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.
References:
[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 () Abstr 2255 [www.page-meeting.org/?abstract=2255]
Poster: Oral: Target mediated drug disposition