Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients
Autor(a) principal: | |
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Data de Publicação: | 2005 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
Texto Completo: | http://repositorio.unifesp.br/handle/11600/2515 http://dx.doi.org/10.1590/S0100-879X2005000500005 |
Resumo: | FTY720 is a new and effective immunosuppressive agent, which produces peripheral blood lymphopenia through a lymphocyte homing effect. We investigated the relationship between the dose of FTY720 or blood concentration (pharmacokinetics, PK) and peripheral lymphopenia (pharmacodynamics, PD) in 23 kidney transplant recipients randomized to receive FTY720 (0.25-2.5 mg/day) or mofetil mycophenolate (2 mg/day) in combination with cyclosporine and steroids. FTY720 dose, blood concentrations and lymphocyte counts were determined weekly before and 4 to 12 weeks after transplantation. The effect of PD was calculated as the absolute lymphocyte count or its reductions. PK/PD modeling was used to find the best-fit model. Mean FTY720 concentrations were 0.36 ± 0.05 (0.25 mg), 0.73 ± 0.12 (0.5 mg), 3.26 ± 0.51 (1 mg), and 7.15 ± 1.41 ng/ml (2.5 mg) between 4 and 12 weeks after transplantation. FTY720 PK was linear with dose (r² = 0.98) and showed low inter- and intra-individual variability. FTY720 produced a dose-dependent increase in mean percent reduction of peripheral lymphocyte counts (38 vs 42 vs 56 vs 77, P < 0.01, respectively). The simple Emax model [E = (Emax * C)/(C + EC50)] was the best-fit PK/PD modeling for FTY720 dose (Emax = 87.8 ± 5.3% and ED50 = 0.48 ± 0.08 mg, r² = 0.94) or concentration (Emax = 78.3 ± 2.9% and EC50 = 0.59 ± 0.09 ng/ml, r² = 0.89) vs effect (% reduction in peripheral lymphocytes). FTY720 PK/PD is dose dependent and follows an Emax model (EC50 = 0.5 mg or 0.6 ng/ml). Using lymphopenia as an FTY720 PD surrogate marker, high % reductions (~80%) in peripheral lymphocytes are required to achieve best efficacy to prevent acute allograft rejection. |
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Park, Sung In [UNIFESP]Felipe, Claudia Rosso [UNIFESP]Machado, Paula Goulart Pinheiro [UNIFESP]Garcia, Riberto [UNIFESP]Skerjanec, AndrejSchmouder, RobertTedesco-Silva Junior, Hélio [UNIFESP]Pestana, Jose Osmar Medina [UNIFESP]Universidade Federal de São Paulo (UNIFESP)Novartis Pharmaceuticals2015-06-14T13:31:34Z2015-06-14T13:31:34Z2005-05-01Brazilian Journal of Medical and Biological Research. Associação Brasileira de Divulgação Científica, v. 38, n. 5, p. 683-694, 2005.0100-879Xhttp://repositorio.unifesp.br/handle/11600/2515http://dx.doi.org/10.1590/S0100-879X2005000500005S0100-879X2005000500005.pdfS0100-879X200500050000510.1590/S0100-879X2005000500005WOS:000229605000005FTY720 is a new and effective immunosuppressive agent, which produces peripheral blood lymphopenia through a lymphocyte homing effect. We investigated the relationship between the dose of FTY720 or blood concentration (pharmacokinetics, PK) and peripheral lymphopenia (pharmacodynamics, PD) in 23 kidney transplant recipients randomized to receive FTY720 (0.25-2.5 mg/day) or mofetil mycophenolate (2 mg/day) in combination with cyclosporine and steroids. FTY720 dose, blood concentrations and lymphocyte counts were determined weekly before and 4 to 12 weeks after transplantation. The effect of PD was calculated as the absolute lymphocyte count or its reductions. PK/PD modeling was used to find the best-fit model. Mean FTY720 concentrations were 0.36 ± 0.05 (0.25 mg), 0.73 ± 0.12 (0.5 mg), 3.26 ± 0.51 (1 mg), and 7.15 ± 1.41 ng/ml (2.5 mg) between 4 