Skip to main content

Advertisement

SpringerLink
Log in

A quantitative systems pharmacology model of colonic motility with applications in drug development

  • Original Paper
  • Published:
Journal of Pharmacokinetics and Pharmacodynamics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Lembo A, Camilleri M (2003) Chronic constipation. N Engl J Med 349:1360–1368

    CAS  PubMed  Google Scholar 

  2. Mawe GM, Hoffman JM (2013) Serotonin signalling in the gut–functions, dysfunctions and therapeutic targets. Nat Rev Gastroenterol Hepatol 10:473–486

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Bharucha AE (2012) High amplitude propagated contractions. Neurogastroenterol Motil 24:977–982

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Bassotti G, Chiarioni G, Vantini I, Betti C, Fusaro C, Pelli MA, Morelli A (1994) Anorectal manometric abnormalities and colonic propulsive impairment in patients with severe chronic idiopathic constipation. Dig Dis Sci 39:1558–1564

    CAS  PubMed  Google Scholar 

  5. Rao SSC, Sadeghi P, Beaty J, Kavlock R (2004) Ambulatory 24-hour colonic manometry in slow-transit constipation. Am J Gastroenterol 99:2405–2416

    PubMed  Google Scholar 

  6. Narducci F, Bassotti G, Gaburri M, Morelli A (1987) Twenty four hour manometric recording of colonic motor activity in healthy man. Gut 28:17–25

    CAS  PubMed  PubMed Central  Google Scholar 

  7. De Schryver AMP, Andriesse GI, Samsom M, Smout AJPM, Gooszen HG, Akkermans LMA (2002) The effects of the specific 5HT(4) receptor agonist, prucalopride, on colonic motility in healthy volunteers. Aliment Pharmacol Ther 16:603–612

    PubMed  Google Scholar 

  8. Bassotti G (1988) Colonic mass movements in idiopathic chronic constipation. Gut 29:1173–1179

    CAS  PubMed  PubMed Central  Google Scholar 

  9. McRorie J, Brown S, Cooper R (2000) Effects of dietary fibre and olestra on regional apparent viscosity and water content of digesta residue in porcine large intestine. Aliment. Pharmacol, Ther

    Google Scholar 

  10. Kiela PR, Ghishan FK (2016) Physiology of Intestinal Absorption and Secretion. Best Pract Res Clin Gastroenterol 30:145–159

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kramer P, Kearney MS, Ingelfinger FJ (1962) The effect of specific foods and water loading on the ileal excreta of ileostomized human subjects. Gastroenterology 42:535–546

    CAS  PubMed  Google Scholar 

  12. Furness JB, Jones C, Nurgali K, Clerc N (2004) Intrinsic primary afferent neurons and nerve circuits within the intestine. Prog Neurobiol 72:143–164

    CAS  PubMed  Google Scholar 

  13. Furness JB (2012) The enteric nervous system and neurogastroenterology. Nature Reviews Gastroenterology and Hepatology 9:286–294

    CAS  PubMed  Google Scholar 

  14. Shin A, Camilleri M, Kolar G, Erwin P, West CP, Murad MH (2014) Systematic review with meta-analysis: highly selective 5-HT4 agonists (prucalopride, velusetrag or naronapride) in chronic constipation. Aliment Pharmacol Ther 39:239–253

    CAS  PubMed  Google Scholar 

  15. Gershon MD (2004) Review article: serotonin receptors and transporters - roles in normal and abnormal gastrointestinal motility. Aliment Pharmacol Ther 20:3–14

    CAS  PubMed  Google Scholar 

  16. Gershon MD, Tack J (2007) The Serotonin Signaling System: From Basic Understanding To Drug Development for Functional GI Disorders. Gastroenterology 132:397–414

    CAS  PubMed  Google Scholar 

  17. Wiesel PH, Norton C, Glickman S, Kamm MA (2001) Pathophysiology and management of bowel dysfunction in multiple sclerosis. Eur J Gastroenterol Hepatol 13:441–448

    CAS  PubMed  Google Scholar 

  18. Dilokthornsakul P, Valuck RJ, Nair KV, Corboy JR, Allen RR, Campbell JD (2016) Multiple sclerosis prevalence in the United States commercially insured population. Neurology 86:1014–1021

    PubMed  PubMed Central  Google Scholar 

  19. Williams R, Rigby AS, Airey M, Robinson M, Ford H (1995) Multiple sclerosis: it epidemiological, genetic, and health care impact. J Epidemiol Community Health 49:563–569

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Gulick EE (2010) Comparison of Prevalence, Related Medical History, Symptoms, and Interventions Regarding Bowel Dysfunction in Persons With Multiple Sclerosis. J Neurosci Nurs 42:E12

