Assessing the Impact of HER2 Status on the Antitumor Activity of an HSP90 Inhibitor in Human Tumor Xenograft Mice Using Pharmacokinetic–Pharmacodynamic Modeling

Summary:The purpose of this study is to assess the impact of human epidermal growth factor receptor 2 (HER2) status on the antitumor activity of CH5164840, an orally available heat shock protein 90 (HSP90) inhibitor, using pharmacokinetic–pharmacodynamic modeling. Athymic mice, each implanted with one of eight human tumor xenografts, were treated with CH5164840 once daily at doses of 3.13 to 50 mg/kg. Plasma concentrations of CH5164840 were described by a one-compartment model with first-order absorption rate. Time profiles of tumor growth inhibition in the eight xenograft models were well captured by an indirect response model with a maximum tumor-killing rate constant (Emax model). Threshold plasma concentrations for tumor stasis, which are determined by multiple pharmacodynamic parameters, Emax, EC50 and tumor growth rate constant, were significantly lower in HER2-positive tumors (1.96-3.85μΜ) than in HER2-negative tumors (4.48-23.4 μΜ). The results suggest that CH5164840 was more efficacious in HER2-positive tumors than in HER2-negative tumors in terms of the lower effective concentration of the drug in preclinical animal models.