Development of a Preclinical PK/PD Model to Assess Antitumor Response of a Sequential Aflibercept and Doxorubicin-Dosing Strategy in Acute Myeloid Leukemia
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Timing of the anti-angiogenic agent with respect to the chemotherapeutic agent may be crucial in determining the success of combination therapy in cancer. We investigated the effects of sequential therapy with the potent VEGF inhibitor, aflibercept, and doxorubicin (DOX) in preclinical acute myeloid leukemia (AML) models. Mice were engrafted with human HL-60 and HEL-luciferase leukemia cells via S.C. and/or I.V. injection and treated with two to three doses of aflibercept (5–25 mg/kg) up to 3–7 days prior to doxorubicin (30 mg/kg) administration. Leukemia growth was determined by local tumor measurements (days 0–16) and systemic bioluminescent imaging (days 0–28) in animals receiving DOX (3 mg/kg) with or without aflibercept. A PK/PD model was developed to characterize how prior administration of aflibercept altered intratumoral DOX uptake. DOX concentration–time profiles were described using a four-compartment PK model with linear elimination. We determined that intratumoral DOX concentrations were 6-fold higher in the aflibercept plus DOX treatment group versus DOX alone in association with increased drug uptake rates (from 0.125 to 0.471 ml/h/kg) into tumor without affecting drug efflux. PD modeling demonstrated that the observed growth retardation was mainly due to the combination of DOX plus TRAP group; 0.00794 vs. 0.0043 h−1. This PK/PD modeling approach in leukemia enabled us to predict the effects of dosing frequency and sequence for the combination of anti-VEGF and cytotoxic agents on AML growth in both xenograft and marrow, and may be useful in the design of future rational combinatorial dosing regimens in hematological malignancies.
KEY WORDSacute myeloid leukemia aflibercept doxorubicin pharmacokinetics/pharmacodynamics VEGF TRAP
We would like to acknowledge Ashleigh Lamson M. S. for technical support. This research was supported by an American Cancer Society Mentored Research Scientist Award MRSG-06-044-01-LIB (to E.S.W) and the Szefel Leukemia Research Fund (to E.S.W). Core institute resource support was provided by the NCI Cancer Center Support Grant (CA016156).
- 22.Brown RP, Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP. Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Heal. 1997;13(4):407–84. Epub 1997/07/01.Google Scholar
- 24.Gjedde SB, Gjedde A. Organ blood flow rates and cardiac output of the BALB/c mouse. Comp Biochem Physiol Part A: Physiology. 1980;67(4):5.Google Scholar
- 25.D’Argenio DZ, A. Schumitzky and X. Wang. ADAPT 5 User’s Guide: Pharmacokinetic/Pharmacodynamic Systems Analysis Software. Biomed Simul Resour. 2009.Google Scholar
- 31.Troiani T, Serkova NJ, Gustafson DL, Henthorn TK, Lockerbie O, Merz A, et al. Investigation of two dosing schedules of vandetanib (ZD6474), an inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling, in combination with irinotecan in a human colon cancer xenograft model. Clin Cancer Res. 2007;13(21):6450–8. Epub 2007/11/03.PubMedCrossRefGoogle Scholar
- 43.Feldman EJ, Lancet JE, Kolitz JE, Ritchie EK, Roboz GJ, List AF, et al. First-in-man study of CPX-351: a liposomal carrier containing cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory acute myeloid leukemia. J Clin Oncol. 2011;29(8):979–85. Epub 2011/02/02.PubMedCrossRefGoogle Scholar
- 48.Giles FJ, Bellamy WT, Estrov Z, O’Brien SM, Verstovsek S, Ravandi F, et al. The anti-angiogenesis agent, AG-013736, has minimal activity in elderly patients with poor prognosis acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Leuk Res. 2006;30(7):801–11. Epub 2005/12/08.PubMedCrossRefGoogle Scholar
- 49.Fiedler W, Serve H, Dohner H, Schwittay M, Ottmann OG, O’Farrell AM, et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood. 2005;105(3):986–93. Epub 2004/10/02.PubMedCrossRefGoogle Scholar
- 51.Karp JE, Gojo I, Pili R, Gocke CD, Greer J, Guo C, et al. Targeting vascular endothelial growth factor for relapsed and refractory adult acute myelogenous leukemias: therapy with sequential 1-beta-d-arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clin Cancer Res. 2004;10(11):3577–85.PubMedCrossRefGoogle Scholar
- 53.Ortholan C, Durivault J, Hannoun-Levi JM, Guyot M, Bourcier C, Ambrosetti D, et al. Bevacizumab/docetaxel association is more efficient than docetaxel alone in reducing breast and prostate cancer cell growth: a new paradigm for understanding the therapeutic effect of combined treatment. Eur J Cancer. 2010;46(16):3022–36. Epub 2010/08/24.PubMedCrossRefGoogle Scholar