Links Between Cyclosporin Exposure in Tissues and Graft-Versus-Host Disease in Pediatric Bone Marrow Transplantation: Analysis by a PBPK Model

Gérard, Christophe; Bleyzac, Nathalie; Girard, Pascal; Bertrand, Yves; Tod, Michel

doi:10.1007/s11095-010-0299-z

Cited by 13 publications

(11 citation statements)

References 25 publications

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“…Several investigators have reported cyclosporine AUC in HSCT patients after i.v. administration [3,[10][11][12][13][14][16][17][18][19]26,27]. The method used to calculate or estimate cyclosporine AUC was not described in some of these reports [13], and serum rather than whole blood concentrations (the accepted standard matrix) were reported in another [10].…”

Section: Discussionmentioning

confidence: 99%

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Prediction of Area under the Cyclosporine Concentration Versus Time Curve in Children Undergoing Hematopoietic Stem Cell Transplantation

Dupuis¹,

Seto²,

Teuffel³

et al. 2013

Biology of Blood and Marrow Transplantation

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This prospective study aimed to validate a previously developed first-dose limited sampling strategy (LSS) to predict the area under the cyclosporine concentration-versus-time curve (AUC) and to develop and then validate an LSS to predict cyclosporine AUC at steady state. This two-center Canadian study included children (ages .4 to 17.2 years) undergoing myeloablative allogeneic hematopoietic stem cell transplantation receiving cyclosporine for acute graft-versus-host disease prophylaxis. There were three cohorts, each incorporating 24 AUC determinations: first-dose LSS validation, steady-state LSS development, and steady-state LSS validation. Patients contributing data to either of the development cohorts were excluded from the corresponding validation group. Cyclosporine was given every 12 hours as a 2-hour infusion. Cyclosporine AUC was determined after administration of the first cyclosporine dose (8 samples) and then once weekly (9 samples) until engraftment. Steady-state LSSs were developed using stepwise multiple linear regression. An LSS was considered to provide an acceptable estimate of AUC if the lower limit of the 95% confidence limit (CL) of the intraclass coefficient was .8 or higher and both bias and precision were 15% or less. Fifty-three children age .4 to 18 years participated. Cyclosporine concentrations drawn up to 4 hours from the start of the infusion correlated most strongly with AUC. The previously developed first-dose LSSs and three steady-state LSSs met criteria for acceptability. The intraclass coefficients of the three-point first-dose LSS validation cohort, three-point steady-state LSS development cohort, and three-point steady-state LSS validation cohort were .974 (95% CL: .941 to .988), .984 (95% CL: .965 to .993), and .993 (95% CL: .984 to .997), respectively. The three-point first-dose (2, 6, and 8 hours) and steady-state (2, 2.5, and 8 hours) LSSs are valid measures of cyclosporine AUC after intravenous administration over 2 hours. Their use in a prospective evaluation of the relationship between cyclosporine AUC and hematopoietic stem cell transplantation clinical outcomes in children is suggested.

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Section: Discussionmentioning

confidence: 99%

“…The relationship between cyclosporine AUC after i.v. administration and HSCT outcomes such as aGVHD is just beginning to be explored [11,13,[17][18][19]26,27]. Among these are 2 pediatric studies.…”

Section: Discussionmentioning

confidence: 99%

Prediction of Area under the Cyclosporine Concentration Versus Time Curve in Children Undergoing Hematopoietic Stem Cell Transplantation

Dupuis¹,

Seto²,

Teuffel³

et al. 2013

Biology of Blood and Marrow Transplantation

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“…Early post-transplantation exposure to CsA has been related to acute GvHD (aGvHD) severity. [8][9][10] It is now generally agreed that CsA trough blood concentration (TBC) is the pharmacokinetic parameter that best correlates with GvHD outcome. 11,12 Nevertheless, there are no data regarding specific values of CsA TBC to target to favor mild aGvHD without increasing the incidence of severe GvHD.…”

