Impact of Erythrocyte Duffy Antigen Genetic Polymorphism on the Distribution of GroB-T, a Novel Human CXC Chemokine

Timothy W Hepburn1, LeeAnn P Tobia1, Wei Shi1, Timothy A McIntyre2, Charles B Davis2

1Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania
2Drug Metabolism and Pharmacokinetics, GlaxosSmithKline, Collegeville, Pennsylvania

Abstract


Purpose. GroB-T, a human CXC chemokine, has been studied for its potential to mobilize stem cells. Chemokines bind specifically to receptors on target immune cells but also to a homologous erythrocyte blood group antigen, the Duffy Antigen/Receptor for Chemokines (DARC) that is subject to genetic polymorphism in humans. A mutation in the DARC gene is common among African Americans and results in lack of expression of the erythrocyte antigen. We used a combination of in vitro studies of GroB-DARC interaction and pharmacokinetic simulation to anticipate the potential impact of this polymorphism on the pharmacokinetics of GroB-T. Methods. [125I]GroB-T was incubated in Caucasian blood to characterize the concentration dependence of the blood to plasma concentration ratio (B/P). Affinity and capacity of binding was estimated by Scatchard analysis; specificity was investigated by competitive displacement with a CC chemokine. The B/P value (7 nM) was then determined in blood from 8 African American subjects. Duffy antigen expression was determined by antibody agglutination. A pharmacokinetic model was developed which accounted for blood-cell binding. Simulations were performed to explore effects of dose regimen and DARC expression on the GroB-T plasma concentration-time profile. Results. GroB-T affinity and capacity for DARC (Caucasian blood) were 23.0 +/- 1.2 and 37.7 +/- 0.6 nM, respectively; excess CC chemokine fully displaced [125I]GroB-T. Chemokine binding was highly correlated with the presence or absence of the Duffy antigen (p<0.01) in African American blood; the proportion of subjects for which binding was observed (3/8), was consistent with the reported frequency of DARC expression in this population. Counter to intuition, in the terminal disposition phase at low doses, concentrations of free GroB-T in the presence of DARC may be substantially higher than in the absence of DARC. Conclusion. Dissociation from the erythrocyte antigen may lead to greater persistence, at low doses, of free GroB-T in the blood of individuals expressing the chemokine sink.

J Pharm Pharm Sci, 10 (4): 486-495, 2007

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