Optimizing the use of cyclosporin in allogeneic stem cell transplantation

Duncan, Nick; Craddock, Charles

doi:10.1038/sj.bmt.1705404

Cited by 40 publications

(55 citation statements)

References 50 publications

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“…This therapeutic range was not adjusted specifically for HSCT recipients and/or for time after transplantation, as no reliable reference range exists for this group of patients. 23,24 Causality assessment Causality for each ADE, caused directly by a drug or indirectly through a pDDI, was assessed according to the WHO Uppsala Monitoring Centre causality assessment system. 25 An ADE was classified as unlikely if the temporal relationship was not clear and if there were other more likely reasons explaining the ADE observed.…”

Section: Evaluation Of Adesmentioning

confidence: 99%

Drug interactions and adverse events associated with antimycotic drugs used for invasive aspergillosis in hematopoietic SCT

Egger

Meier

Leu

et al. 2009

Bone Marrow Transplant

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The aim of this study was to assess the frequency of potential drug-drug interactions (pDDIs) and adverse drug events (ADEs) associated with antimycotics in hospitalized patients with hematopoietic SCT (HSCT). Of the 120 HSCT recipients evaluated, 36 received antimycotics. A total of 124 ADEs were recorded in 32 of the 36 patients treated, with 54 ADEs being possibly and 9 probably related to antimycotics. Of the treatments with amphotericin B, 93% were associated with one or more possible and 36% with probable ADEs. The corresponding figures for lipid-based amphotericin B were 100% and 7%, for voriconazole 68% and 11% and for caspofungin 70% and 0%. A total of 57 potentially severe DDIs associated with antimycotics were detected in 31 of the 36 patients. Of these, 14 DDIs were a possible cause of an ADE and 5 (4 times a combination of voriconazole with CYA and once a combination of CYA with conventional amphotericin B) were probably related. Although the prevalence of pDDIs and ADEs is high in HSCT patients, ADEs related with a high probability to treatment with antimycotics are rare. Regarding the high prevalence of pDDIs, our findings underscore the importance of close monitoring of laboratory and clinical parameters, as well as dose adjustment for critical drugs, in patients with HSCT.

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Section: Evaluation Of Adesmentioning

confidence: 99%

Drug interactions and adverse events associated with antimycotic drugs used for invasive aspergillosis in hematopoietic SCT

Egger

Meier

Leu

et al. 2009

Bone Marrow Transplant

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“…The most commonly used prophylactic immunosuppressive agent in HSCT is ciclosporin (cyclosporin A, CsA) [3,4]. The pharmacodynamics and pharmacokinetics of CsA are complex and, as a result, drug exposure is difficult to predict.…”

Section: Introductionmentioning

confidence: 99%

“…In all, insufficient post transplant immunosuppression is one of the most important determinants of relapse risk through its impact on the potency of an immunologically mediated graft vs. malignancy effect. This is particularly relevant in patients undergoing allogeneic HSCT using a reduced-intensity conditioning regimen, where a graft vs. malignancy effect represents the dominant anti-tumour mechanism [4,[17][18][19][20][21][22]. Therefore, a model that predicts ciclosporin pharmacokinetics and dose requirements to achieve the desired therapeutic target in an individual HSCT patient would be highly useful.…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy

Wilhelm¹,

Graaf²,

Veldkamp³

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The population pharmacokinetics and limited sampling strategies for ciclosporin monitoring have been extensively studied in renal and liver transplant recipients. Little is known about the pharmacokinetics of ciclosporin in patients undergoing haematopoietic allogeneic stem cell transplantation (HSCT).• It is anticipated that there is a difference in pharmacokinetics in patients after kidney or liver transplantation compared with patients undergoing stem cell transplantation, because of mucositis and interacting drugs (e.g. fluconazole).• Data on the pharmacokinetics of ciclosporin and the relationship between its systemic exposure, as reflected by the area under the curve (AUC), and the biological effect as graft vs. host-disease (GVHD) prophylaxis and graft vs. tumour (GVT) response are scarce in patients after HSCT. WHAT THIS STUDY ADDS• A pharmacokinetic model was developed for orally and intravenously administered ciclosporin, enabling an adequate estimate of the systemic exposure of ciclosporin in patients after HSCT. A limited sampling strategy was tested that may serve as a tool to study the optimum systemic exposure (AUC) of ciclosporin in HSCT to prevent GVHD but establish adequate GVT response and to guide therapeutic drug monitoring. AIMTo develop a population pharmacokinetic model of ciclosporin (CsA) in haematopoietic allogeneic stem cell transplantation to facilitate a limited sampling strategy to determine systemic exposure (area under the curve [AUC]), in order to optimize CsA therapy in this patient population. METHODSThe pharmacokinetics of CsA were investigated prospectively in 20 patients following allogeneic haematopoietic stem cell transplantation (HSCT). CsA was given twice daily, as a 3 h i.v. infusion starting at day 1 of the conditioning scheme, and orally later on, when oral intake was well tolerated. Fluconazole was given as antimycotic prophylaxis. Pharmacokinetic parameter estimation was performed using nonlinear mixed effect modelling as implemented in the NONMEM program. A first order absorption model with lag time was compared with Erlang frequency distribution and Weibull distribution models. The influence of demographic variables on the individual empirical Bayesian estimates of clearance and distribution volume was tested. Subsequently two limited sampling strategies (LSS) were evaluated: posterior Bayesian fitting and limited sampling equations. RESULTSTwenty patients were included and 435 samples were collected after i.v. and oral administration of CsA. A two compartment model with first order absorption best described the data. Clearance (CL) was 21.9 l h -1 (relative standard deviation [RSD] Ϯ 5.2%) with an inter-individual variability of 21%. The central volume of distribution (Vc) was 18.3 l (RSD Ϯ 8.7%) with an inter-individual variability of 29%. Bioavailability (F) was 0.71 (RSD Ϯ 9.9%) with and inter-individual variability of 25% and lag time (tlag) was 0.44 h (RSD 5.5%). Weight, body surface area, haematocrit, albumin, ALAT...

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“…CsA is currently a cornerstone for the treatment and/or prevention of GVHD. 16 Unexpectedly, we found that Lig IV À/À human pre-B lymphocytes were selectively sensitive to killing by CsA (Figure 2a). Similarly, when CsA was used in combination with BU and FluD, we found that the LigIV À/À pre-B lymphocytes were more sensitive than their WT counterparts (Figure 2b).…”

Section: Resultsmentioning

confidence: 94%

“…CsA is a widely used prophylaxis for GVHD, which represents a significant post transplantation complication. 15,16 CsA binds to the cyclophilin class of proteins that can then function as an inhibitor of calcineurin, a serine-threonine phosphatase (also called PP2B). CsA's utility as an immunosuppressive agent is thought to derive from its ability to prevent nuclear localization of transcription factor NFAT (nuclear transcription factor in activated T cells).…”

Section: Introductionmentioning

confidence: 99%

CsA can induce DNA double-strand breaks: implications for BMT regimens particularly for individuals with defective DNA repair

O’Driscoll

Jeggo

2008

Bone Marrow Transplant

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Optimizing the use of cyclosporin in allogeneic stem cell transplantation

Cited by 40 publications

References 50 publications

Drug interactions and adverse events associated with antimycotic drugs used for invasive aspergillosis in hematopoietic SCT

Drug interactions and adverse events associated with antimycotic drugs used for invasive aspergillosis in hematopoietic SCT

Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy

CsA can induce DNA double-strand breaks: implications for BMT regimens particularly for individuals with defective DNA repair

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