Clinical Cancer esearch cer Therapy : Preclinical rmacokinetic / Pharmacodynamic Modeling Identifies 0000 and SN 29751 as Tirapazamine Analogues with roved Tissue Penetration and Hypoxic R l Killing in Tumors

wnloaded pose: Tirapazamine (TPZ) has attractive features for targeting hypoxic cells in tumors but has limlinical activity, in part because of poor extravascular penetration. Here, we identify improved TPZ gues by using a spatially resolved pharmacokinetic/pharmacodynamic (SR-PKPD) model that contissue penetration explicitly during lead optimization. erimental design: The SR-PKPD model was used to guide the progression of 281 TPZ analogues h a hierarchical screen. For compounds exceeding hypoxic selectivity thresholds in single-cell culSR-PKPD model parameters (kinetics of bioreductive metabolism, clonogenic cell killing potency, ion coefficients in multicellular layers, and plasma pharmacokinetics at well tolerated doses in were measured to prioritize testing in xenograft models in combination with radiation. ults: SR-PKPD–guided lead optimization identified SN29751 and SN30000 as the most promispoxic cytotoxins from two different structural subseries. Both were reduced to the corresponding e selectively under hypoxia by HT29 cells, with an oxygen dependence quantitatively similar to f TPZ. SN30000, in particular, showed higher hypoxic potency and selectivity than TPZ in tumor ltures and faster diffusion through HT29 and SiHa multicellular layers. Both compounds also ed superior plasma PK in mice and rats at equivalent toxicity. In agreement with SR-PKPD prens, both were more active than TPZ with single dose or fractionated radiation against multiple n tumor xenografts. clusions: SN30000 and SN29751 are improved TPZ analogues with potential for targeting tumor Con hypoxia in humans. Novel SR-PKPD modeling approaches can be used for lead optimization during anticancer drug development. Clin Cancer Res; 16(20); 4946–57. ©2010 AACR.