A dynamic model of colonic concentrations of delayed‐release 5‐aminosalicylic acid (Asacol)

Abstract

SUMMARYBackround 5-ASA in a pH sensitive tablet (Asacol) is administered as three doses ⁄ day to treat ulcerative colitis. Once daily dosing may improve patient adherence. Simulation of colonic levels of 5-ASA can be used to compare dosing regimens. AimTo create a dynamic model of colonic concentrations of delayed-release 5-aminosalicylic acid (Asacol). MethodsUsing published data, we created a computer model with STELLA software to simulate amounts of colonic 5-ASA in the total colon, right, transverse, descending and sigmoid ⁄ rectum after daily and three time ⁄ day Asacol. ResultsThe model predicted similar total and regional amounts of 5-ASA with both regimens. Distribution of 5-ASA was 38% in the right colon, 33% in the transverse colon and 14% each in the descending and sigmoid ⁄ rectal colon. Simulated increases in colonic motility and defecation rate exaggerated this 5-ASA distribution, resulting in negligible amounts of 5-ASA in the sigmoid ⁄ rectal region. ConclusionsThis computer model suggests that Asacol can be administered as a single daily dose. The model supports experimental and clinical observations that alternate dose or route of administration may be necessary to achieve adequate 5-ASA amounts in the distal colon during acute exacerbations of ulcerative colitis. This simulation cannot account for all sources of variability in the clinical setting, but provides a rationale for further investigation.

Modelling and Simulation of the Drug Release from a Solid Dosage Form in the Human Ascending Colon: The Influence of Different Motility Patterns and Fluid Viscosities

“…Thorpe et al [60], using a dynamic model of colonic concentrations that mimics published transit time data, reported that the distribution of 5-ASA within the colon was shown to change in response to a change in motility patterns with reduced motility resulting in higher concentrations of 5-ASA [60] which is also consistent with data from our model. This work considered a simple immediate release formulation as a first step in the development of the model.…”

Systematic review: molecular chemoprevention of colorectal malignancy by mesalazine

“…The effectiveness of the drug is related to its mucosal concentration, 10 the type of release formulation (e.g. pH‐dependent) and the individual intraluminal pH as well as motility 11 . On a molecular level, 5‐ASA inhibits cyclooxygenase‐2 (COX‐2)/prostaglandin E2 synthesis, 12,13 decreases transcriptional activity of NF‐κB by modulating RelA/p65 phosphorylation 14 and interferes with Wnt pathway through protein phosphatase 2A (PP2A) 15 …”

“…pH-dependent) and the individual intraluminal pH as well as motility. 11 On a molecular level, 5-ASA inhibits cyclooxygenase-2 (COX-2) ⁄ prostaglandin E2 synthesis, 12,13 decreases transcriptional activity of NF-jB by modulating RelA ⁄ p65 phosphorylation 14 and interferes with Wnt pathway through protein phosphatase 2A (PP2A). 15 Although clinical evidence for chemopreventive effects of 5-ASA in patients with IBD suggests specific anti-inflammatory or oxygen scavenging properties, this drug seems to possess multiple modes of action which, despite numerous experimental studies, remain partially unknown.…”

Patients with newly diagnosed cervical cancer should be screened for anal human papilloma virus and anal dysplasia: Results of a pilot study using a STELLA computer simulation and economic model

“…Examples of the use of STELLA modeling in the medical literature include benefit estimates of treatment options in pediatric patients with Crohn's disease [30] , and utility of information technology for prevention of adverse drug events [31] . Our group has previously applied STELLA modeling to predict colonic levels of topically active gastrointestinal drugs that are unmeasurable using conventional techniques [32] . We chose this method in the current study because objective values for several parameters built into the model were either not available in the medical literature, or needed to be estimated from findings in other patient groups, (such as MSM).…”