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
P
Department of Drug Metabolism and Pharmacokinetics, SmithKline Beecham, King of Prussia, Pennsylvania 19406, USA. Parnian_Zia_Amirhosseini-1@sbphrd.com
Minthorn
E
E
Benincosa
L J
LJ
Hart
T K
TK
Hottenstein
C S
CS
Tobia
L A
LA
Davis
C B
CB
D000465:Algorithms; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000918:Antibody Specificity; D019540:Area Under Curve; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D003429:Cross Reactions; D004804:Eosinophils / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D015848:Interleukin-5 / Q000276:immunology*; D008163:Luminescent Measurements; D008252:Macaca fascicularis
D000911:Antibodies, Monoclonal; D015848:Interleukin-5