Aksana Kaefer(1), Jianning Yang(2), Hao Xiong(2), Rajendra Pradhan(2), Markus Jaeger(1), Peter Noertersheuser(1), Sven Mensing(1)
(1) Abbott, Ludwighafen, Germany (2) Abbott, Abbott Park, IL, USA
Objectives: Navitoclax (ABT-263) is a novel small molecule that inhibits Bcl-2 family proteins and promotes apoptosis. Thrombocytopenia is a primary dose limiting toxicity of navitoclax monotherapy, Navitoclax induced accelerated apoptosis of circulating platelets, which differs from typical chemotherapy. Data from Phase 1/2a studies showed a fast drop of platelets after initial administration and a long-term (more than one year) platelets decline in 10-20% patients following continuous administration of navitoclax. The aim of this work was hence to develop a platelet model which is able to describe navitoclax effect on platelet time-course, with an emphasis on the long-term decline.
Methods: The proposed semi-physiological model has 5 compartments, describing the maturation of the platelets in bone marrow and the circulating platelets in blood. Compared with the previously published models that describe drug induced myelosuppression [1,2], the model established in this analysis applied a different feedback mechanism and introduced a new concept of progenitor cell “pool”, which describes the levels of bone marrow reserve of platelet progenitor cells at the beginning of navitoclax treatment. The initial size of the “pool” was estimated using the data. The new model better captured the fast drop of the platelets.as well as the long-term decline in platelets following navitoclax administration. Drug effect of navitoclax on circulating platelets was incorporated via an Emax-model. This semi-physiological model was implemented in NONMEM 7.2.0 via ODE’s using ADVAN 13.
Results: The proposed semi-physiological model approach was able to describe the long-term decline and the initial drop in platelets seen in our Phase 1/2a studies in cancer patients. The agreement of the model with the data is shown by GoF-Plots as well as VPCs and bootstrap analyses.
Conclusions: We have developed a new semi-physiological platelet model for describing fast drop of platelets after initial navitoclax administration and long-term decline of platelets after continuous administration of navitoclax.
References:
[1] Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol (2002); 20(24):4713-4721. doi:10.1200/JCO.2002.02.140
[2] Quartino A.L., Friberg L.E., Karlsson M.O. A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model. Invest New Drugs (2010); DOI 10.1007/s10637-010-9603-3.
Reference: PAGE 21 (2012) Abstr 2389 [www.page-meeting.org/?abstract=2389]
Poster: New Modelling Approaches