Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients
Braz. j. med. biol. res
;
38(5): 683-694, May 2005. ilus, tab
Article
Dans Anglais
| LILACS
| ID: lil-400952
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.
Texte intégral:
Disponible
Indice:
LILAS (Amériques)
Sujet Principal:
Propylène glycols
/
Lymphocytes
/
Transplantation rénale
/
Cyclosérine
/
Immunosuppresseurs
/
Acide mycophénolique
Type d'étude:
Essai clinique contrôlé
/
Étude observationnelle
/
Étude pronostique
Limites du sujet:
Adolescent
/
Adulte
/
Femelle
/
Humains
/
Mâle
langue:
Anglais
Texte intégral:
Braz. j. med. biol. res
Thème du journal:
Biologie
/
Médicament
Année:
2005
Type:
Article
/
Congrès et conférence
Pays d'affiliation:
Brésil
/
États-Unis d'Amérique
Institution/Pays d'affiliation:
Novartis Pharmaceuticals/US
/
Universidade Federal de São Paulo/BR
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