    Google Scholar 

  21. Weber J, Grise P, Roquebert M, Hellot MF, Mihout B, Samson M, Beuret-Blanquart F, Pasquis P, Denis P (1987) Radiopaque markers transit and anorectal manometry in 16 patients with multiple sclerosis and urinary bladder dysfunction. Dis Colon Rectum 30:95–100

    CAS  PubMed  Google Scholar 

  22. Glick ME, Meshkinpour H, Haldeman S, Bhatia NN, Bradley WE (1982) Colonic dysfunction in multiple sclerosis. Gastroenterology 83:1002–1007

    CAS  PubMed  Google Scholar 

  23. Munteis E, Andreu M, Martinez-Rodriguez J, Ois A, Bory F, Roquer J (2008) Manometric correlations of anorectal dysfunction and biofeedback outcome in patients with multiple sclerosis. Mult Scler 14:237–242

    CAS  PubMed  Google Scholar 

  24. Bassotti G, Villanacci V (2006) Slow transit constipation: a functional disorder becomes an enteric neuropathy. World J Gastroenterol 12:4609–4613

    PubMed  PubMed Central  Google Scholar 

  25. Hasler WL, Saad RJ, Rao SS et al (2009) Heightened colon motor activity measured by a wireless capsule in patients with constipation: relation to colon transit and IBS. Am J Physiol Gastrointest Liver Physiol 297:G1107–G1114

    CAS  PubMed  Google Scholar 

  26. Shah N, Baijal R, Kumar P, Gupta D, Kulkarni S, Doshi S, Amarapurkar D (2014) Clinical and investigative assessment of constipation: A study from a referral center in western India. Indian J Gastroenterol 33:530–536

    PubMed  Google Scholar 

  27. Wong BS, Manabe N, Camilleri M (2010) Role of prucalopride, a serotonin (5-HT(4)) receptor agonist, for the treatment of chronic constipation. Clin Exp Gastroenterol 3:49–56

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Nijsen MJMA, Wu F, Bansal L et al (2018) Preclinical QSP Modeling in the Pharmaceutical Industry: an IQ Consortium Survey Examining the Current Landscape. CPT Pharm Syst Pharmacol 7:135–146

    CAS  Google Scholar 

  29. Zineh I (2019) Quantitative systems pharmacology: a regulatory perspective on translation. CPT Pharm Syst Pharmacol. https://doi.org/10.1002/psp4.12403

    Article  Google Scholar 

  30. Peterson MC, Riggs MM (2015) FDA Advisory Meeting Clinical Pharmacology Review Utilizes a Quantitative Systems Pharmacology (QSP) Model: A Watershed Moment? CPT Pharmacometrics Syst Pharmacol 4:e00020

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Bliss DZ, Savik K, Jung H, Jensen L, LeMoine M, Lowry A (1999) Comparison of subjective classification of stool consistency and stool water content. Journal of Wound, Ostomy and Continence Nursing 26:137–141

    CAS  Google Scholar 

  32. Kay RM, Cohen Z, Siu KP, Petrunka CN, Strasberg SM (1979) Ileal excretion and bacterial modification of bile acids and cholesterol in patients with continent ileostomy. Gut 21:128–132

    Google Scholar 

  33. Rendtorff RC, Kashgarian M (1967) Stool patterns of healthy adult males. Dis Colon Rectum 10:222–228

    CAS  PubMed  Google Scholar 

  34. Heaton KW, Radvan J, Cripps H, Mountford RA, Braddon FE, Hughes AO (1992) Defecation frequency and timing, and stool form in the general population: a prospective study. Gut 33:818–824

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Borman RA, Burleigh DE (1995) Functional evidence for a 5-HT2B receptor mediating contraction of longitudinal muscle in human small intestine. Br J Pharmacol 114:1525–1527

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Keef KD, Ward SM, Stevens RJ, Frey BW, Sanders KM (1992) Electrical and mechanical effects of acetylcholine and substance P in subregions of canine colon. Am J Physiol 262:G298–307

    CAS  PubMed  Google Scholar 

  37. Hoffman JM, Tyler K, MacEachern SJ et al (2012) Activation of colonic mucosal 5-HT4 receptors accelerates propulsive motility and inhibits visceral hypersensitivity. Gastroenterology 142:844–854

    CAS  PubMed  Google Scholar 

  38. Bouras EP, Camilleri M, Burton DD, Thomforde G, McKinzie S, Zinsmeister AR (2001) Prucalopride accelerates gastrointestinal and colonic transit in patients with constipation without a rectal evacuation disorder. Gastroenterology 120:354–360

