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

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Abstract
Background 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. Methods 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. Results 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 μg/L, and 5.37 ± 1.31 hours, respectively. Conclusions 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. Clinical Pharmacology & Therapeutics (2005) 77, 427–436; doi: 10.1016/j.clpt.2004.12.268

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