A Pharmacokinetic-Pharmacodynamic model for the mobilization of CD34+ hematopoietic progenitor cells by AMD3100

Lack, N., Green, B., Dale, D., Calandra, G., Lee, H., MacFarland, R., Badel, K., Liles, W. C. and Bridger, G. (2005) A Pharmacokinetic-Pharmacodynamic model for the mobilization of CD34+ hematopoietic progenitor cells by AMD3100. Clinical Pharmacology and Therapeutics, 77 5: 427-436. doi:10.1016/j.clpt.2004.12.268


Author Lack, N.
Green, B.
Dale, D.
Calandra, G.
Lee, H.
MacFarland, R.
Badel, K.
Liles, W. C.
Bridger, G.
Title A Pharmacokinetic-Pharmacodynamic model for the mobilization of CD34+ hematopoietic progenitor cells by AMD3100
Formatted title
A pharmacokinetic-pharmacodynamic model for the mobilization of CD34 + hematopoietic progenitor cells by AMD3100
Journal name Clinical Pharmacology and Therapeutics   Check publisher's open access policy
ISSN 0009-9236
Publication date 2005-05
Sub-type Article (original research)
DOI 10.1016/j.clpt.2004.12.268
Volume 77
Issue 5
Start page 427
End page 436
Total pages 10
Editor C. M. Stein
C. A. Anderson
M. M. Reidenberg
Place of publication New York, N.Y., United States
Publisher Nature Publishing
Language eng
Subject C1
730108 Cancer and related disorders
111502 Clinical Pharmacology and Therapeutics
1115 Pharmacology and Pharmaceutical Sciences
1112 Oncology and Carcinogenesis
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 g/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.
Keyword Pharmacology & Pharmacy
Bone-marrow Transplantation
Colony-stimulating Factor
Non-hodgkins-lymphoma
Peripheral-blood
Chemokine Receptor
Cxcr4 Antagonist
Randomized Trial
Human Volunteers
Gene-expression
Sdf-1
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
2006 Higher Education Research Data Collection
School of Pharmacy Publications
 
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Created: Fri, 21 Dec 2007, 08:37:05 EST by Laura McTaggart on behalf of School of Pharmacy