Section: Introductionmentioning

confidence: 99%

Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis

Bleyzac

Cuzzubbo

Rénard

et al. 2016

Bone Marrow Transplant

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There is currently a major concern regarding the optimal immunosuppression therapy to be administered after hematopoietic stem cell transplantation (HSCT) to reduce both the toxicity of GvHD and the rate of relapse. We report the outcome of high-risk leukemia children transplanted with a new way of managing cyclosporine (CsA)-based GvHD prophylaxis. A total of 110 HSCT in 109 ALL or AML children who received CsA without mycophenolate or methotrexate in matched related as well as in matched or mismatched unrelated stem cell transplantation were included. CsA dosage regimens were individualized to obtain specific trough blood concentrations values. The incidences of grade I-II and III-IV acute GvHD were 69.1% and 1.8%, respectively, and 8.4% for chronic GvHD. GvHD was neither more frequent nor severe in unrelated than in related HSCT. GvHD occurred in 87% of patients with a mean CsA trough concentration ⩽ 120 ng/mL versus 43% with concentration 4120 ng/mL (Po 0.0001). Five-year disease-free survival (DFS) and overall survival were 78% and 83.6%, respectively. DFS was 76.9% for ALL and 80.4% for AML patients. There was no difference in DFS between matched siblings and matched unrelated or mismatched unrelated HSCT. DFS in patients with minimal residual disease (MRD) ⩾ 10 − 3 and in those with MRD o 10 − 3 before SCT was comparable. Our results indicate that a GvHD prophylaxis regimen based on CsA without mycophenolate or methotrexate is safe and effective whatever the donor compatibility is. These results suggest that GvL effect may be enhanced by this strategy of GvHD prophylaxis.

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“…158 Shortly thereafter, the association of cyclosporine trough concentrations with renal dysfunction 159 and GVHD risk were reported. 160–162 TCI of cyclosporine trough concentrations was rapidly adopted and is still used for both cyclosporine and tacrolimus. 161,163 Since then, only TCI of the whole blood trough concentrations of sirolimus has been adopted.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II

Bemer

Long‐Boyle

2015

Clin Pharmacokinet

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Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of the calcineurin inhibitors and methotrexate. In this article, part II, we review the pharmacokinetics, pharmacodynamics, and pharmacogenomics of mycophenolic acid (MPA), sirolimus, and the antithymocyte globulins (ATG). We then discuss target concentration intervention (TCI) of these postgraft immunosuppressants in alloHCT patients, with a focus on current evidence for TCI and on how TCI may improve clinical management in these patients. Currently, TCI using trough concentrations is conducted for sirolimus in alloHCT patients. There are several studies demonstrating that MPA plasma exposure is associated with clinical outcomes, with an increasing number of alloHCT patients needing TCI of MPA. Compared to MPA, there are fewer pharmacokinetic/dynamic studies of rabbit ATG and horse ATG in alloHCT patients. Future pharmacokinetic/dynamic research of postgraft immunosuppressants should include “–omics” based tools: pharmacogenomics may be used to gain an improved understanding of the covariates influencing pharmacokinetics and proteomics and metabolomics as novel methods to elucidate pharmacodynamic responses.

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Links Between Cyclosporin Exposure in Tissues and Graft-Versus-Host Disease in Pediatric Bone Marrow Transplantation: Analysis by a PBPK Model

Abstract: Hence, AUC in blood maybe used as an index of cyclosporin efficacy. Using our model, target AUCs in blood could be defined for malignant and non-malignant diseases, as well as the equivalent target values for C(2) and C(0) concentrations.

Cited by 13 publications

References 25 publications

Prediction of Area under the Cyclosporine Concentration Versus Time Curve in Children Undergoing Hematopoietic Stem Cell Transplantation

Prediction of Area under the Cyclosporine Concentration Versus Time Curve in Children Undergoing Hematopoietic Stem Cell Transplantation

Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis

Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II

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