Abstract
Objective
Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor and promotes apoptosis. Thrombocytopenia is a primary dose-limiting toxicity of navitoclax which exhibited a distinct time profile in circulating platelets from that caused by traditional chemotherapies. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the pharmacokinetic of navitoclax as well as the time course of the platelet counts in cancer patients receiving navitoclax.
Methods
Data from 256 patients who received oral navitoclax (dose range 10–475 mg) as a 14/21-day schedule or a continuous once daily (QD) schedule were used to construct the model using NONMEM. The PK model was a two-compartmental model with a lag-time and a transit compartment in absorption. The PD model was a semi-physiological model that comprised a progenitor cell compartment, three transition compartments representing the maturation chain in the bone marrow and a peripheral blood compartment. Compared with the previously published models, the model established in this analysis applied a different feedback mechanism and introduced a new concept of progenitor cell “pool”, which describes a large pool of platelet progenitor cells at the beginning of navitoclax treatment.
Results
The PD model was able to describe a slight downward trend of platelet counts over the long-term navitoclax treatment as observed in around 8 % of the patients and the initial drop in platelets seen in our Phase 1/2a studies.
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.
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References
Wilson WH, O’Connor OA, Czuczman MS et al (2010) Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol 11:1149–1159
Tse C, Schoemaker AR, Adickes J et al (2008) ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 68(9):3421–3428
Gandhi L, Camidge DR, Ribeiro de Oliveira M, Bonomi P, Gandara D, Khaira D, Hann CL, McKeegan EM, Litvinovich E, Hemken PM, Dive C, Enschede SH, Nolan C, Chiu YL, Busman T, Xiong H, Krivoshik AP, Humerickhouse R, Shapiro GI, Rudin CM (2011) Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J Clin Oncol 29(7):909–916. doi:10.1200/JCO.2010.31.6208JCO.2010.31.6208
Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, Carney DA, He SZ, Huang DC, Xiong H, Cui Y, Busman TA, McKeegan EM, Krivoshik AP, Enschede SH, Humerickhouse R (2012) Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol 30(5):488–496. doi:10.1200/JCO.2011.34.7898JCO.2011.34.7898
Davids MS, Letai A (2012) Targeting the B-cell lymphoma/leukemia 2 family in cancer. J Clin Oncol 30(25):3127–3135. doi:10.1200/JCO.2011.37.0981JCO.2011.37.0981
Tomek M, Akiyama T, Dass CR (2012) Role of Bcl-2 in tumour cell survival and implications for pharmacotherapy. J Pharm Pharmacol 64(12):1695–1702. doi:10.1111/j.2042-7158.2012.01526.x
Roberts AW, Seymour JF, Brown JR et al (2012) Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol 30:488–496
Eradat H, Grosicki S, Catalono J, Cosolo W, Dyagil I, Kipps TJ, Zheng B, Yalamanchili S, Sahasranaman S, Hurst D, Ho W, Pylypenko H (2012) Preliminary results of a Phase II open-label, randomized study of the BH3 mimetic protein navitoclax (ABT-263) with or without rituximab for treatment of previously untreated B-Cell chronic lymphocytic leukemia. Presented at ASH, 2012
Zhang H, Nimmer PM, Tahir SK et al (2007) Bcl-2 family proteins are essential for platelet survival. Cell Death Differ 14(5):943–951
Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO (2002) Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol 20(24):4713–4721
Quartino AL, Friberg LE, Karlsson MO (2010) A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model. Invest New Drugs 30(2):833–845
Serby M, Ahmed T, Yang J, Xiong H, Lee A, Shen J (2013) Metabolism and disposition of ABT-263 in humans. Paper presented at the Great Lakes Drug Metabolism Discussion Group annual meeting, Toledo, OH, May 9–10
Rai KR, Keating MJ(2000) Chronic lymphocytic leukemia. In: Bast Jr RC, Kufe DW, Pollock RE et al. (eds) Holland-Frei cancer medicine. 5th edition. BC Decker, Hamilton. Chapter 127
Conflict of interest
This study was sponsored by AbbVie Inc. AbbVie Inc. contributed to the study design; research; data interpretation; and writing, review and approval of the manuscript for publication. Aksana Kaefer, Jianning Yang, Peter Noertersheuser, Sven Mensing, Rod Humerickhouse, Walid Awni, Hao Xiong are employees of AbbVie Inc.
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Kaefer, A., Yang, J., Noertersheuser, P. et al. Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia. Cancer Chemother Pharmacol 74, 593–602 (2014). https://doi.org/10.1007/s00280-014-2530-9
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DOI: https://doi.org/10.1007/s00280-014-2530-9