Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients

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dc.contributor.authorPark, Sung In [UNIFESP]
dc.contributor.authorFelipe, Claudia Rosso [UNIFESP]
dc.contributor.authorMachado, Paula Goulart Pinheiro [UNIFESP]
dc.contributor.authorGarcia, Riberto [UNIFESP]
dc.contributor.authorSkerjanec, Andrej
dc.contributor.authorSchmouder, Robert
dc.contributor.authorTedesco-Silva Junior, Hélio [UNIFESP]
dc.contributor.authorPestana, Jose Osmar Medina [UNIFESP]
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionNovartis Pharmaceuticals
dc.date.accessioned2015-06-14T13:31:34Z
dc.date.available2015-06-14T13:31:34Z
dc.date.issued2005-05-01
dc.description.abstractFTY720 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.en
dc.description.affiliationUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Hospital do Rim e Hipertensão
dc.description.affiliationNovartis Pharmaceuticals
dc.description.affiliationUnifespUNIFESP, EPM, Hospital do Rim e Hipertensão
dc.description.sourceSciELO
dc.format.extent683-694
dc.identifierhttp://dx.doi.org/10.1590/S0100-879X2005000500005
dc.identifier.citationBrazilian Journal of Medical and Biological Research. Associação Brasileira de Divulgação Científica, v. 38, n. 5, p. 683-694, 2005.
dc.identifier.doi10.1590/S0100-879X2005000500005
dc.identifier.fileS0100-879X2005000500005.pdf
dc.identifier.issn0100-879X
dc.identifier.scieloS0100-879X2005000500005
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/2515
dc.identifier.wosWOS:000229605000005
dc.language.isoeng
dc.publisherAssociação Brasileira de Divulgação Científica
dc.relation.ispartofBrazilian Journal of Medical and Biological Research
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectFTY720en
dc.subjectLymphopeniaen
dc.subjectPharmacokineticsen
dc.subjectPharmacodynamicsen
dc.subjectImmunosuppressionen
dc.subjectRenal transplantsen
dc.titlePharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipientsen
dc.typeinfo:eu-repo/semantics/article
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