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Mesalazine in the treatment of ulcerative colitis



Anja St Clair Jones Dip Pharm MSc
Lead Pharmacist, Division of Surgery,
Brighton and Sussex University
Hospitals NHS Trust, UK
Ulcerative colitis (UC) is a lifelong disease arising from an interaction between genetic and environmental factors observed predominantly in the developed countries. The disease is characterised by diffuse mucosal inflammation divided into distal (proctitis and proctosimoiditis) or more extensive diseases (left-sided colitis, extensive colitis and pancolitis).
The precise aetiology is unknown and a medical therapy to cure the disease is not yet available. Current treatment goals are symptom control and the maintenance of remission; however, evidence is emerging that endoscopic mucosal healing is the optimal treatment outcome and a shift in disease assessment is taking place by the development of an Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and its validation.
Mesalazine as first-line therapy
Mesalazine (5-aminosalicylic acid; 5-ASA) is the first-line therapy for the induction and maintenance of remission of mild-to-moderate UC but the choice of 5-ASA cannot be made on the grounds of efficacy alone. The route of delivery, disease pattern, dose-frequency and patient acceptability are also relevant factors in the choice of formulation, in addition to cost and availability.
5-ASA has a topical action on epithelial cells and is therefore more active in UC (a mucosal disease) than in Crohn’s disease (a transmural disease). However, oral mesalazine is absorbed completely in the small intestine whereas it is absorbed poorly in the colon. To obtain a high concentration of 5-ASA at the site of inflammation, it is essential to minimise systemic exposure and ensure delivery to the affected tissue. It is therefore important to understand the pharmacokinetic profiles of mesalazine formulations to enable the practitioner to choose the product suitable for the disease picture that is presenting.
Mode of action
Sulphasalazine (i) is the azo-bond prodrug of 5-ASA and sulphapyridine, which relies on anaerobic bacteria in the colon to enzymatically cleave the azo-bond and release the active drug (Figure 1).
Mesalazine (ii) is the therapeutically active moiety of sulphasalazine (i). The inactive moiety, sulphapyridine (iii), by contrast, is associated with a number of dose-dependent adverse drug reactions because of the sulphur content, such as nausea, dyspepsia, headaches, reversible skin reactions, allergies and blood dyscrasia.
In experimental studies, 5-ASAs have an inhibitory effect on the inflammatory cascade similar to non-steroidal anti-inflammatory drugs, interfering with inflammation, proliferation and/or apotosis.
5-ASA is thought to modulate inflammatory cytokine secretion, inhibition of leucotrienes, prostaglandins and nuclear factor (NFκΒ) responsible for the subsequent expression of pro-inflammatory molecules.(1–3)
Evidence is emerging that mesalazine could have antineoplastic and potentially prophylactic chemopreventive properties.(1) Recent evidence suggests that 5-ASA may produce effects similar to activation of γ-peroxisome-proliferator-activated receptors (PPARγ). These receptors play a role in inflammatory- and non-inflammatory-driven processes including carcinogenesis. PPARγ molecules are expressed in the epithelium of the colon and adipose tissue in higher concentration than in the small intestine, thereby providing a possible explanation for the higher efficacy of 5-ASA in UC.(2) Current research is targeted at identifying compounds with similar chemical properties able to bind to PPARγ, such as thiazolidinedione ligands used in type-2-diabetes, for example, rosiglitazone, which was under investigation for use in UC.(3)
Emerging data also propose an effect of mesalazine on gut flora by altering microbial gene expression.(4)
Recent trials have investigated high-dose or once-daily treatment regimens and evidence is emerging that acute flares should be treated with doses of mesalazine 4g/day or above adding mesalazine 1g/day rectal enema for 4 weeks and maintaining remission with doses of mesalazine 2g/day of above (Tables 1 and 2).
Absorption and metabolism
Orally ingested 5-ASA is readily absorbed in the proximal small intestine and extensively metabolised by N-acetyltransferase 1 (NAT1) in intestinal epithelial cells and the liver to the inert N-acetyl-5-aminosalicylic acid (Ac-5-ASA). Ac-5-ASA, together with free 5-ASA, is excreted in the urine.
