We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
A comprehensive pharmacokinetic/pharmacodynamics analysis of the novel IGF1R/INSR inhibitor BI 893923 applying in vitro, in vivo and in silico modeling techniques.
- Authors
Titze, Melanie; Schaaf, Otmar; Hofmann, Marco; Sanderson, Michael; Zahn, Stephan; Quant, Jens; Lehr, Thorsten; Titze, Melanie I; Hofmann, Marco H; Sanderson, Michael P; Zahn, Stephan K
- Abstract
<bold>Purpose: </bold>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. <bold>Methods: </bold>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. <bold>Results: </bold>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. <bold>Conclusion: </bold>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.
- Subjects
PHARMACOKINETICS; PHARMACODYNAMICS; PROTEIN-tyrosine kinase inhibitors; TUMOR growth prevention; BIOMARKERS; DRUG development; DRUG dosage; THERAPEUTICS
- Publication
Cancer Chemotherapy & Pharmacology, 2016, Vol 77, Issue 6, p1303
- ISSN
0344-5704
- Publication type
journal article
- DOI
10.1007/s00280-016-3049-z