title: Assessing the impact of HER2 status on the antitumor activity of an HSP90 inhibitor in human tumor xenograft mice using pharmacokinetic-pharmacodynamic modeling.
abstract: 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 (1.96-3.85 µM) than in HER2-negative tumors (4.48-23.4 µM). 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.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Saitoh
authors.forename: Miho
authors.initials: M
authors.lastname: Nagayasu
authors.forename: Norihito
authors.initials: N
authors.lastname: Shibahara
authors.forename: Naomi
authors.initials: N
authors.lastname: Ono
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suda
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.forename: Masaki
authors.initials: M
authors.lastname: Ishigai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016227:Benzoquinones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008819:Mice, Nude; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D014408:Biomarkers, Tumor; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018719:Erb-b2 Receptor Tyrosine Kinases; C570831:CH5164840; C508053:ERBB2 protein, human