Quantitative systems pharmacology model-based investigation of adverse gastrointestinal events associated with prolonged treatment with PI3-kinase inhibitors.

ABSTRACT: Several PI3K inhibitors are in clinical development for the treatment of various forms of cancers, including pan-PI3K inhibitors targeting all four PI3K isoforms (α, β, γ, and δ), and isoform-selective inhibitors. Diarrhea and immune-mediated colitis are among the adverse events observed with PI3K inhibition which limits the maximal tolerated dose. A quantitative systems pharmacology model was developed to investigate PI3K-inhibitor-induced colitis. The effects of individual PI3K isoforms on relevant cellular pathways were incorporated into a mechanistic representation of mucosal inflammation. A virtual clinical population captures the observed clinical variability in the onset timing and rates of diarrhea and colitis for seven clinically tested PI3K inhibitors. Model-based analysis sugges

SUBMITTER: Gadkar K 

PROVIDER: S-EPMC9124351 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature