Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients
Rev. bras. pesqui. méd. biol
; Braz. j. med. biol. res;38(5): 683-694, May 2005. ilus, tab
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| ID: lil-400952
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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 percent and ED50 = 0.48 ± 0.08 mg, r² = 0.94) or concentration (Emax = 78.3 ± 2.9 percent and EC50 = 0.59 ± 0.09 ng/ml, r² = 0.89) vs effect ( percent 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 percent reductions ( about 80 percent) in peripheral lymphocytes are required to achieve best efficacy to prevent acute allograft rejection.
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Índice:
LILACS
Asunto principal:
Glicoles de Propileno
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Linfocitos
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Trasplante de Riñón
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Cicloserina
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Inmunosupresores
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Ácido Micofenólico
Tipo de estudio:
Clinical_trials
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Observational_studies
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Prognostic_studies
Límite:
Adolescent
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Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
Braz J Med Biol Res
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Braz. j. med. biol. res
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Braz. j. med. biol. res. (Online)
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Brazilian journal of medical and biological research
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Brazilian journal of medical and biological research (Impresso)
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Rev. bras. pesqui. méd. biol
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Revista brasileira de pesquisas médicas e biológicas
Asunto de la revista:
BIOLOGIA
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MEDICINA
Año:
2005
Tipo del documento:
Article
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Congress and conference