TY - JOUR T1 - Pharmacokinetics and Pharmacodynamics of SB-240563, a Humanized Monoclonal Antibody Directed to Human Interleukin-5, in Monkeys JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1060 LP - 1067 VL - 291 IS - 3 AU - P. Zia-Amirhosseini AU - E. Minthorn AU - L. J. Benincosa AU - T. K. Hart AU - C. S. Hottenstein AU - L. A. P. Tobia AU - C. B. Davis Y1 - 1999/12/01 UR - http://jpet.aspetjournals.org/content/291/3/1060.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -