Safety and Tolerability of Cyclosporine and Cyclosporine Microemulsion During 18 Months of Follow-Up in Stable Renal Transplant Recipients

Cole, Edward; Keown, Paul; Landsberg, David; Halloran, Philip F.; Shoker, Ahmed; Rush, D.; Jeffrey, John; Russell, David; Stiller, C; Muirhead, Norman; Paul, Leen; Zaltzman, Jeffrey S.; Loertscher, Rolf; Daloze, P; Dandavino, R; Boucher, Anne; Handa, Paul; Lawen, Joseph; Belitsky, P; Parfrey, Patrick; Tan, Annette; Hendricks, Lisa Anne

doi:10.1097/00007890-199802270-00009

Cited by 63 publications

(20 citation statements)

References 6 publications

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“…4 In addition, it has been described that the maximal pharmacodynamic response, as measured by inhibition of calcineurin activity, coincides with the peak concentration B2 h after dose intake. 19 This indicates that monitoring the AUC or a concentration 2 h after CsA dose intake (C2) could be a better indicator of drug exposure than trough levels. In fact, a study in solid organ transplantation shows a relationship between C2 and graft rejection.…”

Section: Discussionmentioning

confidence: 99%

CsA exposure is associated with acute GVHD and relapse in children after SCT

Willemze

Press

Lankester

et al. 2009

Bone Marrow Transplant

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CsA is commonly used after haematological SCT (HSCT) as GVHD prophylaxis. In solid organ transplantation, area under the blood concentration vs time curve (AUC) correlates with clinical outcome. However, in HSCT, it has not been determined whether the AUC is superior to trough level monitoring to optimize clinical efficacy of CsA therapy. Therefore, the aim of this study was to investigate the relationships between CsA trough levels and/or AUC early after HSCT with clinical outcome. A total of 91 children (1.1-17.3 years) were treated consecutively with HSCT for a haematological malignancy. CsA trough levels were obtained and were used to estimate the AUC, retrospectively, with a NONMEM (Non-Linear Mixed Effects Modelling) method. Subsequently, these exposure parameters were correlated to the occurrence of acute GVHD, relapse risk (RR) and OS. Low CsA trough levels were found to correlate with the occurrence of acute GVHD. In addition, a CsA AUC over 3000 mcg h/l in AML patients was associated with a higher RR and a reduced OS. This was not the case for ALL patients. Thus, monitoring CsA exposure early after HSCT and adjusting the CsA dose to a predefined target trough level and AUC may provide a tool to influence GVHD/GVL balance.

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Section: Discussionmentioning

confidence: 99%

CsA exposure is associated with acute GVHD and relapse in children after SCT

Willemze

Press

Lankester

et al. 2009

Bone Marrow Transplant

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“…At 18 months no significant differences with regard to the incidence of neurological adverse events were observed. The incidences of specific adverse events for the respective groups CsA-ME vs CsA were headache: 19% vs 17.4 YO, paresthesia 4.9 Yo vs 3.7 Yo and tremor 2.7 % vs 2.0 % [16]. Nevertheless, one may cautiously interpret these data in the way that improved bioavailability of cyclosporine is accompanied by a tendency, albeit it not significant of increased neurological adverse events.…”

Section: Overview Of Csa-associated Neurotoxicitymentioning

confidence: 90%

“…Probably the best data available on neurotoxicity in renal transplant patients were obtained by the Canadian Neoral Renal Study Group [16]. A total of 1097 patients were entered into a randomized trial, 356 continued treatment with a conventional formulation of cyclosporin (CsA), while 737 were randomized to receive Neoral (CsA-ME), the microemulsion form of cyclosporine with increased bioavailability.…”

Section: Overview Of Csa-associated Neurotoxicitymentioning

confidence: 99%

Neurotoxicity of calcineurin inhibitors: impact and clinical management

Bechstein¹

2000

Transplant Int

476

284

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Between 10 %-28 % of patients who receive the immunosuppressant cyclosporine (CsA) experience some form of neurotoxic adverse event. Both sensorial motoric functions may be adversely affected, and thus patients present with a wide range of neurological and psychiatrical disorders. Mild symptoms are common and include tremor, neuralgia, and peripheral neuropathy. Severe symptoms affect up to 5 % of patients and include psychoses, hallucinations, blindness, seizures, cerebellar ataxia, motoric weakness, or leukoencephalopathy.

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“…4 This is particularly important in this group of patients who very often have problems of intestinal absorption. The aim of our study was to determine the optimal initial dose of oral Neoral after intravenous infusion of CsA in allogeneic bone marrow transplant recipients.…”

mentioning

confidence: 99%

New oral formulation of cyclosporin A (Neoral) pharmacokinetics in allogeneic bone marrow transplant recipients

Parquet

Reigneau

Humbert

et al. 2000

Bone Marrow Transplant

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Summary:Cyclosporin A (CsA) absorption is variable in bone marrow transplant (BMT) patients compromising the efficacy of graft-versus-host disease prevention. Neoral, a new microemulsion formulation of CsA which has an improved bioavailibility, increases intestinal absorption of the drug with less variable pharmacokinetic parameters in non-BMT patients. In order to predict the best dosage of Neoral when patients are switched from i.v. to oral administration we performed a randomised study comparing two oral doses, either the same or twice the last i.v. dose used after BMT. Fourteen adults were randomised around day 25 after BMT. Whole blood CSA concentrations were measured 2 and 12 h after the oral administration of Neoral on days 0, 7 and 14 to determine residual and maximum concentration, and modified whenever necessary to maintain blood level CsA concentration within therapeutic range (150-250 ng/ml). We found that patients who received twice the last i.v. dose had better concentrations than patients from the other group while toxicity was identical in both groups. We conclude that doubling the last i.v. dose during the switch to oral administration of Neoral gives the best therapeutic range concentration and should be recommended for graft-versus-host prevention. Bone Marrow Transplantation (2000) 25, 965-968. Keywords: bone marrow transplantation; cyclosporin A; pharmacokineticsIn an attempt to improve the bioavailibility of oral cyclosporin A (CsA) and to reduce variability in absorption, a new microemulsion formulation of CsA has been developed (Neoral).Pharmacokinetic studies conducted in healthy volunteers and renal, liver and cardiac transplant recipients have consistently demonstrated that absorption was increased by an average of 30% in the area-under-the-curve and was faster after Neoral than after Sandimmun. This results in an increased bioavailibility, a lower dependency on food, bile or pancreatic enzymes and a markedly reduced variability

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Safety and Tolerability of Cyclosporine and Cyclosporine Microemulsion During 18 Months of Follow-Up in Stable Renal Transplant Recipients

Abstract: Tolerance to CsA and CsA-ME was similar. Renal function over 18 months was not adversely affected by the increased drug exposure with CsA-ME, although there was a transient increase in nephrotoxicity. The frequency of acute and chronic rejection did not change.

Cited by 63 publications

References 6 publications

CsA exposure is associated with acute GVHD and relapse in children after SCT

CsA exposure is associated with acute GVHD and relapse in children after SCT

Neurotoxicity of calcineurin inhibitors: impact and clinical management

New oral formulation of cyclosporin A (Neoral) pharmacokinetics in allogeneic bone marrow transplant recipients

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