A pharmacokinetic-pharmacodynamic model for the mobilization of CD34 hematopoietic progenitor cells by AMD3100

Abstract

AMD3100 is a small-molecule CXCR4 antagonist that has been shown to induce the mobilization of CD34 + hematopoietic progenitor cells from bone marrow to peripheral blood. AMD3100 has also been shown to augment the mobilization of CD34 + cells in cancer patients when administered in combination with granulocyte colony-stimulating factor (G-CSF) (filgrastim). The purpose of this study was to characterize the exposure-response relationship of AMD3100 in mobilizing CD34 + cells when administered as a single agent in healthy volunteers. AMD3100 concentrations and CD34 + cell counts obtained from 29 healthy subjects in a single-dose, intensively sampled pharmacokinetic/pharmacodynamic (PK-PD) study were analyzed by use of nonlinear mixed effects regression with the software NONMEM. FOCE (first order conditional estimation) with interaction was the estimation method, and simultaneous PK-PD fitting was adopted. The pharmacokinetics of AMD3100 was described by a 2-compartment model with first-order absorption. The population estimates (+/-SE) for clearance and central volume of distribution were 5.17 +/- 0.49 L/h and 16.9 +/- 3.79 L, respectively. CD34 + cell mobilization was best described by an indirect effect model that stimulates the entry process of CD34 + from bone marrow to peripheral blood in the form of a sigmoid maximum effect model. The population estimates (+/-SE) of maximum effect, concentration causing 50% of maximum response, and equilibration time were 12.6 +/- 4.89, 53.6 +/- 11.9 mug/L, and 5.37 +/- 1.31 hours, respectively. This study characterizes the exposure-response relationship of AMD3100 in mobilizing CD34 + cells after subcutaneous administration. This PK-PD model will be useful in assessing relevant covariates and for optimizing the use of AMD3100 in various patient populations.