Pharmacokinetics and pharmacodynamics of SB-240563, a humanized monoclonalantibody directed to human interleukin-5, in monkeys

The pharmacokinetics (PK) of SB-240563 have been investigated after i.v. an d s.c. administration to cynomolgus monkeys. Approximately linear PK was ob served 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 biexponent ial manner with a mean terminal half-life of 13 +/- 2 days. The plasma clea rance and volume of distribution at steady state were similar to 0.2 ml/h/k g 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-2405 63. The maximal response (81-96% decrease in eosinophil count relative to b aseline) following a single s.c. administration occurred at 3 weeks postdos ing. Suppression of eosinophil count also was observed following multiple m onthly administrations of SB-240563 to monkeys. The pharmacokinetic/pharmac odynamic relationship was generally well described with an indirect pharmac ologic response model with an estimated IC50 value of 1.43 mu g/ml. The com bination of a low IC50 value for reduction of circulating eosinophils and a long terminal half-life suggests the possibility of an infrequent dosing r egimen for SB-240563 for treatment of diseases associated with increased eo sinophil function such as asthma.