Bruce Green (1,2) , Howard Lee (1), Nathan Lack (3), D Dale (3), G Calandra (3), Ron MacFarland (3), K Badel (3), W Liles (4), G Bridger (3), Carl Peck (1)
(1) Center for Drug Development Science, University of California San Francisco, (2) School of Pharmacy, University of Queensland, (3) AnorMed Inc, (4) Department of Medicine University of Washington
Background: AMD3100 is a small molecule CXCR4 antagonist that has been shown to induce the mobilization of hematopoietic stem cells (CD34+) from the bone marrow to peripheral blood. The purpose of this study was to characterize the exposure-response (ER) relationship of AMD3100 in mobilizing CD34+ cells.
Methods: AMD3100 concentrations and CD34+ cell counts obtained from 29 healthy subjects in a single dose, intensively sampled PK-PD study were analyzed using nonlinear mixed effects regression with the software NONMEM. FOCE with interaction was the estimation method and simultaneous PK-PD fitting was adopted.
Results: The PK of AMD3100 was described by a two compartment model with first order absorption. The population estimates for clearance (CL) and central volume of distribution (V) (± SE) were 5.17 L/hr (0.49) and 16.9 L (3.79) respectively. CD34+ cell mobilization was best described by an indirect effect model that stimulates the entry process of CD34+ from the bone marrow to peripheral blood in the form of sigmoid Emax model. The population estimates of Emax, EC50 and equilibration time (± SE) were 12.6 (4.89), 53.6 mcg/L (11.9) and 5.37 hours (1.31) respectively.
Conclusions: The ER relationship of AMD3100 in mobilizing CD34+ cells following subcutaneous administration was adequately characterized. Experimentation in patient populations is required to characterize the ER relationship further.
Reference: PAGE 14 () Abstr 697 [www.page-meeting.org/?abstract=697]
Poster: poster