A pharmacokinetic-pharmacodynamic model for the mobilization of CD34+ hematopoietic progenitor cells by AMD3100.
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 mug/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.
Lack
N A
NA
Department of Medicine, University of Washington, Seattle, USA.
Green
B
B
Dale
D C
DC
Calandra
G B
GB
Lee
H
H
MacFarland
R T
RT
Badel
K
K
Liles
W C
WC
Bridger
G
G
D000328:Adult; D000465:Algorithms; D018952:Antigens, CD34 / Q000187:drug effects* / Q000502:physiology*; D001596:Benzylamines; D002465:Cell Movement / Q000187:drug effects; D017326:Clinical Trials, Phase III as Topic; D000080027:Cyclams; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007279:Injections, Subcutaneous; D007958:Leukocyte Count / Q000379:methods; D008297:Male
D018952:Antigens, CD34; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; C088327:plerixafor