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- Title
A pharmacokinetic-pharmacodynamic model for the mobilization of CD34<sup>+</sup> hematopoietic progenitor cells by AMD3100.
- Authors
Lack, N. A.; Green, B.; Dale, D. C.; Calandra, G. B.; Lee, H.; MacFarland, R. T.; Badel, K.; Liles, W. C.; Bridger, G.
- 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 singledose, 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.
- Subjects
PHARMACODYNAMICS; RECOMBINANT proteins; IMMUNE system; CHEMICAL kinetics; HEMATOPOIETIC agents; DRUG metabolism
- Publication
Clinical Pharmacology & Therapeutics, 2005, Vol 77, Issue 5, p427
- ISSN
0009-9236
- Publication type
Article
- DOI
10.1016/j.clpt.2004.12.268