title: An allometric pharmacokinetic/pharmacodynamics model for BI 893923, a novel IGF-1 receptor inhibitor.
abstract: BI 893923 is a novel IGF1R/INSR inhibitor with promising anti-tumor efficacy. Dose-limiting hyperglycemia has been observed for other IGF1R/INSR inhibitors in clinical trials. To counterbalance anti-tumor efficacy with the risk of hyperglycemia and to determine the therapeutic window, we aimed to develop a translational pharmacokinetic/pharmacodynamics model for BI 893923. This aimed to translate pharmacokinetics and pharmacodynamics from animals to humans by an allometrically scaled semi-mechanistic model.
  
  
  
  Model development was based on a previously published PK/PD model for BI 893923 in mice (Titze et al., Cancer Chemother Pharmacol 77:1303-1314, 13). PK and blood glucose parameters were scaled by allometric principles using body weight as a scaling factor along with an estimation of the parameter exponents. Biomarker and tumor growth parameters were extrapolated from mouse to human using the body weight ratio as scaling factor.
  
  
  
  The allometric PK/PD model successfully described BI 893923 pharmacokinetics and blood glucose across mouse, rat, dog, minipig, and monkey. BI 893923 human exposure as well as blood glucose and tumor growth were predicted and compared for different dosing scenarios. A comprehensive risk-benefit analysis was conducted by determining the net clinical benefit for each schedule. An oral dose of 2750 mg BI 893923 divided in three evenly distributed doses was identified as the optimal human dosing regimen, predicting a tumor growth inhibition of 90.4% without associated hyperglycemia.
  
  
  
  Our model supported human therapeutic dose estimation by rationalizing the optimal efficacious dosing regimen with minimal undesired effects. This modeling approach may be useful for PK/PD scaling of other IGF1R/INSR inhibitors.
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: D000465:Algorithms; D000818:Animals; D015703:Antigens, CD; D014408:Biomarkers, Tumor / Q000097:blood; D001786:Blood Glucose; D001835:Body Weight; D003198:Computer Simulation; D004285:Dogs; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000139:chemically induced*; D008252:Macaca fascicularis; D051379:Mice; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D011743:Pyrimidines / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D017208:Rats, Wistar; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors*; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors*; D018570:Risk Assessment; D013552:Swine; D013556:Swine, Miniature; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; C000613985:BI 893923; D014408:Biomarkers, Tumor; D001786:Blood Glucose; C000597236:IGF1R protein, human; D011743:Pyrimidines; D017451:Receptors, Somatomedin; C435941:INSR protein, human; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin
keywords: Allometric scaling; Human therapeutic dose estimation; IGF1R/INSR inhibitor; Net clinical benefit; PK/PD modeling