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  2. Learning and confirming with preclinical studies: modeling and simulation in the discovery of GDC-0917, an inhibitor of apoptosis proteins antagonist

Learning and confirming with preclinical studies: modeling and simulation in the discovery of GDC-0917, an inhibitor of apoptosis proteins antagonist

  • Drug Metab Dispos. 2013 Dec;41(12):2104-13. doi: 10.1124/dmd.113.053926.
Harvey Wong 1 Stephen E Gould Nageshwar Budha Walter C Darbonne Edward E Kadel 3rd Hank La Bruno Alicke Jason S Halladay Rebecca Erickson Chia Portera Anthony W Tolcher Jeffery R Infante Michael Mamounas John A Flygare Cornelis E C A Hop Wayne J Fairbrother
Affiliations

Affiliation

  • 1 Departments of Drug Metabolism and Pharmacokinetics (H.W., H.L., J.S.H., C.E.C.A.H.), Translational Oncology (S.E.G., B.A.), Clinical Pharmacokinetics (N.B.), Oncology Biomarkers (W.C.D., E.E.K.), Exploratory Clinical Development (C.P., M.M.), Safety Assessment (R.E.), Medicinal Chemistry (J.A.F.), and Early Discovery Biochemistry (W.J.F.), Genentech, Inc., South San Francisco, California; South Texas Accelerated Research Therapeutics, LLC, San Antonio, Texas (A.W.T.); and Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee (J.R.I.).
Abstract

The application of modeling and simulation techniques is increasingly common in the preclinical stages of the drug development process. GDC-0917 [(S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-(2-(oxazol-2-yl)-4-phenylthiazol-5-yl)pyrrolidine-2-carboxamide] is a potent second-generation antagonist of inhibitor of Apoptosis (IAP) proteins that is being developed for the treatment of various cancers. GDC-0917 has low to moderate clearance in the mouse (12.0 ml/min/kg), rat (27.0 ml/min/kg), and dog (15.3 ml/min/kg), and high clearance in the monkey (67.6 ml/min/kg). Accordingly, oral bioavailability was lowest in monkeys compared with other species. Based on our experience with a prototype molecule with similar structure, in vitro-in vivo extrapolation was used to predict a moderate clearance (11.5 ml/min/kg) in humans. The predicted human volume of distribution was estimated using simple allometry at 6.69 l/kg. Translational pharmacokinetic-pharmacodynamic (PK-PD) analysis using results from MDA-MB-231-X1.1 breast Cancer xenograft studies and predicted human pharmacokinetics suggests that ED50 and ED90 targets can be achieved in humans using acceptable doses (72 mg and 660 mg, respectively) and under an acceptable time frame. The relationship between GDC-0917 concentrations and pharmacodynamic response (cIAP1 degradation) was characterized using an in vitro peripheral blood mononuclear cell immunoassay. Simulations of human GDC-0917 plasma concentration-time profile and cIAP1 degradation at the 5-mg starting dose in the phase 1 clinical trial agreed well with observations. This work shows the importance of leveraging information from prototype molecules and illustrates how modeling and simulation can be used to add value to preclinical studies in the early stages of the drug development process.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15835
    99.01%, IAP 抑制剂
    IAP