Learning and Confirming with Preclinical Studies: Modeling and Simulation in the Discovery of GDC-0917, an Inhibitor of Apoptosis Proteins Antagonist

TLDR

Modeling and simulation are increasingly used in preclinical drug development, exemplified by GDC‑0917, a potent second‑generation inhibitor of apoptosis proteins being developed for various cancers. Using in vitro–in vivo extrapolation, allometric scaling, and translational PK‑PD analysis, the authors predicted moderate human clearance, a volume of distribution of 6.69 l/kg, and that ED50 and ED90 can be reached with 72 mg and 660 mg doses, with cIAP1 degradation linked to plasma concentrations measured in PBMC assays. GDC‑0917 shows low‑to‑moderate clearance in rodents and dogs but high clearance in monkeys, leading to lower oral bioavailability in that species; human plasma concentration and cIAP1 degradation simulations at the 5‑mg phase‑1 starting dose matched observed data, underscoring the value of prototype‑based modeling in early drug development.

Abstract

The application of modeling and simulation techniques is increasingly common in the preclinical stages of the drug development process. GDC-0917 [(<i>S</i>)-1-((<i>S</i>)-2-cyclohexyl-2-((<i>S</i>)-2-(methylamino)propanamido)acetyl)-<i>N</i>-(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.