and 12 weeks after transplantation. FTY720 PK was linear with dose (r² = 0.98) and showed low inter- and intra-individual variability. FTY720 produced a dose-dependent increase in mean percent reduction of peripheral lymphocyte counts (38 vs 42 vs 56 vs 77, P < 0.01, respectively). The simple Emax model [E = (Emax * C)/(C + EC50)] was the best-fit PK/PD modeling for FTY720 dose (Emax = 87.8 ± 5.3% and ED50 = 0.48 ± 0.08 mg, r² = 0.94) or concentration (Emax = 78.3 ± 2.9% and EC50 = 0.59 ± 0.09 ng/ml, r² = 0.89) vs effect (% reduction in peripheral lymphocytes). FTY720 PK/PD is dose dependent and follows an Emax model (EC50 = 0.5 mg or 0.6 ng/ml). Using lymphopenia as an FTY720 PD surrogate marker, high % reductions (~80%) in peripheral lymphocytes are required to achieve best efficacy to prevent acute allograft rejection.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Hospital do Rim e HipertensãoNovartis PharmaceuticalsUNIFESP, EPM, Hospital do Rim e HipertensãoSciELO683-694engAssociação Brasileira de Divulgação CientíficaBrazilian Journal of Medical and Biological ResearchFTY720LymphopeniaPharmacokineticsPharmacodynamicsImmunosuppressionRenal transplantsPharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipientsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESPORIGINALS0100-879X2005000500005.pdfapplication/pdf832532${dspace.ui.url}/bitstream/11600/2515/1/S0100-879X2005000500005.pdf881f100ca1cccba4d09032da9a9995b1MD51open accessTEXTS0100-879X2005000500005.pdf.txtS0100-879X2005000500005.pdf.txtExtracted texttext/plain40220${dspace.ui.url}/bitstream/11600/2515/2/S0100-879X2005000500005.pdf.txt06b29d2c1ac82dcdbcfec9a29d588066MD52open access11600/25152022-11-04 15:08:30.453open accessoai:repositorio.unifesp.br:11600/2515Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestopendoar:34652023-05-25T12:28:55.452306Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.en.fl_str_mv |
Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients |
title |
Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients |
spellingShingle |
Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients Park, Sung In [UNIFESP] FTY720 Lymphopenia Pharmacokinetics Pharmacodynamics Immunosuppression Renal transplants |
title_short |
Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients |
title_full |
Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients |
title_fullStr |
Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients |
title_full_unstemmed |
Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients |
title_sort |
Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients |
author |
Park, Sung In [UNIFESP] |
author_facet |
Park, Sung In [UNIFESP] Felipe, Claudia Rosso [UNIFESP] Machado, Paula Goulart Pinheiro [UNIFESP] Garcia, Riberto [UNIFESP] Skerjanec, Andrej Schmouder, Robert Tedesco-Silva Junior, Hélio [UNIFESP] Pestana, Jose Osmar Medina [UNIFESP] |
author_role |
author |
author2 |
Felipe, Claudia Rosso [UNIFESP] Machado, Paula Goulart Pinheiro [UNIFESP] Garcia, Riberto [UNIFESP] Skerjanec, Andrej Schmouder, Robert Tedesco-Silva Junior, Hélio [UNIFESP] Pestana, Jose Osmar Medina [UNIFESP] |
author2_role |
author author author author author author author |
dc.contributor.institution.none.fl_str_mv |
Universidade Federal de São Paulo (UNIFESP) Novartis Pharmaceuticals |
dc.contributor.author.fl_str_mv |
Park, Sung In [UNIFESP] Felipe, Claudia Rosso [UNIFESP] Machado, Paula Goulart Pinheiro [UNIFESP] Garcia, Riberto [UNIFESP] Skerjanec, Andrej Schmouder, Robert Tedesco-Silva Junior, Hélio [UNIFESP] Pestana, Jose Osmar Medina [UNIFESP] |
