Method Profile
Organoid cell dynamics, physiologically based pharmacokinetic (PBPK) exposure estimates and epithelial turnover are integrated to examine clinical diarrhea incidence and severity.
Comparing antiproliferative epithelial injury across oral drugs, exposure assumptions and clinical dosing regimens.
Human small-intestinal organoids derived from adult stem cells from one donor, obtained from the HUB Biobank.
Time-course imaging combined with organoid, human epithelial turnover and PBPK models.
Organoids and cell measurements
Adult-derived small-intestinal organoids; proliferative and non-proliferative cell counts assessed across time points from 0 to 96 hours.
Imaging and modeling
ImageXpress Micro XLS imaging, MATLAB R2021b and Simcyp V24, with the M-ADAM gut-wall model used for local exposure estimates.
Model resources
The paper provides equations and parameters and identifies BioModels accession MODEL2212120003 for model code.
Fit concentration- and time-dependent cell changes, simulate crypt exposure using plasma or enterocyte unbound concentrations as alternative surrogates, and fit the relationship between villus injury and clinical diarrhea.
Six-drug comparison with reported clinical observations, two exposure scenarios and a fitted injury-to-diarrhea relationship.
Abemaciclib, ribociclib, poziotinib, lazertinib, mobocertinib and osimertinib, with multiple clinical regimens and trial reports.
Vehicle controls, unbound plasma versus enterocyte exposure and reported clinical diarrhea incidence.
Table 2 reports abemaciclib injury estimates of 1.8–2.6% with plasma exposure and 46.5–51.8% with enterocyte exposure; mobocertinib estimates were 7.2% and 100%, respectively. The enterocyte scenario better matched clinical findings in this drug set.
A six-drug study combines human intestinal organoid injury, epithelial turnover and pharmacokinetic models. Accounting for local intestinal exposure improves agreement with reported clinical diarrhea for drugs whose plasma concentrations understate the modeled intestinal effect.
