Evolutionary Advances in the Delivery of Aminosalicylates for the Treatment of Ulcerative Colitis

R. D. Cohen


Aliment Pharmacol Ther. 2006;24(3):465-474. 

In This Article

Limitations of Current 5-ASA Delivery Systems

The inconvenience of frequent daily dosing, together with the number of tablets/capsules required per day, have been identified as key factors in reducing patient compliance with therapy in UC.[19,20]

In an early study of compliance to sulphasalazine maintenance therapy among patients with inflammatory bowel disease, regular monitoring of serum sulphapyridine levels revealed that a substantial proportion of patients failed to take their prescribed dose.[21] Among 51 outpatients who had been treated with sulphasalazine during a recent period of hospitalization, and advised to continue to take a maintenance dose during a 6-month follow-up period on leaving hospital, serum sulphapyridine levels were considerably lower during the 6-month follow-up than on discharge for 21 (41%) patients. Moreover, in 21 of 175 outpatients prescribed a maintenance dose of sulphasalazine, sulphapyridine was not detected at all during a follow-up of up to 4 years.[21] Interestingly, when questioned, most patients still claimed they took their medication as prescribed.

The reasons for non-compliance with 5-ASA therapy are complex. Male gender, single status, full-time employment and three-times daily dosing have all been identified as independent predictors of non-compliance.[20,22] Compliance may be particularly difficult to maintain during periods of symptomatic quiescence, when there are no symptomatic reminders of the underlying chronic disease. In one observational study of 94 patients with quiescent UC, 60% failed to adhere to their prescribed regimen, with an average consumption of just 70% of their prescribed dose (based on prescriptions filled over at least a 6-month period).[22] A more recent cross-sectional study used direct enquiry and monitoring of 5-ASA levels in urine samples to assess compliance of 98 outpatients to the prescribed maintenance dose of mesalazine. The study showed that 43% of patients took <80% of their prescribed dose.[20] Among a cohort of patients with quiescent UC who were asked why they did not take their medication as prescribed, 35 (50%) of the 70 patients who responded said they 'just forgot'; notably, 21 (30%) said that there were too many pills and 14 (20%) did not believe they needed that much medication.[19]

Rectal formulations of 5-ASA have proven effective for patients with distal colitis.[23] These formulations deliver therapeutic mesalazine concentrations to the terminal regions of the colon, which are not adequately dosed using current oral formulations.[24] However, such delivery methods are associated with leakage as well as problems with retention, burning sensation and bloating.[25,26] Rectal formulations require patients to retain the formulation for as long as possible, which may be difficult during times when they are suffering from diarrhoea. Also, rectal formulations may be particularly intrusive for young adults at a time when they are most likely to be establishing personal and intimate relationships.

The inconvenience of current 5-ASA formulations and the impact of frequent daily dosing on normal activities is likely to play a pivotal role in non-compliance with prescribed treatment regimens and thereby reduce the overall clinical effectiveness of the therapy.

Most patients with UC will experience at least one symptomatic relapse following their initial diagnostic episode. In a 10-year follow-up of 95 patients receiving oral or rectal 5-ASA therapy for a variety of subtypes of UC, all patients experienced at least one symptomatic relapse following initial diagnosis.[27] Patients with pancolitis and left-sided colitis relapsed most quickly, within 2-3 years of diagnosis, while those with proctosigmoiditis or proctitis relapsed within 9-10 years of diagnosis.[27]

While non-compliance with prescribed treatment regimen may contribute to symptomatic relapse in a proportion of patients, even those who do adhere to treatment remain at risk of their disease returning. Compliance with 5-ASA medication was monitored for up to 2 years in a prospective study of 99 patients with quiescent UC.[19] Among 40 patients who refilled >80% of prescriptions and were thus considered compliant with therapy, eight (20%) reported a recurrence of symptoms.[19] These results suggest that patients remain at risk despite compliance with treatment.

