2011 - Athens - Greece

PAGE 2011: Target mediated drug disposition
Angelica Quartino

An integrated G-CSF-myelosuppression model characterizing the target mediated disposition of endogenous G-CSF in breast cancer patients following chemotherapy

Angelica L. Quartino (1), Mats O. Karlsson (1), Henrik Lindman (2) and Lena E. Friberg (1)

(1) Department of Pharmaceutical Biosciences, Uppsala University, Sweden; (2) Department of Oncology, Uppsala University Hospital, Sweden

Objectives: Granulocyte colony stimulating factor (G-CSF) is the main regulating factor for neutrophils (ANC) and recombinant G-CSF is frequently used as supportive therapy for patients with or at risk of severe chemotherapy-induced neutropenia. The dominating elimination pathway for G-CSF is through binding to its receptor on ANC, however, the dynamics and interplay of endogenous G-CSF with ANC following chemotherapy has not been characterized. Such knowledge will be valuable for optimization of chemotherapy and assist in identification of patients in need of recombinant G-CSF. The aim of this study was to describe the interaction between endogenous G-CSF and ANC following chemotherapy.

Methods: A prospective study was performed which included 49 breast cancer patients receiving adjuvant chemotherapy with three courses of FEC regimen followed by three courses of docetaxel. Endogenous G-CSF and ANC were measured during the first, second and fourth course. In addition, ANC was monitored at predose and at nadir for all courses. In total, 514 G-CSF and 967 ANC measurements were simultaneously analyzed in NONMEM. A model for myelosuppression [1] formed the basis for ANC but the empirical feedback function on ANC production was substituted with functions of G-CSF.

Results: Endogenous G-CSF was well described by a turnover model with zero-order production. The elimination of G-CSF was proportional (4.7 h/(109 cells/L)) to ANC in the circulation. A linear non-specific elimination was also significant (0.50 /h). A rapid increase in G-CSF following glucocorticoid treatment was incorporated as an extra release of G-CSF.

Chemotherapy treatment reduced the proliferative ANC precursors. The proliferation rate of ANC was controlled by G-CSF through a feedback mechanism equal to (G-CSFcirc/G-CSF0)γ. An additional feedback mechanism, where increased G-CSF levels reduced the mean maturation time, resulted in an OFV drop of 115. Model parameters were in line with previous estimates for these treatments [2].

Visual predictive checks showed that the final model captured both the initial rise in endogenous G-CSF following chemotherapy-induced neutropenia and the parallel return to baseline for both G-CSF and ANC.

Conclusions: The integrated G-CSF-myelosuppression model characterized the target-mediated disposition of endogenous G-CSF following chemotherapy and confirms the self-regulatory properties of the system. The model may be a useful tool in further characterization of the system and in schedule optimization of chemotherapy treatment.

[1] Friberg, L.E., et al., Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol, 2002. 20(24): p. 4713-21.
[2] Hansson, E.K., et al., Limited inter-occasion variability in relation to inter-individual variability in chemotherapy-induced myelosuppression. Cancer Chemotherapy and Pharmacology, 2010. 65(5): p. 839-848.

Reference: PAGE 20 (2011) Abstr 2255 [www.page-meeting.org/?abstract=2255]
Oral: Target mediated drug disposition
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