Abstract 3581: Investigation of the mechanism of aflibercept mediated modulation of doxorubicin anti-tumor effects in a preclinical model of leukemia: Development of a pharmacokinetic-pharmacodynamic model to guide combination dosing strategies

Combination therapy utilizing an anti-angiogenic agent and cytotoxic chemotherapy represents a standard therapeutic approach in several cancers. However, in order to maximize anti-tumor effects, the in vivo mechanism of action as well as timing of administration of the anti-angiogenic agent with respect to the cytotoxic agent may be crucial. Using a systems pharmacology approach, we investigated the mechanism of action of aflibercept mediated increased intra-tumoral accumulation of doxorubicin in a human leukemia xenograft model and correlated it with the effects of combination therapy on tumor growth. Mice bearing HL-60 tumors were administered 2 doses of aflibercept (25mg/kg) or PBS (control) i.p., at day 0 and day 3. On day 7, 30 mg/kg doxorubicin was administered i.p. to the animals. Plasma, tumor and tissue samples were collected at various times post-dose, and analyzed for doxorubicin using an HPLC assay. A pharmacokinetic (PK) model describing the time course of doxorubicin pharmacokinetics was developed. The PK parameters derived from the model were then fixed and used to build a pharmacodynamic (PD) model for tumor growth in mice treated with 3.0 mg/kg doxorubicin with or without alfibercept and followed for tumor growth for 12 days. The PK/PD model used was the one developed by Simeoni et al. A 4 compartment model with a first order absorption from the peritoneum described the pharmacokinetic profiles. Estimates of doxorubicin clearance out of the tumor were significantly different (p<0.05) between animals treated with or without aflibercept. This clearance was 0.282 ml/hr for animals treated without aflibercept, while it was 0.074 ml/hr for animals treated with aflibercept, indicating that the accumulation of doxorubicin in the tumor may be a result of reduced clearance of the drug out of the tumor. Uptake of doxorubicin in aflibercept treated animals was 1.7 fold higher compared to those treated with doxorubicin alone. This resulted in a 2.2 fold increase in the, tumor efficiency index of doxorubicin in alfibercept treated animals. These findings suggest that a reduction in doxorubicin clearance out of the tumor due to the presence of aflibercept results in an increase in the efficiency of tumor growth retardation. Future steps involve inclusion of aflibercept pharmacokinetics to predict the time course of response. The PKPD model developed will enable us to predict the effects of different dosing frequency and schedules of anti-VEGF therapy in combination with cytotoxic agents on tumoral clearance. Thus, this approach will provide insight about rational dosing regimens between anti-angiogenic agents and cytotoxic drugs.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3581.