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Mechanism Of Action
The mechanism of action of mesalamine is not fully understood, but appears to have a topical anti-inflammatory effect on the colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase and lipoxygenase pathways, is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon.
Mesalamine has the potential to inhibit the activation of nuclear factor kappa B (NFκB) and consequently the production of key pro-inflammatory cytokines. It has been proposed that reduced expression of PPARγ nuclear receptorsγ-form of peroxisome proliferator-activated receptors) may be implicated in ulcerative colitis. There is evidence that mesalamine produces pharmacodynamic effects through direct activation of PPARγ receptors in the colonic/rectal epithelium.
The pharmacodynamic actions of mesalamine occur in the colonic/rectal mucosae local to the delivery of drug from LIALDA into the lumen. There is information suggesting that severity of colonic inflammation in ulcerative colitis patients treated with mesalamine is inversely correlated with mucosal concentrations of mesalamine. Plasma concentrations representing systemically absorbed mesalamine are not believed to contribute extensively to efficacy.
The total absorption of mesalamine from LIALDA 2.4 g or 4.8 g given once daily for 14 days to healthy volunteers was found to be approximately 21-22% of the administered dose.
Gamma-scintigraphy studies have shown that a single dose of LIALDA 1.2 g (one tablet) passed intact through the upper gastrointestinal tract of fasted healthy volunteers. Scintigraphic images showed a trail of radio-labeled tracer in the colon, suggesting that mesalamine had distributed through this region of the gastrointestinal tract.
In a single dose study, LIALDA 1.2 g, 2.4 g and 4.8 g were administered in the fasted state to healthy subjects. Plasma concentrations of mesalamine were detectable after 2 hours and reached a maximum by 9-12 hours on average for the doses studied. The pharmacokinetic parameters are highly variable among subjects (Table 3). Mesalamine systemic exposure in terms of area under the plasma concentration-time curve (AUC) was slightly more than dose proportional between 1.2 g and 4.8 g LIALDA. Maximum plasma concentrations (Cmax) of mesalamine increased approximately dose proportionately between 1.2 g and 2.4 g and sub-proportionately between 2.4 g and 4.8 g LIALDA, with the dose normalized value at 4.8 g representing, on average, 74% of that at 2.4 g based on geometric means.
Table 3: Mean (SD) PK Parameters for Mesalamine
Following Single Dose Administration of LIALDA Under Fasting Conditions
|Parameter1 of Mesalamine||LIALDA 1.2 g
|LIALDA 2.4 g
|LIALDA 4.8 g
|AUC0-t (ng.h/mL)||9039+ (5054)||20538 (12980)||41434 (26640)|
|AUC0-∞ (ng•h/mL)||9578• (5214)||21084 (13185)||44775# (30302)|
|Cmax (ng/mL)||857 (638)||1595 (1484)||2154 (1140)|
|Tmax* (h)||9.0**(4.0-32.1)||12.0 (4.0-34.1)||12.0 (4.0-34.0)|
|Tlag* (h)||2.0** (0-8.0)||2.0 (1.0-4.0)||2.0 (1.0-4.0)|
|T½ (h) (Terminal Phase)||8.56• (6.38)||7.05§ (5.54)||7.25# (8.32)|
|1Arithmetic mean of parameter values are presented except
for Tmax and Tlag.
*Median (min, max); +N=43, •N=27, §N=33,#N=36, **N=46
Administration of a single dose of LIALDA 4.8 g with a high fat meal resulted in further delay in absorption, and plasma concentrations of mesalamine were detectable 4 hours following dosing. However, a high fat meal increased systemic exposure of mesalamine (mean Cmax: 91%; mean AUC: 16%) compared to results in the fasted state. LIALDA was administered with food in the controlled clinical trials that supported its approval.
In a single and multiple dose pharmacokinetic study of LIALDA, 2.4 g or 4.8 g was administered once daily with standard meals to 28 healthy volunteers per dose group. Plasma concentrations of mesalamine were detectable after 4 hours and were maximal by 8 hours after the single dose. Steady state was achieved generally by 2 days after dosing. Mean AUC at steady state was only modestly greater (1.1- to 1.4-fold) than predictable from single dose pharmacokinetics.
In a single dose pharmacokinetic study of LIALDA, 4.8 g was administered in the fasted state to 71 healthy male and female volunteers (28 young (18-35yrs); 28 elderly (65-75yrs); 15 elderly ( > 75yrs)). Increased age resulted in increased systemic exposure (approximately 2-fold in Cmax), to mesalamine and its metabolite N-acetyl-5-aminosalicylic acid. Increased age resulted in a slower apparent elimination of mesalamine, though there was high between-subject variability. Systemic exposures in individual subjects were inversely correlated with renal function as assessed by estimated creatinine clearance.
Table 4: Mean (SD) PK Parameters for Mesalamine
Following Single Dose Administration of LIALDA 4.8 g under Fasting Conditions
to Young and Elderly Subjects
|Parameter of 5-ASA||Young Subjects (18-35 yrs)
|Elderly Subjects (65-75 yrs)
|Elderly Subjects ( > 75 yrs)
|AUC0-t (ng.h/mL)||51570 (23870)||73001 (42608)||65820 (25283)|
|AUC0-∞(ng•h/mL)||58057b (22429)||89612c (40596)||63067d (22531)|
|Cmax (ng/mL)||2243 (1410)||4999 (4381)||4832 (4383)|
|tmax a (h)||22.0 (5.98 – 48.0)||12.5 (4.00 – 36.0)||16.0 (4.00 – 26.0)|
|tlag a (h)||2.00 (1.00 – 6.00)||2.00 (1.00 – 4.00)||2.00 (2.00 – 4.00)|
|t½ (h), terminal phase||5.68b (2.83)||9.68c (7.47)||8.67d (5.84)|
|Renal clearance (L/h)||2.05 (1.33)||2.04 (1.16)||2.13 (1.20)|
|Arithmetic mean (SD) data are
presented, N = Number of subjects
aMedian (min - max),
Mesalamine is approximately 43% bound to plasma proteins at the concentration of 2.5 μg/mL.