    CAS  PubMed  Google Scholar 

  39. Camilleri M, Kerstens R, Rykx A, Vandeplassche L (2008) A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med 358:2344–2354

    CAS  PubMed  Google Scholar 

  40. Poen AC, Felt-Bersma RJ, Van Dongen PA, Meuwissen SG (1999) Effect of prucalopride, a new enterokinetic agent, on gastrointestinal transit and anorectal function in healthy volunteers. Aliment Pharmacol Ther 13:1493–1497

    CAS  PubMed  Google Scholar 

  41. Sloots CEJ, Poen AC, Kerstens R, Stevens M, De Pauw M, Van Oene JC, Meuwissen SGM, Felt-Bersma RJF (2002) Effects of prucalopride on colonic transit, anorectal function and bowel habits in patients with chronic constipation. Aliment Pharmacol Ther 16:759–767

    CAS  PubMed  Google Scholar 

  42. De Lisle RC (2012) Lubiprostone stimulates small intestinal mucin release. BMC Gastroenterol 12:156

    PubMed  PubMed Central  Google Scholar 

  43. Sun X, Wang X, Wang G-D, Xia Y, Liu S (2011) Lubiprostone reverses the inhibitory action of morphine on mucosal secretion in human small intestine. Dig Dis Sci 56:330–338

    PubMed  Google Scholar 

  44. Barish CF, Drossman D, Johanson JF, Ueno R (2010) Efficacy and safety of lubiprostone in patients with chronic constipation. Dig Dis Sci 55:1090–1097

    CAS  PubMed  Google Scholar 

  45. Beattie DT, Armstrong SR, Vickery RG et al (2011) The pharmacology of TD-8954, a potent and selective 5-HT(4) receptor agonist with gastrointestinal prokinetic properties. Front Pharmacol 2:25

    PubMed  PubMed Central  Google Scholar 

  46. Ratuapli SK, Bharucha AE, Noelting J, Harvey DM, Zinsmeister AR (2013) Phenotypic identification and classification of functional defecatory disorders using high resolution anorectal manometry. Gastroenterology 144:314–322.e2

    PubMed  Google Scholar 

  47. Faville RA, Pullan AJ, Sanders KM, Smith NP (2008) A biophysically based mathematical model of unitary potential activity in interstitial cells of Cajal. Biophys J 95:88–104

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Du P, Poh YC, Lim JL, Gajendiran V, O’Grady G, Buist ML, Pullan AJ, Cheng LK (2011) A preliminary model of gastrointestinal electromechanical coupling. IEEE Trans Biomed Eng 58:3491–3495

    PubMed  PubMed Central  Google Scholar 

  49. Youm JB, Leem CH, Lee SR, Song I-S, Kim HK, Heo HJ, Kim BJ, Kim N, Han J (2014) Modeling of stochastic behavior of pacemaker potential in interstitial cells of Cajal. Prog Biophys Mol Biol 116:56–69

    PubMed  Google Scholar 

  50. Du P, Paskaranandavadivel N, Angeli TR, Cheng LK, O’Grady G (2016) The virtual intestine: in silico modeling of small intestinal electrophysiology and motility and the applications. Wiley Interdiscip Rev Syst Biol Med 8:69–85

    PubMed  Google Scholar 

  51. Higgins PDR, Johanson JF (2004) Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol 99:750–759

    PubMed  Google Scholar 

  52. Camilleri M (1990) Disorders of gastrointestinal motility in neurologie diseases. Mayo Clin Proc 65:825–846

    CAS  PubMed  Google Scholar 

  53. Hinds JP, Eidelman BH, Wald A (1990) Prevalence of bowel dysfunction in multiple sclerosis. A population survey. Gastroenterology 98:1538–1542

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Applied BioMath, Concord, MA, USA

    Raibatak Das, Lucia Wille, Joshua F. Apgar, John M. Burke & Fei Hua

  2. Takeda Pharmaceutical Inc., Cambridge, MA, USA

    Liming Zhang, Chunlin Chen, Wendy Winchester, Jangir Selimkhanov, Jill Wykosky, Mark Rogge & Majid Vakilynejad

Authors
  1. Raibatak Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lucia Wille
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liming Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chunlin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wendy Winchester
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jangir Selimkhanov
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jill Wykosky
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Joshua F. Apgar
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. John M. Burke
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mark Rogge
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Fei Hua
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Majid Vakilynejad
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Majid Vakilynejad.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 32 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Das, R., Wille, L., Zhang, L. et al. A quantitative systems pharmacology model of colonic motility with applications in drug development. J Pharmacokinet Pharmacodyn 46, 485–498 (2019). https://doi.org/10.1007/s10928-019-09651-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10928-019-09651-6

Keywords

Search

Navigation