Mechanistically-based pharmacodynamics: molecular response to geldanamycin derivatives in human tumor xenographs

17-(allylamino)-17-demethoxygeldanamycin (17AAG) and its primary metabolite 17-(amino)-17demethoxy-geldanamycin (17AG) are anti-cancer agents. The tumor cell concentration-time profiles of 17AAG and 17AG, predicted by a physiologically-based pharmacokinetic model of human xenograph bearing mice, were used to study the molecular response in tumor cells by developing mechanistically-based pharmacodynamic models for the molecular markers $onco-proteins Raf-1, erbB2 and heat shock proteins HSP70 and HSP90. Bayesian inference was employed in these models to incorporate prior information of physiological and molecular parameters. Estimates of model parameter were in good agreements with values measured in vitro and general knowledge of biological processes. The comprehensive model of HSP90 and HSP70 was a novel effort to characterize the processes of auto-regulation feedback on gene transcriptional level and the signal transduction delay involved.