A quantitative systems pharmacology model of colonic motility with applications in drug development.
J Pharmacokinet Pharmacodyn
; 46(5): 485-498, 2019 Oct.
Article
in En
| MEDLINE
| ID: mdl-31432345
ABSTRACT
We developed a mathematical model of colon physiology driven by serotonin signaling in the enteric nervous system. No such models are currently available to assist drug discovery and development for GI motility disorders. Model parameterization was informed by published preclinical and clinical data. Our simulations provide clinically relevant readouts of bowel movement frequency and stool consistency. The model recapitulates healthy and slow transit constipation phenotypes, and the effect of a 5-HT4 receptor agonist in healthy volunteers. Using the calibrated model, we predicted the agonist dose to normalize defecation frequency in slow transit constipation while avoiding the onset of diarrhea. Model sensitivity analysis predicted that changes in HAPC frequency and liquid secretion have the greatest impact on colonic motility. However, exclusively increasing the liquid secretion can lead to diarrhea. In contrast, increasing HAPC frequency alone can enhance bowel frequency without leading to diarrhea. The quantitative systems pharmacology approach used here demonstrates how mechanistic modeling of disease pathophysiology expands our understanding of biology and supports judicious hypothesis generation for therapeutic intervention.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Colon
/
Drug Development
/
Gastrointestinal Motility
/
Models, Biological
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
J Pharmacokinet Pharmacodyn
Journal subject:
FARMACOLOGIA
Year:
2019
Type:
Article
Affiliation country:
United States