A dynamic model of once-daily 5-aminosalicylic acid predicts clinical efficacy.

Abstract

New once daily mesalamine formulations may improve adherence to medication usage. Response to Asacol and other forms of 5-aminosalicyclic acid (5-ASA) is better correlated with tissue concentrations and best predicted by concentrations of the drug within the lumen of the colon. Our group used computer simulation to predict colonic 5-ASA levels after Asacol administration. In our study, the model simulated Asacol distribution in the healthy colon, and during quiescent and active ulcerative colitis. An Asacol dosage of 800 mg, three times a day, was compared to 2400 mg given once a day. Under ideal conditions, the predicted maximum drug in the total colon and individual colonic segments over 100 d differed by less than 3% between single and multiple doses. Despite changes in motility and defection rates, the predicted maximum and average 5-ASA concentrations in the total colon and individual colonic segments differed by less than 10% between dosing regimens. Asymmetric distribution of 5-ASA in the colon was influenced by frequency of bowel movements and colonic transit rate. In active colitis, sigmoid 5-ASA concentration becomes negligible. Our model supports once daily administration of Asacol as standard treatment for ulcerative colitis.

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A dynamic model of once-daily 5-aminosalicylic acid
predicts clinical efficacy
Deepak Parakkal, Department of Gastroenterology, North­
Shore University Hospital, 2650 Ridge Ave Evanston, IL
60201­1718, United States
Eli D Ehrenpreis, Chief of Gastroenterology and Endoscopy,
Highland Park Hospital, NorthShore University Health System
and Clinical Associate Professor of Medicine, University of
Chicago,777 Park Avenue West, Highland Park, IL 60035,
United States
Matthew P Thorpe, Division of Nutritional Sciences, Univer­
sity of Illinois, Urbana, IL 61801, United States
Karson S Putt, Department of Biochemistry, University of
Illinois, Urbana, IL 61801, United States
Bruce Hannon, Department of Geography/NCSA, University
of Illinois, Urbana, IL 61801, United States
Author contributions: Parakkal D, Ehrenpreis ED, Thorpe MP,
Putt KS and Hannon B contributed equally to this work; All
authors designed and performed the research; Thorpe MP, Putt
KS, Hannon B contributed to the new analytic tools; All authors
analyzed the data; Parakkal D and Ehrenpreis ED wrote the
paper.
Correspondence to: Eli D Ehrenpreis, Chief of Gastro­
enterology and Endoscopy, Highland Park Hospital, NorthShore
University Health System and Clinical Associate Professor
of Medicine, University of Chicago, 777 Park Avenue West,
Highland Park, IL 60035, United States. ehrenpreis@gipharm.net
Telephone: +1­847­6305398 Fax: +1­847­9265350
Received: November 8, 2009 Revised: November 25, 2009
Accepted: December 2, 2009
Published online: January 7, 2010
Abstract
New once daily mesalamine formulations may improve
adherence to medication usage. Response to Asacol and
other forms of 5-aminosalicyclic acid (5-ASA) is better
correlated with tissue concentrations and best predicted
by concentrations of the drug within the lumen of the
colon. Our group used computer simulation to predict
colonic 5-ASA levels after Asacol administration. In
our study, the model simulated Asacol distribution in
the healthy colon, and during quiescent and active
ulcerative colitis. An Asacol dosage of 800 mg, three
times a day, was compared to 2400 mg given once a
day. Under ideal conditions, the predicted maximum
drug in the total colon and individual colonic segments
over 100 d differed by less than 3% between single
and multiple doses. Despite changes in motility and
defection rates, the predicted maximum and average
5-ASA concentrations in the total colon and individual
colonic segments differed by less than 10% between
dosing regimens. Asymmetric distribution of 5-ASA
in the colon was influenced by frequency of bowel
movements and colonic transit rate. In active colitis,
sigmoid 5-ASA concentration becomes negligible. Our
model supports once daily administration of Asacol as
standard treatment for ulcerative colitis.
© 2010 Baishideng. All rights reserved.
Key words: Ulcerative colitis; 5-aminosalicylate; Mesa-
lazine; Asacol; Once-daily
Peer reviewer: Dr. Sigal Fishman, MD, Gastroenterology and
Liver Diseases Department, Tel Aviv Sourasky Medical Center,
Tel Aviv, 64239, Israel
Parakkal D, Ehrenpreis ED, Thorpe MP, Putt KS, Hannon B.
A dynamic model of once­daily 5­aminosalicylic acid predicts
clinical efficacy. World J Gastroenterol 2010; 16(1): 136­137
Available from: URL: http://www.wjgnet.com/1007­9327/full/
v16/i1/136.htm DOI: http://dx.doi.org/10.3748/wjg.v16.i1.136
TO THE EDITOR
We read with a great interest the editorial by Lakatos[1]
that summarizes the available literature on the short
and medium term efficacy and safety of the new once-