Non-compliance with prescribed medication regimens is known to affect long-term treatment outcomes[28] by reducing the efficacy of treatment and, for many patients, resulting in a flare-up of the disease and subsequently reduced QoL. In the University of Chicago's study of patients with quiescent UC, compliant patients were more likely to remain in remission than non-compliant patients (89% vs. 39%; P < 0.001).[19] Those patients who did not adhere to their prescribed regimen had a fivefold greater risk of recurrence than did compliant patients.[19]

Several studies have shown that the QoL of patients with UC is related to the severity of symptoms.[29,30,31,32,33] Patients experiencing a disease flare reported significantly poorer overall QoL than those in symptomatic remission.[29,30] Among 160 UC patients with active disease, all aspects of QoL [as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ)] were significantly lower than for those in symptomatic remission.[30] A further, large-scale, multicentre study involving 528 patients with UC found that patients with active disease of any severity experienced impairment in their QoL across all domains of the IBDQ and that patients with moderate-to-severe disease reported the greatest impairment across all domains.[29]

A recent cross-sectional study investigated predictors of disease-specific QoL in patients with UC (n = 111).[31] All patients completed the IBDQ, the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the Illness Perception Questionnaire (IPQ). Multivariate regression modelling showed that disease activity was the major explanatory variable for each of the four IBDQ domains (bowel, systemic, emotional and social domains) and for the total IBDQ score. In addition, bivariate analyses showed that symptom-related disease activity, elements of illness representation measured by the IPQ and elements of physical and mental health measured by the SF-36 were strongly or moderately correlated with disease-specific QoL.

Given that the symptoms of UC are strongly correlated with health-related QoL, improving compliance and thus decreasing the risk of disease flare may be an effective strategy to improve QoL.

The limitations of current oral and rectal formulations have driven the evolution of 5-ASA therapeutics to ensure patient compliance as well as improve delivery of active drug to all affected areas of the colon. Recent developments include high-dose tablet formulations with the hope of improved efficacy, once-daily regimens of existing formulations in an attempt to simplify dosing and improve compliance, and novel formulations offering more convenient dosing in addition to improved drug delivery to the whole colon. These new developments are summarized in Table 1 [34,35,36,37,38,39,40] and discussed in detail below.

The efficacy of increasing the dose of 5-ASA per tablet, in combination with increasing the dose per day, was evaluated in two phase III, randomized, double-blind, controlled trials. In the ASCEND I (n = 268) and ASCEND II (n = 286) studies,[35] patients were randomized to receive either mesalazine 800 mg tablets (2 × 800 mg three times daily [4.8 g/day]), which utilize the same delivery system as the marketed 400 mg Asacol tablet, or 400 mg Asacol tablets [2 × 400 mg three times daily (2.4 g/day)]. The primary efficacy endpoint of both trials was 'treatment success', defined as either complete remission or an improvement in both PGA score and at least one other clinical parameter, with no worsening in any other clinical parameter compared to baseline.

In the ASCEND I trial, the primary efficacy analysis included patients with mild-to-moderate disease. There was no difference between the two doses in terms of treatment success (51.3% vs. 55.9% for 2.4 and 4.8 g/day respectively; P = 0.441) at week 6.[35] However, a prespecified subgroup analysis of treatment success in patients with moderate disease (n = 169) revealed a difference between the two doses in favour of the higher dose (72.4% vs. 57.0% for the 4.8 and 2.4 g/day dose groups respectively; P = 0.0384).[35]

In light of these results, the ASCEND II protocol was amended to restrict entry criteria to patients with moderately active disease (while the study was still blinded and enrolling patients). The authors of the ASCEND II trial reported that the 4.8 g/day dose was superior to the 2.4 g/day dose for treatment success (71.8% vs. 59.2%; P = 0.036) and for time to achieve resolution of rectal bleeding (9 days vs. 16 days; P = 0.0352).[35] However, no significant improvements were observed for the 4.8 g/day dose over the 2.4 g/day dose for any of the other secondary endpoints in the study (including proportions of patients with improvements in stool frequency, rectal bleeding, PGA score and sigmoidoscopy score).[35]

An analysis of combined data from these two trials (n = 423) showed that the 4.8 g/day dose provided benefits over the 2.4 g/day dose in terms of treatment success, improvement in PGA score and sigmoidoscopic improvement among patients with moderate disease (Figure 1)[34]. However, no additional benefit was seen with the 4.8 g/day dose over the 2.4 g/day dose for the proportion of patients who achieved remission, or an improvement in stool frequency, rectal bleeding or patient's functioning score (Figure 1).[34] No additional benefit over 2.4 g/day dose was seen with the 4.8 g/day dose in patients with mild disease or mild-to-moderate disease in either trial.[34,35]

Treatment success rates for the ASCEND I and ASCEND II trials (combined data) after 6 weeks of treatment with high-dose Asacol tablets [2 × 800 mg t.d.s. (4.8 g/day)] or conventional Asacol tablets [2 × 400 mg t.d.s. (2.4 g/day)].[35] t.d.s., three times daily; PGA, Physician's Global Assessment; PFA, patient functional assessment.

