Division of Gastroenterology, Department of Medicine, University of Pennsylvania Health System, GI Administration Offices, 7th Floor Perelman Center, Room 753, 3400 Civic Center Boulevard, Philadelphia, PA 19104-4283 USA
Find articles by Gary R. Lichtenstein
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Division of Gastroenterology, Department of Medicine, University of Pennsylvania Health System, GI Administration Offices, 7th Floor Perelman Center, Room 753, 3400 Civic Center Boulevard, Philadelphia, PA 19104-4283 USA
Gary R. Lichtenstein, Phone: 215-349-8222, Email: ude.nnepu.shpu@lrg.
Received 2015 Aug 19; Accepted 2015 Sep 18.
Copyright © The Author[s] 2015
Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License [//creativecommons.org/licenses/by-nc/4.0/], which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author[s] and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Abstract
Ulcerative colitis [UC] is a chronic idiopathic inflammatory disorder in which patients cycle between active disease and remission. Budesonide multi-matrix [MMX] is an oral second-generation corticosteroid designed to deliver active drug throughout the colon. In pharmacokinetic studies, the mean relative absorption of budesonide in the region between the ascending colon and the descending/sigmoid colon was 95.9 %. In 2 identically designed, phase 3 studies [CORE I and II], budesonide MMX 9 mg once daily was efficacious and well tolerated for induction of remission of mild to moderate UC. Clinical and endoscopic remission rates were 17.9 % [CORE I] and 17.4 % [CORE II] for budesonide MMX 9 mg compared with 7.4 and 4.5 %, respectively, with placebo [p 1 year with budesonide MMX 6 mg versus 181 days [p = 0.02] with placebo; however, further studies are needed. In the CORE studies, budesonide MMX exhibited a favorable safety profile; the majority of adverse events were mild or moderate in intensity, and serious adverse events were uncommon. Furthermore, rates of potential glucocorticoid-related adverse events were comparable across treatment groups. The long-term [12-month] safety of budesonide MMX appears to be comparable with placebo. Data support budesonide MMX in the management algorithm of UC.
Keywords: Budesonide MMX, Induction therapy, Remission, Ulcerative colitis
Introduction
Ulcerative colitis [UC] is a chronic idiopathic inflammatory disorder involving the colonic mucosa. It is characterized by periods of active symptomatic disease interspersed with periods of clinical remission [1]. A 2012 systematic review indicated worldwide UC prevalence rates of up to 249 per 100,000 persons in North America and 505 per 100,000 persons in Europe; the highest reported annual incidence rates of UC were 19.2 per 100,000 person-years in North America and 24.3 per 100,000 person-years in Europe [2]. The highest incidence appears to occur during the age range of 20–30 years, although there is some evidence for a second peak in incidence later in life [2].
Endoscopic examination of the colon in patients with UC reveals a number of characteristic changes seen in the mucosa, including loss of vascular pattern, erythema, granularity, friability, erosions, and ulceration [1, 3]. Mucosal healing, which has been defined as complete resolution of the visible alterations or lesions, regardless of their baseline nature or severity, is emerging as an important goal in the management of inflammatory bowel diseases such as UC; increasing evidence indicates that mucosal healing is associated with reductions in the number of disease flares, hospitalizations, and the need for colectomy in patients with UC [4].
Classic symptoms of UC include rectal bleeding, diarrhea, urgency, tenesmus, and abdominal pain [1], and these can impose a substantial burden on patients. Patients with UC report problems in a number of aspects of their daily lives, including withdrawal from social situations, employment disruption, increased anxiety, and decrease in health-related quality of life [5–7].
Current US [8] and European [9] guidelines recommend treatment with 5-aminosalicylates [5-ASAs] as first-line therapy for the induction of remission in patients with mild to moderate UC; such treatment is considered most effective when combinations of both topical and oral preparations are used [8, 9]. Corticosteroids may be indicated in patients in whom 5-ASA formulations are ineffective in inducing remission [8, 9]. However, first-generation corticosteroids, such as prednisone, are associated with a number of potential safety concerns, including increased risks of serious infections, bone disease, the development of cushingoid features, and increased risk of mortality [8, 10–12].