To protect 5-ASA from this rapid and nearly complete absorption in the stomach and proximal small bowel, delayed release and controlled release preparations or pro-drugs have been formulated. These formulations release the majority of the 5-ASA in the distal lumen or colon, making the drug available at the site of inflammation in UC. Once released, a significant portion of 5-ASA is absorbed into the epithelial gut wall where it undergoes acetylation by NAT1 and is either secreted back into the gut lumen and excreted into the faeces or systemically absorbed and excreted in the urine. The genotype of NAT1, despite being polymorphic, does not seem to influence the efficacy of 5-ASA. There also seems to be little acetylation of 5-ASA by colonic bacteria.
Plasma concentration
Systemic absorption of 5-ASA is comparable for all preparations. Whereas reported troughs, peaks and random plasma concentrations are of little value because they are difficult to interpret and have high interpatient varation, studies of pharmacokinetic values, such as Tmax, Cmax and AUC are of some value.
Sandborn and Hanauer’s review reports comparable data for all formulations,(16) concluding that systemic absorption for all formulations is similar.
Urinary and faecal excretion
Sandborn and Hanauer suggest that formulations releasing at pH >6 might have increased urinary excretion of total 5-ASA, owing to increased absorption in the small intestine.(16)
It has been suggested that increased renal excretion may lead to nephrotoxicity but a causal relationship is still unclear. The plasma concentration in patients taking 5-ASA is lower than in patients taking other salicylates at recommended doses, and studies have shown that proteinuria is more likely related to disease activity. Reports of long-term, high-dose 5-ASA (7.2g/day for up to 5.2 years) showed no significant detrimental effect on renal function.(17)
Faecal excretion of 5-ASA and Ac-5-ASA is also comparable but in the presence of diarrhoea (induced by administration of bisacodyl in healthy volunteers), faecal excretion of the prodrugs sulphasalazine and olsalazine (and likely balsalzide) is markedly increased compared with pH- or time-controlled release formulations, suggesting that the efficacy of these prodrugs could be reduced.(16) It remains to be seen if accelerated passage through the colon affects the pharmacokinetics of mesalazine MMX adversely.
Intraluminal colonic concentration and delivery mechanisms
The action of 5-ASA is predominantly topical and the clinical aim of treatment is to deliver active drug to the site of inflammation while minimising systemic absorption.
A review of methods of assessing 5-ASA release, intraluminal concentration and colonic distribution concluded that while assessing 5-ASA release was important, randomised clinical studies remained the best guide for dosing and treatment regime decisions because of the limitations of the individual techniques (see Table 3).(18) The need to develop standard assessment indices for UC is paramount to evaluate the efficacy of different formulations because only trial data can accurately determine the effect of formulation on response and intraluminal concentration assessment methods remain limited in their usefulness. In view of the importance of mucosal healing, the development of a UCEIS has been developed and now needs to be validated.(19)
Additional drawbacks may be with formulations that release 5-ASA as a delayed bolus in the proximal colon and insufficient concentrations are achieved in the distal part of the colon. Considering that only 15% of patients initially presenting with UC have disease extending beyond the splenic flexure, azo-bonded and delayed pH-dependent release formulations may not deliver therapeutically effective concentrations to the left side of the colon. Formulations such as MMX Multi Matrix and pH-independent delayed release system might address this problem. However these formulations may not deliver high enough concentrations to be effective, particularly at low doses. Further investigations that take into account the limitations of techniques assessing effective intraluminal concentrations are required.
A summary of formulations and their characteristics are detailed in Table 4.
Ipocol and Mesren MR are generic versions of Asacol 400mg MR. The in vitro dissolution profile of Mesren MR is nearly identical to that of Asacol 400mg MR, whereas the dissolution profile of Ipocol is different. Ipocol, because of its thinner layer of Eudragit, dissolves at a slightly lower pH and more swiftly than Asacol, with possible higher systemic absorption and smaller intracolonic concentration. Mesren MR has not been compared with other mesalazine MR preparations in patient studies because to obtain a licence as a generic medicine, the product needs only to demonstrate bioequivalence to the brand leader. It is also worth noting that Asacol formulations in different countries are not equivalent. Octasa is considered equivalent to Asacol but it is to be noted that the coating of the 800mg tablet is not the same and unlikely to produce the same release profile. The few studies comparing Octasa with Pentasa need to be interpreted with care because patient numbers are small and the methodology and statistical analyses are questionable. More high-quality, comparative trials are required to understand the differences between formulations.