Existing Formulations. The short-term outcomes of once-daily mesalazine (Asacol) vs. conventional dosing (twice or three times daily) in maintaining quiescent UC were assessed in a pilot feasibility study of 22 patients.[41] Patients continued to take their prescribed daily dose, but those assigned to the once-daily group took a sufficient number of tablets to reach this daily dose once a day instead of divided doses. After 3 months, all 12 patients assigned to the once-daily regimen remained compliant compared with only seven of the 10 patients who continued with their conventional dosing regimen (P = 0.04; between-group comparison). At the 6-month follow-up, the compliance rates for the two groups were similar and one patient in each dosing group had experienced a symptomatic relapse; neither of these patients was compliant to the assigned regimen.[41] Although the conclusions that can be drawn from such a small-scale study are limited, these results do not indicate any long-term benefit, in terms of relapse prevention, from once-daily dosing with current oral formulations.

A Novel Formulation. MMX mesalazine (SPD476, Shire Pharmaceuticals Inc., Wayne, PA, USA) is a once-daily, high-strength (1.2 g 5-ASA/tablet) formulation that combines a pH-dependent, gastro-resistant film, to delay initial release of the active drug until the terminal ileum, with a series of hydrophilic and lipophilic matrices, designed to extend consistent delivery of 5-ASA throughout the entire colon.[40]

Initial results from two large-scale, double-blind, randomized, placebo-controlled phase III clinical trials have shown MMX mesalazine to be efficacious for the induction of remission, sigmoidoscopic improvement and improvement of symptoms in patients with mild-to-moderate UC following 8 weeks once- or twice-daily dosing of 2.4 g/day or once-daily dosing of 4.8 g/day MMX mesalazine.[38,39] The primary endpoint for both studies was remission, defined as a UC-Disease Activity Index (UC-DAI) score of ≤1, rectal bleeding and stool frequency scores of 0, and a ≥1-point reduction in sigmoidoscopy score from baseline.

In the first study (n = 280), patients received either MMX mesalazine 2.4 g/day (1.2 g given twice daily), MMX mesalazine 4.8 g/day once daily, or placebo. A greater proportion of patients in both MMX mesalazine groups (2.4 and 4.8 g/day) achieved remission (34.1% and 29.2% vs. 12.9%; P ≤ 0.01), clinical improvement (55.7% and 59.6% vs. 25.9%; P ≤ 0.001), clinical remission (complete resolution of symptoms; 37.5% and 32.6% vs. 18.8%; P ≤ 0.05) and improved sigmoidoscopy score (64.8% and 71.9% vs. 36.5%; P ≤ 0.01) compared with placebo (Figure 2).[39] Both the 2.4 g/day and 4.8 g/day dose of MMX mesalazine also led to a reduced proportion of patients deemed treatment failures (unchanged, worsened or missing UC-DAI score from baseline) compared with placebo (28.4% and 24.7% vs. 54.1%; P ≤ 0.001).

Treatment outcomes after up to 8 weeks treatment with MMX mesalazine 2.4 g/day (b.d.), MMX mesalazine 4.8 g/day (q.d.s.) or placebo.[39] b.d., twice daily; q.d.s., once daily.

In the second trial, 343 patients were randomized to treatment with MMX mesalazine 2.4 g/day or 4.8 g/day given once daily, Asacol 2.4 g/day (0.8 g given three times daily) or placebo.[38] Again, a significantly greater proportion of patients receiving either dosing regimen of MMX mesalazine achieved remission or clinical remission compared with placebo (Figure 3). The proportion of patients treated with Asacol who achieved either endpoint was not significantly superior to placebo. Both MMX mesalazine and Asacol produced clinical and sigmoidoscopic improvements compared with placebo (P ≤ 0.033). Again, both the 2.4 g/day and 4.8 g/day dose of MMX mesalazine led to a reduced proportion of patients deemed treatment failures, compared with placebo (21.4% and 20.0% vs. 47.7%; P ≤ 0.033).