daily mesalazine formulations. Single dose regimens
may improve adherence to medication usage. However,
older forms of 5-aminosalicylic acid (5-ASA) may also
be administered in a single daily dosage, apparently with
adequate effects[2]. Most pharmacokinetic studies on
Deepak Parakkal, Eli D Ehrenpreis, Matthew P Thorpe, Karson S Putt, Bruce Hannon
LETTERS TO THE EDITOR
World J Gastroenterol 2010 January 7; 16(1): 136-137
ISSN 1007-9327 (print)
© 2010 Baishideng. All rights reserved.
Online Submissions: http://www.wjgnet.com/1007-9327office
wjg@wjgnet.com
doi:10.3748/wjg.v16.i1.136
January 7, 2010|Volume 1|Issue 1|
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Asacol and other forms of 5-ASA are limited to data
collected from serum, urine or fecal drug concentra-
tions. However, response is better correlated with tissue
than with plasma concentrations, and is best predicted
by concentrations of the drug within the lumen of the
colon[3,4]. A number of factors influence the concentra-
tions of drugs in colon, such as 5-ASA. Our group[5] cre-
ated a computer model to predict 5-ASA levels in colon
after Asacol administration using STELLA software (Isee
Systems, Inc., Lebanon NH, USA). This model divides
the intestinal system into individual compartments-upper
GI tract, right colon, transverse colon, descending colon
and the recto-sigmoid colon, and predicts the movement
of 5-ASA from one compartment to the other. Retro-
spective data for drug concentrations based on serum
levels have been utilized[6,7]. In addition to local transfer
of the drug, each colonic compartment loses a fraction
of its drug concentration due to mass movements with
defecation[8]. In our study, the model was run to simulate
Asacol distribution in a healthy colon, and during quies-
cent and active ulcerative colitis. To achieve this, simula-
tions were performed with increasing defecation rates
up to 12 bowel movements daily along with variation of
upper GI and colonic motility. One hundred 24 h cycles
were studied. An Asacol dosage of 800 mg, three times
a day, was compared to 2400 mg given once a day. Under
ideal conditions, the predicted maximum drug in the to-
tal colon and individual colonic segments over 100 d dif-
fered by less than 3% between single and multiple doses.
Despite changes in motility and defection rates, the pre-
dicted maximum and average 5-ASA concentrations in
the total colon and individual colonic segments differed
by less than 10% between dosing regimens. The model
could also predict almost no drug within the lumen of
the recto-sigmoid colon during severe disease activities[5].
Our model supports the once daily administration
of Asacol, a concept catching on with new clinical trials.
Asymmetric distribution of 5-ASA in the colon is influ-
enced by frequency of bowel movements and the rate
of colonic transit is an important factor in determining
5-ASA dosing in active ulcerative colitis.
REFERENCES
1
Lakatos PL. Use of new once-daily 5-aminosalicylic acid
preparations in the treatment of ulcerative colitis: Is there
anything new under the sun? World J Gastroenterol 2009; 15:
1799-1804
Kane S, Huo D, Magnanti K. A pilot feasibility study of
once daily versus conventional dosing mesalamine for
maintenance of ulcerative colitis. Clin Gastroenterol Hepatol
2003; 1: 170-173
Frieri G, Giacomelli R, Pimpo M, Palumbo G, Passacantando
A, Pantaleoni G, Caprilli R. Mucosal 5-aminosalicylic acid
concentration inversely correlates with severity of colonic
inflammation in patients with ulcerative colitis. Gut 2000; 47:
410-414
Naganuma M, Iwao Y, Ogata H, Inoue N, Funakoshi S,
Yamamoto S, Nakamura Y, Ishii H, Hibi T. Measurement
of colonic mucosal concentrations of 5-aminosalicylic
acid is useful for estimating its therapeutic efficacy in
distal ulcerative colitis: comparison of orally administered
mesalamine and sulfasalazine. Inflamm Bowel Dis 2001; 7:
221-225
Thorpe MP, Ehrenpreis ED, Putt KS, Hannon B. A dynamic
model of colonic concentrations of delayed-release
5-aminosalicylic acid (Asacol). Aliment Pharmacol Ther 2009;
29: 1193-1201
Brunner M, Assandri R, Kletter K, Tschurlovits M, Corrado
ME, Villa R, Eichler HG, Müller M. Gastrointestinal transit
and 5-ASA release from a new mesalazine extended-release
formulation. Aliment Pharmacol Ther 2003; 17: 395-402
Brunner M, Greinwald R, Kletter K, Kvaternik H, Corrado
ME, Eichler HG, Müller M. Gastrointestinal transit and
release of 5-aminosalicylic acid from 153Sm-labelled
mesalazine pellets vs. tablets in male healthy volunteers.
Aliment Pharmacol Ther 2003; 17: 1163-1169
Krogh K, Olsen N, Christensen P, Madsen JL, Laurberg S.
Colorectal transport in normal defaecation. Colorectal Dis
2003; 5: 185-192
2
3
4
5
6
7
8
S- Editor Wang YR L- Editor Wang XL E- Editor Lin YP
Parakkal D et al. Computer modeling of once-daily 5-ASA
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