In vivo-in vitro correlation of antitumor activity of heat shock protein 90 (HSP90) inhibitors with a pharmacokinetics/pharmacodynamics analysis using NCI-N87 xenograft mice.

The in vitro antitumor activity (e.g. IC50) of anticancer drugs is important for selecting candidate compounds for in vivo drug efficacy study in the early stage of drug discovery. In this study, we investigated the relationship between in vitro IC50 and in vivo EC50 using six heat shock protein 90 (HSP90) inhibitors.IC50 of each compound was calculated from in vitro cell proliferation assays using the NCI-N87 cancer cell line. Each compound was administered to NCI-N87 xenograft mice, and EC50 and the maximum tumour-killing rate constant were calculated from pharmacokinetics/pharmacodynamics analyses using plasma concentrations and tumour volumes.IC50 obtained in vitro was poorly correlated with EC50 obtained in vivo, while a good correlation (r = 0.856) was observed between them when corrected with the unbound fraction ratio.The results of this study using of HSP90 inhibitors as model compounds suggest importance of the consideration of an unbound fraction to evaluate the relationship between IC50 and EC50. These results will contribute to improvement in the prediction accuracy of in vivo drug efficacy from in vitro activity and the efficiency of drug discovery research.