Treatment outcomes after up to 8 weeks treatment with MMX mesalazine 2.4 g/day (q.d.s.), MMX mesalazine 4.8 g/day (q.d.s.), Asacol 2.4 g/day (800 mg t.d.s.) or placebo.[38] q.d.s., once daily; t.d.s., three times daily.

In both studies, patients who received MMX mesalazine 4.8 g/day tended toward better sigmoidoscopic improvement compared with those who received 2.4 g/day, consistent with the higher mucosal levels of 5-ASA and its derivative, N-acetyl 5-ASA, seen with 4.8 g/day over 2.4 g/day MMX mesalazine.[42] The once-daily MMX mesalazine dosing schedule offers greater convenience and is thus likely to improve patient compliance to therapy.

Micropellet formulations of 5-ASA, provided as individual sachets containing granules, have also been studied with the aim of providing less frequent dosing in an easy-to-swallow formulation.[36,43,44] Preclinical studies have employed pharmacoscintigraphy to analyse the colonic availability of 5-ASA released from pellets vs. conventional tablets in healthy volunteers. In these studies, the drug was labelled with a radioactive tracer, which allows gastrointestinal transit, time and region of disintegration of the delivery system, and release of the active drug to be determined precisely.

In one study of 14 healthy male volunteers, mesalazine-containing pellets (500 mg) released 5-ASA in the same target region (the ileo-caecal region) and in a comparable timeframe to mesalazine tablets (Salofalk, 500 mg; Dr Falk Pharma GmbH, Freiburg, Germany) under fasting conditions.[43] Pharmacokinetic analyses showed that the plasma area-under-the-curve values were significantly lower for the micropellet formulation than for the tablet formulation, suggesting a more prolonged release of 5-ASA,[43] although whether this equates to increased colonic exposure is unclear, as mucosal epithelial cell concentrations were not assessed. Similar results were obtained in a study comparing mesalazine-containing pellets (1.5 g per sachet) with enteric-coated mesalazine tablets (Claversal, three 500 mg tablets; Merckle GmbH, Ulm, Germany) in 24 healthy volunteers.[44] Pharmacokinetic analyses revealed comparable systemic exposure following administration of the two formulations and pharmacoscintigraphy showed that for both formulations active drug was released in the terminal ileum and ascending colon. In contrast to the study of Brunner et al.[43] disintegration of the tablet formulations took place at a slightly later time point than for the micropellet formulation[44] although, again, it is unclear whether there was any relevant difference in the extent of colonic exposure as a result.

The efficacy of mesalazine micropellets [1.5 g per sachet, taken twice daily (3 g/day)] and tablets (2 × 500 mg tablets, three times daily) in patients with mild-to-moderate UC (n = 362) have been compared in a phase II, double-blind, active-controlled study.[36] The study was designed to show non-inferiority of the micropellet formulation to tablets in terms of clinical remission within 8 weeks. Clinical remission was achieved by 67% of patients who received the micropellet formulation compared with 62.9% of patients who received the tablet formulation (Figure 4), supporting the non-inferiority of the micropellet formulation (OR 1.199; 95% CI: 0.758-1.897). Compliance was excellent in both treatment arms - 96% among patients randomized to the micropellet formulation and 98% among those randomized to the tablet formulation, with similar proportions of patients rating therapy as 'very good' or 'good' (74.4% in the micropellet group and 72.9% in the tablet group).

Clinical and endoscopic remission rates among adult patients with mild-tomoderate ulcerative colitis treated with mesalazine tablets (2 × 500 mg t.d.s.) or micropellets (1.5-g sachet b.d.) for up to 8 weeks.[36] b.d., twice daily; t.d.s., three times daily.

The effects of mesalazine prolonged-release granules [one packet four times daily or two packets twice daily (4 g/day), Pentasa Sachet] were compared with prolonged-release mesalazine tablets [2 × 500 mg four times daily (4 g/day), Pentasa] in 227 patients with mild-to-moderate UC.[37] Once again, the study was designed to confirm the non-inferiority of the granule formulation compared with the tablet formulation. Both dose regimens ofthegranule formulation showed non-inferiority to mesalazine tablets for change in UC-DAI score.[37] Both formulations were equally effective with comparable improvements in overall disease activity. Patient compliance was 97% in all three treatment arms although patients preferred twice-daily dosing with the granules to tablets taken four times daily.[37] Whether this preference translates into improved longer-term compliance to therapy has not yet been reported.


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