Abstract 4915: Physiologically-based PK modeling of liposomal drug delivery points to a key role of tumor deposition in determining the relative efficacy of liposomal vs. free doxorubicin in breast cancer and Kaposi sarcoma

Abstract

Abstract For the chemotherapeutic, doxorubicin, liposomal encapsulation simultaneously (i) protects the heart from doxorubicin-induced cardiotoxicity, (ii) results in passive tumor accumulation via the enhanced permeability and retention effect and (iii) increases its circulation life-time. Clinically, pegylated-liposomal doxorubicin (PLD) shows a dramatic benefit to Kaposi sarcoma (KS) patients relative to free doxorubicin. In contrast, PLD does not show any survival benefit relative to free doxorubicin in patients with metastatic breast cancer. We hypothesized that the differential efficacy observed might be explained by differences in tumor cell exposure to drug. To better understand the effects of liposomal encapsulation on drug exposure, we developed a mechanism-based PK model of liposome biodistribution. The model consists of superimposed PK models for free and liposomal doxorubicin with a common central blood compartment which are then connected to a physiologically-based tumor tissue compartment. The tumor tissue compartment includes vascular, interstitial and cell space and captures rates of blood flow, tumor deposition into the interstitial space, doxorubicin release from the liposomes and the trafficking of free doxorubicin into and out of cells. The model parameters were extensively validated against literature data from in vitro studies, mouse xenografts and human clinical data. With our model we are able to simulate total tumor doxorubicin and DNA-bound doxorubicin in tumors, reproducing observed mouse xenograft data for free vs. liposomal doxorubicin. Analysis of the model revealed dramatically different dynamics in tumor exposure for free vs. liposomal doxorubicin delivery. Further, rates of tumor deposition were rate-limiting for overall tumor cell exposure for liposomally-delivered doxorubicin. Upon scaling the model to reflect human physiology, we demonstrate that the clinically observed liposome accumulation in KS tumors can quantitatively explain the dramatic increase in efficacy relative to free doxorubicin. Furthermore, the model indicates that the lower rates of liposome tumor deposition seen in breast cancer patients result in no survival benefit relative to free doxorubicin, consistent with clinical trial results. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4915. doi:10.1158/1538-7445.AM2011-4915