Pharmacokinetics and pharmacodynamics of SB-240563, a humanized monoclonal antibody directed to human interleukin-5, in monkeys.
The pharmacokinetics (PK) of SB-240563 have been investigated after i.v. and s.c. administration to cynomolgus monkeys. Approximately linear PK was observed following i.v. administration over a 6000-fold dose range (0.05-300 mg/kg). After i.v. dosing, SB-240563 concentration declined in a biexponential manner with a mean terminal half-life of 13 +/- 2 days. The plasma clearance and volume of distribution at steady state were approximately 0.2 ml/h/kg and 70 ml/kg, respectively. Following s.c. administration, SB-240563 was completely absorbed into the systemic circulation. Because interleukin-5 is known to stimulate production, activation, and maturation of eosinophils, eosinophil counts were measured to assess pharmacologic activity of SB-240563. The maximal response (81-96% decrease in eosinophil count relative to baseline) following a single s.c. administration occurred at 3 weeks postdosing. Suppression of eosinophil count also was observed following multiple monthly administrations of SB-240563 to monkeys. The pharmacokinetic/pharmacodynamic relationship was generally well described with an indirect pharmacologic response model with an estimated IC(50) value of 1.43 microg/ml. The combination of a low IC(50) value for reduction of circulating eosinophils and a long terminal half-life suggests the possibility of an infrequent dosing regimen for SB-240563 for treatment of diseases associated with increased eosinophil function such as asthma.
Zia-Amirhosseini, P; Minthorn, E; Benincosa, LJ; Hart, TK; Hottenstein, CS; Tobia, LA; Davis, CB
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