Adherence and non-compliance
Compliance or adherence is an issue in patients with ulcerative colitis in remission. Kane and colleagues found that the overall adherence was approximately 40% in patients using mesalazine for maintenance of quiescent ulcerative colitis.(21) Results were similar in the Manitoba IBD cohort study, with low adherence in approximately one-third of patients.(22) Non-adherence is taking <80% of the prescribed medication and can be related directly to an increased risk of both relapse and of the development of colorectal cancer in the long term.
In a systematic review,(23) Kane found a number of factors and reasons for non-adherence in UC, such as disease duration, male gender, single status, full-time employment, and three-time daily dosing. Patients were stating forgetfulness, questioning need for medication, inconvenient regimes and large number of tablets as reasons for non-adherence.
The clinical impact is considerable by increasing the chance of relapse to 61% in non-adherers compared with 11% in adherers (p=0.001),(23) reducing quality of life and increasing colorectal cancer risk to 31% compared with 3% (p=<0.001).(24)
In 2004 the economic cost for caring for patients with IBD over a six-month period in the UK could range from £73 to £33,254, with a mean cost for UC patients of £1256. Only 14% of IBD patients in the study needed admission but accounted for 49% of the total secondary cost.(25)
Addressing barriers to adherence resulting from patients’ beliefs is complex and proposed interventions are probably of very limited benefit. However, offering simpler, less intrusive, drug delivery methods are of proven value and improve patient compliance.
With the trend of treatment to higher dose regimens, the tablet load needs to be reduced to improve compliance. Higher dose preparations have been formulated, such as Asacol 800mg tablets and Pentasa 2g sachets for the treatment of active disease, which benefit patients when controlling remission.
Evaluation criteria 
The suggestion that a generic mesalazine preparation be substituted on cost-saving grounds is thought to result in short-term savings only. Once current strategies in management of UC and adherence issues are taken into account, it might be possible that the change to the proposed cheaper preparation could result in decreased maintenance of remission and increased admissions to hospital because of reduced patient compliance, and potentially increase the incidence of colorectal cancer. An evaluation of criteria is given in Table 5.
Current treatment goals for UC are the control of symptoms, the maintenance of remission and endoscopic mucosal healing. Efficacy, route of delivery, disease pattern, dose frequency and patient acceptability are relevant factors in the choice of therapy, as well as the cost and availability. To protect 5-ASA from rapid and near-complete absorption in the stomach and proximal small bowel, delayed-release, controlled-release and prodrug versions have been formulated, which differ considerably in their pharmacological properties. Information of pharmacokinetic profiles of oral mesalazine formulations are difficult to interpret but show a comparable range, and therefore randomised clinical studies remain the best guide for dosing and treatment regimen decisions based on efficacy, dose response, toxicity and compliance issues. Compliance is an issue in quiescent UC, with around 60% of patients not adhering to maintenance therapy, and offering simpler, less-intrusive drug delivery methods are of proven value and improve patient compliance. Several trials have shown that Asacol, Pentasa, Mezavant (MMX mesalazine) and Salofalk are effective as once-daily dosing in inducing remission and maintaining remission in UC with the potential to increase efficacy either in subgroups of disease presentation or overall. However, many aspects still need further investigation, such as the effect of clinical disease picture on efficacy, especially with drastically changed pharmacokinetics as seen in diarrhoea, the effect of the formulation and the importance of the intraluminal concentrations and other pharmacokinetic parameters.
Evaluation criteria should concentrate primarily on compliance-inducing factors, such as low pill burden and once-daily administration, and to a lesser extent on price in view of the importance of adherence to maintenance of remission and colorectal cancer protection.
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