The only major metabolite of mesalamine (5-aminosalicylic acid) is N-acetyl-5-aminosalicylic acid. Its formation is brought about by N-acetyltransferase (NAT) activity in the liver and intestinal mucosa cells, principally by NAT-1.
Elimination of mesalamine is mainly via the renal route following metabolism to N-acetyl-5aminosalicylic acid (acetylation). However, there is also limited excretion of the parent drug in urine. Of the approximately 21-22% of the dose absorbed, less than 8% of the dose was excreted unchanged in the urine after 24 hours, compared with greater than 13% for N-acetyl-5-aminosalicylic acid. The apparent terminal half-lives for mesalamine and its major metabolite after administration of LIALDA 2.4 g and 4.8 g were, on average, 7-9 hours and 8-12 hours, respectively.
The potential effect of Lialda (4.8 g given once daily) on the pharmacokinetics of four commonly used antibiotics were evaluated in healthy subjects. The four antibiotics studied and their dosing regimens were as follows: amoxicillin (single 500 mg dose), ciprofloxacin XR (single 500 mg dose), metronidazole (750 mg twice daily for 3.5 days), and sulfamethoxazole/trimethoprim (800 mg/160 mg twice daily for 3.5 days). Coadministration of Lialda did not result in clinically significant changes in the pharmacokinetics of any of the four antibiotics. The change in Cmax and AUC of amoxicillin, ciprofloxacin and metronidazole when they were co-administered with Lialda were all ≤ 3%. There was an increase of 12% in Cmax and an increase of 15% in AUC of sulfamethoxazole when sulfamethoxazole/trimethoprim was coadministered with Lialda [see DRUG INTERACTIONS].
Animal Toxicology And/Or Pharmacology
In animal studies with mesalamine, a 13-week oral toxicity study in mice and 13-week and 52-week oral toxicity studies in rats and cynomolgus monkeys have shown the kidney to be the major target organ of mesalamine toxicity. Oral daily doses of 2400 mg/kg in mice and 1150 mg/kg in rats produced renal lesions including granular and hyaline casts, tubular degeneration, tubular dilation, renal infarct, papillary necrosis, tubular necrosis, and interstitial nephritis. In cynomolgus monkeys, oral daily doses of 250 mg/kg or higher produced nephrosis, papillary edema, and interstitial fibrosis.
Active, Mild to Moderate Ulcerative Colitis
Two similarly designed, randomized, double blind, placebo-controlled trials were conducted in 517 adult patients with active, mild to moderate ulcerative colitis. The study population was primarily Caucasian (80%), had a mean age of 42 years (6% age 65 years or older), and was approximately 50% male. Both studies used LIALDA doses of 2.4 g/day and 4.8 g/day administered once daily for 8 weeks except for the 2.4 g/day group in Study 1, which was given in two divided doses (1.2 g twice daily). The primary efficacy end-point in both trials was to compare the percentage of patients in remission after 8 weeks of treatment for the LIALDA treatment groups versus placebo. Remission was defined as an Ulcerative Colitis Disease Activity Index (UC-DAI) of ≤ 1, with scores of zero for rectal bleeding and for stool frequency, and a sigmoidoscopy score reduction of 1 point or more from baseline.
In both studies, the LIALDA doses of 2.4 g/day and 4.8 g/day demonstrated superiority over placebo in the primary efficacy endpoint (Table 5). Both LIALDA doses also provided consistent benefit in secondary efficacy parameters, including clinical improvement, treatment failure, clinical remission, and sigmoidoscopic improvement. LIALDA 2.4 g/day and 4.8 g/day had similar efficacy profiles.
Table 5: Patients in Remission at Week 8
|LIALDA 2.4 g/day||30/88 (34.1)||34/84 (40.5)|
|LIALDA 4.8 g/day||26/89 (29.2)||35/85 (41.2)|
|Placebo||11/85 (12.9)||19/86 (22.1)|
Maintenance of Remission in Patients with Ulcerative Colitis
A multicenter, randomized, double-blind, active comparator study was conducted in a total of 826 adult patients in remission from ulcerative colitis. The study population had a mean age of 45 years (8% age 65 years or older), were 52% male, and were primarily Caucasian (64%).
Maintenance of remission was assessed using a modified Ulcerative Colitis Disease Activity Index (UCDAI). For this trial, maintenance of remission was based on maintaining endoscopic remission defined as a modified UC-DAI endoscopy subscore of ≤ 1. An endoscopy subscore of 0 represented normal mucosal appearance with intact vascular pattern and no friability or granulation. For this trial the endoscopy score definition of 1 (mild disease) was modified such that it could include erythema, decreased vascular pattern, and minimal granularity; however, it could not include friability.
Subjects were randomized in a 1:1 ratio to receive either LIALDA 2.4 g/day administered once daily or mesalamine delayed release 1.6 g/day administered as 0.8 g twice daily. The proportion of patients who maintained remission at Month 6 in this study using LIALDA 2.4 g once daily (83.7%) was similar to that seen using the comparator (mesalamine delayed release) 1.6 g/day (81.5%).
Last reviewed on RxList: 8/22/2013
This monograph has been modified to include the generic and brand name in many instances.
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