Vol. 291, Issue 3, 1060-1067, December 1999

Pharmacokinetics and Pharmacodynamics of SB-240563, a Humanized Monoclonal Antibody Directed to Human Interleukin-5, in Monkeys

P. Zia-Amirhosseini, E. Minthorn, L. J. Benincosa, T. K. Hart, C. S. Hottenstein, L. A. P. Tobia and C. B. Davis

Departments of Drug Metabolism and Pharmacokinetics (P.Z.-A., E.M., L.J.B., C.S.H., L.A.P.T., C.B.D.) and Safety Assessment (T.K.H.), SmithKline Beecham, King of Prussia, Pennsylvania

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 ~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 IC₅₀ value of 1.43 µg/ml. The combination of a low IC₅₀ 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.