Pharmacokinetic-Pharmacodynamic Modeling of Biomarker Response and Tumor Growth Inhibition to an Orally Available Heat Shock Protein 90 Inhibitor in a Human Tumor Xenograft Mouse Model

PF04942847, 2-amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide, was identified as an orally available, ATP-competitive small molecule inhibitor of heat shock protein 90 (HSP90). The objectives of the present study were to characterize 1) pharmacokinetic-pharmacodynamic relationship of the plasma concentrations of PF04942847 to the inhibition of HSP90-dependent protein kinase, AKT, as biomarker and 2) the relationship of AKT degradation to tumor growth inhibition as pharmacological response (anti-tumor efficacy). Athymic mice implanted with MDA-MB-231 human breast cancer cells were treated with PF04942847 once daily at doses selected to encompass ED 50 9s. Plasma concentrations of PF04942847 were adequately described by a two-compartment pharmacokinetic model. A time-delay (hysteresis) was observed between the plasma concentrations of PF04942847 and the AKT degradation; therefore, a link model was used to account for the hysteresis. The model reasonably fitted the time-courses of AKT degradation with the estimated EC 50 of 18 ng/mL. For tumor growth inhibition, the signal transduction model reasonably fitted the inhibition of individual tumor growth curves with the estimated EC 50 of 7.3 ng/mL. Thus, the EC 50 for AKT degradation roughly corresponded to the EC 50 to EC 80 for the tumor growth inhibition, suggesting that 50% AKT degradation was required for significant anti-tumor efficacy (50 to 80%). The consistent relationship between the AKT degradation and anti-tumor efficacy was also demonstrated by applying a recently proposed integrated signal transduction model for linking AKT degradation to tumor growth inhibition. The present results will be helpful in determining the appropriate dosing regimen and in guiding dose escalation to rapidly achieve efficacious systemic exposure in the clinic.