dc.subject.eng.fl_str_mv |
FTY720 Lymphopenia Pharmacokinetics Pharmacodynamics Immunosuppression Renal transplants |
topic |
FTY720 Lymphopenia Pharmacokinetics Pharmacodynamics Immunosuppression Renal transplants |
description |
FTY720 is a new and effective immunosuppressive agent, which produces peripheral blood lymphopenia through a lymphocyte homing effect. We investigated the relationship between the dose of FTY720 or blood concentration (pharmacokinetics, PK) and peripheral lymphopenia (pharmacodynamics, PD) in 23 kidney transplant recipients randomized to receive FTY720 (0.25-2.5 mg/day) or mofetil mycophenolate (2 mg/day) in combination with cyclosporine and steroids. FTY720 dose, blood concentrations and lymphocyte counts were determined weekly before and 4 to 12 weeks after transplantation. The effect of PD was calculated as the absolute lymphocyte count or its reductions. PK/PD modeling was used to find the best-fit model. Mean FTY720 concentrations were 0.36 ± 0.05 (0.25 mg), 0.73 ± 0.12 (0.5 mg), 3.26 ± 0.51 (1 mg), and 7.15 ± 1.41 ng/ml (2.5 mg) between 4 and 12 weeks after transplantation. FTY720 PK was linear with dose (r² = 0.98) and showed low inter- and intra-individual variability. FTY720 produced a dose-dependent increase in mean percent reduction of peripheral lymphocyte counts (38 vs 42 vs 56 vs 77, P < 0.01, respectively). The simple Emax model [E = (Emax * C)/(C + EC50)] was the best-fit PK/PD modeling for FTY720 dose (Emax = 87.8 ± 5.3% and ED50 = 0.48 ± 0.08 mg, r² = 0.94) or concentration (Emax = 78.3 ± 2.9% and EC50 = 0.59 ± 0.09 ng/ml, r² = 0.89) vs effect (% reduction in peripheral lymphocytes). FTY720 PK/PD is dose dependent and follows an Emax model (EC50 = 0.5 mg or 0.6 ng/ml). Using lymphopenia as an FTY720 PD surrogate marker, high % reductions (~80%) in peripheral lymphocytes are required to achieve best efficacy to prevent acute allograft rejection. |
publishDate |
2005 |
dc.date.issued.fl_str_mv |
2005-05-01 |
dc.date.accessioned.fl_str_mv |
2015-06-14T13:31:34Z |
dc.date.available.fl_str_mv |
2015-06-14T13:31:34Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
Brazilian Journal of Medical and Biological Research. Associação Brasileira de Divulgação Científica, v. 38, n. 5, p. 683-694, 2005. |
dc.identifier.uri.fl_str_mv |
http://repositorio.unifesp.br/handle/11600/2515 http://dx.doi.org/10.1590/S0100-879X2005000500005 |
dc.identifier.issn.none.fl_str_mv |
0100-879X |
dc.identifier.file.none.fl_str_mv |
S0100-879X2005000500005.pdf |
dc.identifier.scielo.none.fl_str_mv |
S0100-879X2005000500005 |
dc.identifier.doi.none.fl_str_mv |
10.1590/S0100-879X2005000500005 |
dc.identifier.wos.none.fl_str_mv |
WOS:000229605000005 |
identifier_str_mv |
Brazilian Journal of Medical and Biological Research. Associação Brasileira de Divulgação Científica, v. 38, n. 5, p. 683-694, 2005. 0100-879X S0100-879X2005000500005.pdf S0100-879X2005000500005 10.1590/S0100-879X2005000500005 WOS:000229605000005 |
url |
http://repositorio.unifesp.br/handle/11600/2515 http://dx.doi.org/10.1590/S0100-879X2005000500005 |
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eng |
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Brazilian Journal of Medical and Biological Research |
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openAccess |
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683-694 |
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Associação Brasileira de Divulgação Científica |
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Associação Brasileira de Divulgação Científica |
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