Budesonide is an orally active, second-generation corticosteroid that has affinity for the glucocorticoid receptor approximately 8.5-fold, 15-fold, and 195-fold greater than those of dexamethasone [13], prednisolone [14], and hydrocortisone [14], respectively. A number of oral formulations are available, including oral budesonide controlled ileocolonic release [CIR] [Entocort® EC, AstraZeneca LP, Wilmington, DE], budesonide capsules [Budenofalk® capsules, Dr Falk Pharma, Freiburg, Germany [not available in the USA]], and budesonide multi-matrix [MMX®; Santarus, Inc.; Raleigh, NC]. Budesonide CIR and budesonide capsules are not indicated for UC, but are indicated only for induction of remission of mild to moderate Crohn’s disease [CD] involving the ileum and/or ascending colon; budesonide CIR is also indicated for maintenance of CD remission. However, budesonide MMX is indicated for induction of remission of mild to moderate UC. Based on data from the Colonic Release Budesonide [CORE] I and II studies [15, 16], which are described later in this review, an updated UC treatment algorithm has recommended budesonide MMX before the introduction of conventional corticosteroids for the induction of remission in patients for whom 5-ASA therapy has been unsuccessful, or for those who relapse during 5-ASA therapy [10].
Several guidelines, developed before the availability of budesonide MMX, do not recommend oral conventional or second-generation corticosteroids for the maintenance of remission in UC [8, 9]; however, data are accumulating to support an acceptable tolerability profile for second-generation corticosteroids. One study, which evaluated the long-term [1-year] safety of budesonide MMX in patients with UC, indicated that oral budesonide MMX 6 mg had a safety profile similar to that of placebo [17]. In addition, the CD clinical trials of budesonide CIR and budesonide capsules support the safety of oral budesonide during long-term [e.g., 1 year] exposure in patients with inflammatory bowel disease [18–28]. This article reviews the efficacy and safety profile of budesonide MMX for the treatment of UC.
Pharmacokinetic Properties of Budesonide
Budesonide is a second-generation corticosteroid with low systemic bioavailability after oral administration because of extensive [~90 %] first-pass hepatic metabolism [29]. It is metabolized predominantly by hepatic cytochrome P450 3A [CYP3A] enzymes to form 2 principal metabolites: 16α-hydroxyprednisolone and 6β-hydroxybudesonide [30]. These metabolites comprise only 1–10 % of the biologic activity of the parent compound [29]. Following oral administration, approximately 75 % of the dose is excreted in the urine and feces [29].
The MMX formulation has been designed to target orally administered drugs to sites in the distal colon [31]. This delivery system utilizes an outer pH-dependent coating consisting of a hydrophilic and inert polymer matrix, which allows passage of active drug through the gastrointestinal tract to the ileum, where the outer layer of the capsule begins to dissolve at a pH > 7.0. The active drug is therefore delivered uniformly throughout the length of the colon, thus minimizing systemic absorption, in contrast to conventional corticosteroid absorption [Fig. 1] [31, 32]. MMX technology has been used effectively for the delivery of 5-ASA to the colon, whereby mesalamine MMX is being used for both induction [31, 33–35] and maintenance [36, 37] of remission in patients with mild to moderate UC.
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Fig. 1
Targeted delivery of budesonide MMX throughout the colon. Original art from Asklepios Medical Atlas/Science Photo Library
In pharmacokinetic studies with budesonide MMX 9 mg, the mean relative absorption of budesonide in the region between the ascending colon and the descending/sigmoid colon was 95.9 % with drug detected between 4 and >24 h postdose [Fig. 2] [38]. This relative absorption profile contrasts with the absorption of other oral budesonide formulations: For example, following administration of budesonide CIR, approximately 69 % of the dose is absorbed in the distal ileum and ascending colon, the sites typically affected by inflammation in patients with CD [39]. Release of the active drug from budesonide CIR and budesonide capsules occurs in a more acidic environment than with budesonide MMX, with absorption beginning at pH values of 5.5 and 6.4, respectively [40, 41].
