Abstract 373: Allometric scaling of the pharmacokinetics of pegylated liposomal anticancer drugs
Authors: Caron Whitney P. , Clewell Harvey , Dedrick Robert , Ramanathan Ramesh K. , Yu Ning , Schellens Jan H. , Beijnen Jos H. , Zamboni William C. 
Published: June 2012

Background: Pegylated liposomal formulations contain lipid conjugated to polyethylene glycol. These formulations of anticancer agents have been designed to prolong the drug circulation time, increase tumor delivery, and improve the therapeutic index. The disposition of encapsulated drug is dictated by the liposomal carriers, thus altering the pharmacokinetic (PK) profile of the drug. Allometric scaling is based on a power-log relationship between body weight (W) and drug clearance (CL) among mammals and has been used to compare the PK of small molecule drugs across species. However, it has not been used to compare PK of liposomes or nanoparticle agents. The objectives of this study were to use allometric scaling to: 1) compare the disposition of pegylated liposomal drugs across species and determine the best scaling model, and 2) predict PK parameters of pegylated liposomal drugs in patients.

Methods: PK studies of pegylated liposomal CKD-602 (S-CKD602), pegylated liposomal doxorubicin (PLD), and pegylated liposomal cisplatin (SPI-077) were performed at the maximum tolerated dose (MTD) in male and female rats and dogs and in patients with advanced solid tumors as part of phase I studies. Plasma samples were analyzed for sum total (encapsulated + released) drug. The standard allometric equation, CL = a(W)m (a = empirical coefficient; m = allometric exponent) was used to evaluate the relationship between W and CL in each species. The relationship between measures of the mononuclear phagocyte system (MPS) and CL were also evaluated, by substituting the MPS-associated factors for W (liver weight, spleen weight, spleen blood flow, liver blood flow, and monocyte count). Dedrick Plots were used to determine scaling feasibility.

Results: Standard allometric scaling using W showed that CL scaled across all agents: [S-CKD602 (R2 = 0.92), PLD (R2 = 0.90), and SPI-077 (R2 = 0.98).] However, the percent (%) difference from scaled predicted and observed PK parameters in humans were still &gt; 30%. All MPS associated factors showed correlation with the CL of all three agents (R2 &gt; 0.90). Based on R2 values, total monocyte count displayed the strongest correlation (R2 = 0.99) with drug clearance across the three species for all three agents.

Conclusions: The model that scaled CL the best across all species was the standard allometric method when using potential measures of the MPS, including liver weight, spleen weight, and total monocyte count compared to W. The selection of PK parameters, physiological variables, and pegylated liposomal agent used in this study all contribute to the determination of the optimal scaling method. However, a consistent and predictive allometric model with new methods of allometric scaling and measures of MPS function need to be developed for pegylated liposomal agents. This potential new method could then be used to facilitate the development of future liposomal and nanoparticle agents.

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 373. doi:10.1158/1538-7445.AM2011-373