The pharmacokinetics of equoral versus neoral in stable renal transplant patients: a multinational multicenter study

Masri, Marwan; Haberal, Mehmet; Rizvi, A; Stephan, A; Bi̇lgi̇n, N; Naqvi, Anwar; Barbari, A; Kamel, G; Zafar, N.; Emiroğlu, R; Colak, T.; Manzoor, K.; Matha, V.; Kamarád, V; Rizk, S; Itany, A.R; Shehedeh, I

doi:10.1016/j.transproceed.2003.11.007

Cited by 21 publications

(15 citation statements)

References 6 publications

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“…CsA at 500 ng/ml was reported to be the optimum concentration for EBV transformation of human B cells [7]. The concentration of 500 ng/ml of CsA is well within the target blood concentration range of 400-750 ng/ml in organ transplant recipients [22,23]. A recent publication indicated that continuous CsA infusion with a target blood level of 450-550 ng/ml is acceptably safe, and significantly prevented the acute graft-versus-host disease compared to that with lower CsA blood levels [24].…”

Section: Discussionmentioning

confidence: 96%

Cyclosporin A-Induced Lipid and Protein Oxidation in Human B-Cells and in Epstein-Barr Virus-Infected B-Cells is Prevented by Antioxidants

Chen

Jeon

Johnston

et al. 2008

Journal of Investigative Surgery

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The incidence of post-transplant lymphoproliferative disorder (PTLD) has increased since cyclosporin A (CsA) became the mainstay of transplant immunosuppression. We have previously shown that, in addition to its potent immunosuppressive property, CsA-induced oxidative stress plays an important role in Epstein-Barr virus (EBV)-related PTLD. Using lipid hydroperoxide and malondialdehyde as markers of lipid oxidation, and protein carbonyls as markers of protein oxidation, we further investigated the in vitro effect of CsA on human B cells and EBV-infected human B cells. We found that CsA at 500 ng/ml, a relatively safe and effective blood concentration in organ transplant recipients, induced the highest lipid hydroperoxide and malondialdehyde after 10 min of treatment in time- and concentration-related kinetic studies. We also found that treatment with CsA at 500 ng/ml for 10 min increased the EBV-infected B cell protein carbonyl formation as assayed by immunoblot method. CsA-induced lipid and protein oxidation could be inhibited by vitamin E, N-acetyl cysteine, and pyrollidine dithiocarbamate. CsA significantly promoted the EBV-B cell transformation as assayed by colony counting, cell counting, and (3)H-thymidine incorporation. Our recent study provides further evidence to support the hypothesis that CsA exerts direct oxidative stress in EBV-infected as well as non-EBV-infected human B cells. A greater understanding of these cellular and molecular mechanisms may benefit the clinical practice and prevention of PTLD.

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Section: Discussionmentioning

confidence: 96%

Cyclosporin A-Induced Lipid and Protein Oxidation in Human B-Cells and in Epstein-Barr Virus-Infected B-Cells is Prevented by Antioxidants

Chen

Jeon

Johnston

et al. 2008

Journal of Investigative Surgery

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“…Since then, other companies are free to manufacture interchangeable generic products. Up to now, several generic CsA formulations have been developed [24][25][26][27][28][29][30][31], and most of them have recently become available in Europe. They demonstrate bioequivalence criteria according to the current regulations [32].…”

Section: The Advent Of Novel Csa Generic Formulationsmentioning

confidence: 99%

“…Moreover, since the patient pool is not homogeneous, for critical drugs like CsA, close monitoring is required when different formulations are switched each others. Equoral (IVAX-CR, Opava, Czech Republic), is a new formulation tested as bioequivalent to CsA Neoral in 12 healthy volunteers [30] and recently confirmed as clinically bioequivalent in 15 stable renal transplant patients switched from Neoral capsules to Equoral capsules [31]. It should be pointed out, however, that bioequivalence studies should be conducted with a large number of subjects, usually 20-40 [42].…”

Section: The Advent Of Novel Csa Generic Formulationsmentioning

confidence: 99%

Generic cyclosporine formulations: more open questions than answers

Cattaneo¹,

Perico²

2005

Transplant Int

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Summary The introduction of cyclosporine (CsA) in clinical practice has significantly improved patient and allograft survival after organ transplantation. The new microemulsion CsA formulation, Neoral, has been associated with a more reproducible absorption and a better patient outcome as compared to the old formulation Sandimmune. Recently, several generic CsA formulations have been tested as bioequivalent to Neoral. Bioequivalence tests have been performed in selected groups of young, healthy male volunteers usually in single‐dose studies, and then extended to completely different population, such as transplant recipients. However, growing body of evidence shows that CsA pharmacokinetics in healthy subjects is different from that of transplant patients, treated chronically with CsA. Therefore, converting patients from Neoral to the new generic formulations could be detrimental, exposing patients to increased risk of graft function deterioration and graft loss. Thus, more research and more accurate bioequivalence tests are required to address the unanswered problems dealing with the generic CsA formulations.

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“…5 In that study, the authors reported a higher rejection rate among Equoral users compared with users of the innovator drug. 5 On the basis of published pharmacokinetic data on healthy individuals 6 and on de novo 7 and long-term transplant patients, 8,9 it is hard to corroborate that the high rejection rate in that uncontrolled and flawed trial is related to the generic CsA Equoral. In summary, considering the comparable CsA dose and the comparable CsA trough levels of both cyclosporine formulations in our study, the data presented here support the assumption that both are interchangeable.…”

Section: Discussionmentioning

confidence: 99%

Maintenance immunosuppressive therapy and generic cyclosporine A use in adult renal transplantation: a single center analysis

Diarra

Riegersperger

Säemann

et al. 2010

Kidney International

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At present, solid organ transplantation relies on chronic immunosuppression. Calcineurin inhibitors (CNIs) still remain one of the most important components in current immunosuppressive regimens. However, life-long immunosuppression of transplant recipients is associated with high costs for the individual, health-care systems, and society. Hence, there is an urgent need of generic drugs that have the potential to exert equivalent therapeutic efficacy at a lower cost. Here, we report our findings of the conversion of 59 stable long-term kidney graft recipients from cyclosporine A (CsA) Neoral to CsA Neoimmun/Equoral. All patients displayed a continuous stable graft function after conversion for a follow-up period of 6 months, and no major side effects associated with the use of CsA Neoimmun/Equoral were observed. Also, CsA dose and trough levels did not differ after conversion to CsA Neoimmun/Equoral. These data indicate that conversion of long-term kidney graft recipients from CsA Neoral to CsA Neoimmun/Equoral is safe and effective, making this specific CsA generic a viable option for CNI therapy in stable renal transplant patients.

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The pharmacokinetics of equoral versus neoral in stable renal transplant patients: a multinational multicenter study

Cited by 21 publications

References 6 publications

Cyclosporin A-Induced Lipid and Protein Oxidation in Human B-Cells and in Epstein-Barr Virus-Infected B-Cells is Prevented by Antioxidants

Cyclosporin A-Induced Lipid and Protein Oxidation in Human B-Cells and in Epstein-Barr Virus-Infected B-Cells is Prevented by Antioxidants

Generic cyclosporine formulations: more open questions than answers

Maintenance immunosuppressive therapy and generic cyclosporine A use in adult renal transplantation: a single center analysis

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