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Fig. 2
Scintigraphic image in a healthy volunteer showing dispersion of [153Sm]-labeled budesonide MMX in the colon. The image was obtained approximately 7 h after administration. Reprinted with permission from Brunner et al. [38]
In a study of healthy volunteers, the mean lag time [tlag] between administration of budesonide MMX 9 mg and detection of budesonide in plasma was 6.8 h; the mean peak plasma concentration [Cmax] was 1768.7 pg/mL, and the time to Cmax [tmax] was 14.0 h [38]. Administration of budesonide MMX with food resulted in significant decreases in both Cmax [p = 0.03] and systemic exposure as measured by the area under the concentration–time curve to 48 h [AUC48h; p = 0.008], but these changes are not considered to be clinically meaningful [38]; hence, budesonide MMX may be administered with or without food [42]. After single dosing in healthy volunteers, Cmax, AUC0–36 h, AUC0–∞, and half-life [t1/2] of budesonide MMX 9 mg were comparable to those of budesonide CIR 9 mg [43]. Median tlag was 6 h for both 9- and 6-mg doses of budesonide MMX, compared with 1 h for budesonide CIR 9 mg [43].
Because budesonide is metabolized predominantly in the liver, bioavailability may be increased in patients with impaired liver function. In a study in patients with primary biliary cirrhosis who received a single dose of budesonide 3 mg [non-MMX formulation], patients with late-stage [stage IV] disease showed significantly greater systemic exposure to budesonide than those patients with early-stage [stage I–II] disease [44]. Mean Cmax was 1.5 ng/mL in patients with early-stage disease, compared with 4.9 ng/mL in patients with late-stage disease [p 1 to ≤5 years, and patients with UC duration >5 years.
Budesonide MMX for the Maintenance of Remission of UC
The efficacy of budesonide MMX for the maintenance of UC remission was investigated in a study of patients who had achieved clinical and endoscopic remission in the CORE I and II studies [15, 16] or patients in CORE I and II who had received an additional 8 weeks of treatment [budesonide MMX 9 mg] in an open-label study [Table 1] [17, 48]. In the maintenance study, patients were randomized to receive budesonide MMX 6 mg or placebo for up to 12 months; the primary efficacy endpoint was clinical remission, assessed after 1, 3, 6, 9, and 12 months. The median time to clinical relapse [defined as rectal bleeding, stool frequency ≥1–2 stools per day, or both] was 181 days in the placebo group, but was not reached in the budesonide MMX group [p = 0.02; Fig. 4] [17]; at 12 months, the probability of relapse was 59.7 and 40.9 %, respectively [17]. However, the percentage of patients in whom remission was maintained for up to 12 months did not differ significantly between the groups, a finding that was potentially attributable to insufficient statistical power. Therefore, the potential benefit of budesonide MMX in maintenance of remission is currently unclear and further studies are required.
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Fig. 4
Kaplan–Meier plot showing the time to clinical relapse [defined as rectal bleeding, stool frequency ≥1–2 stools per day above normal, or both] in patients receiving maintenance therapy with budesonide MMX 6 mg or placebo for up to 1 year [17]. Reprinted with permission from Sandborn et al. [17]
Adverse Effects
In general, the budesonide molecule exhibits a more favorable safety profile than first-generation oral corticosteroids such as prednisone or prednisolone. For example, in a 10-week, double-blind, double-dummy study in 176 patients with CD who received tapering doses of prednisolone or budesonide CIR for 10 weeks, the incidence of glucocorticoid-related adverse effects was significantly lower with budesonide than with prednisolone [33 vs. 55 %, respectively; p = 0.003]. In addition, suppression of the hypothalamic–pituitary–adrenal axis, assessed by measurement of the mean morning plasma cortisol concentration, was significantly greater with prednisolone than with budesonide CIR after 4 weeks [p