Abstract 3355: Evaluation of the efficiency of tumor and tissue delivery of carrier mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric relative distribution index over time (RDI-OT).
Authors: Madden Andrew J. , Rawal Sumit , Chu Kevin , Sandison Katie , Schell Ryan , Feng Lan , Ma Ping , Mumper Russell , DeSimone Joseph , Zamboni William C. 
Published: August 2014

Background: The PK of CMA are dependent upon the carrier system. As a result, CMA PK differ greatly from the PK of SM drugs. Advantages of CMA included prolonged circulation time in plasma, increased delivery to tumors which results in increased antitumor response and decreased toxicity. In theory, the prolonged circulation time of CMA in plasma is thought to result in greater tumor delivery compared with SM. We conducted a meta-analysis evaluating the plasma, tumor, liver, and spleen PK of CMA and SM using standard PK parameters and a novel PK metric RDI-OT which measures efficiency of delivery.

Methods: A literature search identified PK studies of CMA (n=17) and comparative SM (n=15) in plasma, tumor, liver and spleen of mice bearing synergistic and xenograft subcutaneous tumors. The area under the concentration versus time curves (AUC) were calculated. This data was also used to calculate a novel PK metric, RDI-OT. RDI-OT is defined as [Drug]tissue/[Drug]plasma at each time point. RDI-OT versus time plots were generated and the area under the curve (RDI-OT AUC) was calculated from 0 h to 24 h and last time point.

Results: The table below summarizes the mean + SD and range of standard PK parameters and RDI-OT for CMA and SM.

Summary of pharmacokinetic properties by agent type Agent Type CMA SM Mean + SD Range Mean + SD Range AUCplasma (mcg/ml*h) 8,113.7 + 21,620.6 10.5–90,889.6 18.2 + 33.7 0.5–133.8 AUCtumor (mcg/ml*h) 3,605.2 + 8,790.1 13.2–35,400.5 83.8 + 94.4 0.8–243.0 AUCtumor/AUCplasma 1.0 + 1.3 0.04–4.8 8.2 + 11.0 0.3–38.6 SM AUCtumor: AUCplasma 40.6 + 112.3 473.1–0.7 CMA AUCtumor: AUCplasma RDI-OTtumor AUC0-Last 46,289.3 + 179,143.8 3.0–741,095.9 1565.0 + 3053.6 0.8–11057.7 SM RDI-OTtumor AUC 1.7 + 3.1 0.00009–13.4 CMA RDI-OTtumor AUC RDI-OTtumor AUC0-24h 15.4 + 37.1 0.1–121.8 43.4 + 96.8 0.01–361.8 SM RDI-OTtumor AUC0-24h 30.5 + 78.2 0.1–319.2 CMA RDI-OTtumor AUC0-24h

Conclusions: RDI-OT is a novel metric for assessing the efficiency of drug distribution into tumors and tissues. Our results indicate that in mice bearing flank tumor xenografts SM distribute into tumor more efficiently than CMA. The lower efficiency of delivery seen in CMA compared with SM suggests there may be a limit to CMA entry into flank tumors in mice. Further research in additional tumor models that may more closely resemble tumors seen in patients is needed to determine if our results are consistent in different model systems.

Citation Format: Andrew J. Madden, Sumit Rawal, Kevin Chu, Katie Sandison, Ryan Schell, Lan Feng, Ping Ma, Russell Mumper, Joseph DeSimone, William C. Zamboni. Evaluation of the efficiency of tumor and tissue delivery of carrier mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric relative distribution index over time (RDI-OT). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3355. doi:10.1158/1538-7445.AM2013-3355