Systems Pharmacology Model of Gastrointestinal Damage Predicts Species Differences and Optimizes Clinical Dosing Schedules

Abstract

Gastrointestinal (GI) adverse events (AEs) are frequently dose limiting for oncology agents, requiring extensive clinical testing of alternative schedules to identify optimal dosing regimens. Here, we develop a translational mathematical model to predict these clinical AEs starting from preclinical GI toxicity data. The model structure incorporates known biology and includes stem cells, daughter cells, and enterocytes. Published data, including cellular numbers and division times, informed the system parameters for humans and rats. The drug-specific parameters were informed with preclinical histopathology data from rats treated with irinotecan. The model fit the rodent irinotecan-induced pathology changes well. The predicted time course of enterocyte loss in patients treated with weekly doses matched observed AE profiles. The model also correctly predicts a lower level of AEs for every 3 weeks (Q3W), as compared to the weekly schedule.