title: A comprehensive pharmacokinetic/pharmacodynamics analysis of the novel IGF1R/INSR inhibitor BI 893923 applying in vitro, in vivo and in silico modeling techniques.
abstract: OBJECTIVE
  BI 893923 is a novel IGF1R/INSR tyrosine kinase inhibitor demonstrating anti-tumor efficacy and good tolerability. We aimed to characterize the relationship between BI 893923 plasma concentration, tumor biomarker modulation, tumor growth and hyperglycemia in mice using in silico modeling analyses.
  
  
  METHODS
  In vitro molecular and cellular assays were used to demonstrate the potency and selectivity of BI 893923. Diverse in vitro DMPK assays were used to characterize the compound's drug-like properties. Mice xenografted with human GEO tumors were treated with different doses of BI 893923 to demonstrate the compound's efficacy, biomarker modulation and tolerability. PK/PD analyses were performed using nonlinear mixed-effects modeling.
  
  
  RESULTS
  BI 893923 demonstrated potent and selective molecular inhibition of the IGF1R and INSR and demonstrated attractive drug-like properties (permeability, bioavailability). BI 893923 dose-dependently reduced GEO tumor growth and demonstrated good tolerability, characterized by transient hyperglycemia and normal body weight gain. A population PK/PD model was developed, which established relationships between BI 893923 pharmacokinetics, hyperglycemia, pIGF1R reduction and tumor growth.
  
  
  CONCLUSIONS
  BI 893923 demonstrates molecular properties consistent with a highly attractive inhibitor of the IGF1R/INSR. A generic PK/PD model was developed to support preclinical drug development and dose finding in mice.
authors.affiliation: Clinical Pharmacy, Saarland University, Saarbrücken, Germany.
authors.forename: Melanie I
authors.initials: MI
authors.lastname: Titze
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors.forename: Otmar
authors.initials: O
authors.lastname: Schaaf
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors.forename: Marco H
authors.initials: MH
authors.lastname: Hofmann
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Sanderson
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors.forename: Stephan K
authors.initials: SK
authors.lastname: Zahn
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors.forename: Jens
authors.initials: J
authors.lastname: Quant
authors.affiliation: Clinical Pharmacy, Saarland University, Saarbrücken, Germany. thorsten.lehr@mx.uni-saarland.de.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lehr
mesh_terms: D000818:Animals; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D005947:Glucose / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors*; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors*; D013552:Swine; D013556:Swine, Miniature; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; C000613985:BI 893923; C000597236:IGF1R protein, human; D011743:Pyrimidines; D017451:Receptors, Somatomedin; C435941:INSR protein, human; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D005947:Glucose
keywords: Biomarker modeling; Hyperglycemia; IGF1R/INSR inhibitor; PK/PD modeling; Preclinical; Tumor growth inhibition