent immunosuppressant that has been used extensively to attenuate autoimmune symptoms. The molecular biological mechanism of CsA has been investigated extensively in human T cells, and it has been shown to involve modulation of the intracellular calcineurin pathway [23]. The cDNA microarray method showed that CsA‐treated PBMCs displayed significant induction of genes involved in the control of cell‐cycle regulation, apoptosis/DNA repair, DNA metabolism/response to DNA damage stimulus, transcription and cell proliferation [24].…”

Section: Discussionmentioning

confidence: 99%

Selective clinical and immune response of the oligoclonal autoreactive T cells in Omenn patients after cyclosporin A treatment

Lev

Simon

Amariglio

et al. 2012

Clinical and Experimental Immunology

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SummaryThe immunological hallmark of Omenn syndrome (OS) is the expansion and activation of an oligoclonal population of autoreactive T cells. These cells should be controlled rapidly by immunosuppressive agents, such as cyclosporin A (CsA), to avoid tissue infiltration and to improve the general outcome of the patients. Here we studied the clinical and the immune response to CsA in two Omenn patients and also examined the gene expression profile associated with good clinical response to such therapy. T cell receptor diversity was studied in cells obtained from OS patients during CsA therapy. Characterization of gene expression in these cells was carried out by using the TaqMan low-density array. One patient showed complete resolution of his symptoms after CsA therapy. The other patient showed selective response of his oligoclonal T cell population and combination therapy was required to control his symptoms. Transcriptional profile associated with good clinical response to CsA therapy revealed significant changes in 26·6% of the tested genes when compared with the transcriptional profile of the cells before treatment. Different clinical response to CsA in two OS patients is correlated with their immunological response. Varying clonal expansions in OS patients can cause autoimmune features and can respond differently to immunosuppressive therapy; therefore, additional treatment is sometimes indicated. CsA for OS patients causes regulation of genes that are involved closely with self-tolerance and autoimmunity.

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“…The immunosuppressive effects of and incidence of adverse events with TAC correlate with the area under the curve (AUC) (10). The blood trough concentration (C0) of TAC correlates with the AUC and is used for monitoring re- nal transplant recipients as an alternative to the AUC (11).…”

Section: Discussionmentioning

confidence: 99%

The Proton Pump Inhibitor Lansoprazole, but not Rabeprazole, the Increased Blood Concentrations of Calcineurin Inhibitors in Japanese Patients with Connective Tissue Diseases

et al. 2014

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Objective Proton pump inhibitors (PPIs) are frequently coadministered with calcineurin inhibitors (CNIs) such as tacrolimus (TAC) and cyclosporin A (CSA), to treat or prevent upper gastrointestinal complications in Japanese patients with connective tissue diseases (CTDs). The coadministration of PPIs increases the blood concentration of TAC due to drug interaction. We retrospectively investigated the influence of the coadministration of PPIs and CNIs, as well as the influence of the cytochrome P450 (CYP) 2C19 gene polymorphism status, on the blood concentrations of TAC and CSA in patients with CTDs. Methods Patients treated with TAC (n=35) or CSA (n=30) were enrolled and divided into three groups according to the PPI they received: lansoprazole (LPZ)-combined, rabeprazole (RPZ)-combined, and non-PPIcombined groups. We compared the blood concentrations of TAC or CSA and the incidences of adverse events among the three groups. CYP2C19 gene polymorphisms were also assessed to investigate its influence on the blood concentration of TAC or CSA. Results LPZ significantly increased the blood concentration of TAC 12 hours after TAC administration (p= 0.030 and p=0.003, respectively) and CSA (p=0.047 and p=0.014, respectively) in comparison with RPZ and non-PPI-combined treatment. There were no significant differences in the mean CSA blood concentration two hours after administration in patients with or without PPI treatment, in the incidence of adverse events, or in the CYP2C19 gene polymorphism status among the three groups. Conclusion Combining agents that are mainly metabolized by CYP3A4 such as LPZ elevates the blood concentrations of TAC and CSA, which could leading to adverse events.

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Optimal Dose and Target Trough Level in Cyclosporine and Tacrolimus Conversion in Renal Transplantation as Evaluated by Lymphocyte Drug Sensitivity and Pharmacokinetic Parameters

Cited by 23 publications

References 4 publications

Efficacy of Oral Treatment With Tacrolimus in the Renal Transplant Model in Cynomolgus Monkeys

Efficacy of Oral Treatment With Tacrolimus in the Renal Transplant Model in Cynomolgus Monkeys

Selective clinical and immune response of the oligoclonal autoreactive T cells in Omenn patients after cyclosporin A treatment

The Proton Pump Inhibitor Lansoprazole, but not Rabeprazole, the Increased Blood Concentrations of Calcineurin Inhibitors in Japanese Patients with Connective Tissue Diseases

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