Aliment Pharmacol Ther 1997: 11 (Suppl. 3): 98-108.
`
`Reviewarticle: Drug developmentin inflammatory bowel disease:
`budesonide — a model of targeted therapy
`
`R. HAMEDANI, R. D. FELDMAN & B. G. FEAGAN
`The University of Western Ontario, London, Ontario, Canada
`
`SUMMARY
`
`Theuse of non-specific anti-inflammatory drugs such as
`the glucocorticoids is the foundation of medical therapy
`for inflammatory boweldisease. Although conventional
`steroid drugs are highly effective, their use is associated
`with the adverse effects of Cushing’s syndrome.
`However, the therapeutic index of these drugs can be
`improved by chemical modification of the steroid
`
`nucleusandthe use of new drugdelivery systemsthat
`target the bowel wall as the pharmacokinetic
`compartmentof interest. Budesonideis a novel
`glucocorticoid compoundthatillustrates the potential of
`this approachto identify effective and safe new
`treatments. Regional therapy for inflammatory bowel
`disease is an important pharmacological conceptfor the
`future developmentof the new glucocorticoids and
`otherclasses of drugs.
`
`INTRODUCTION
`
`Crohn's disease and ulcerative colitis are idiopathic
`inflammatory disorders of
`the bowel which have a
`worldwide distribution.
`In these conditions, chronic
`inflammation of the intestinal mucosa causes oedema
`and ulcer formation. This process produces the common
`clinical symptomsof diarrhoea, bleeding and abdominal
`pain. In ulcerative colitis, the inflammation is confined
`exclusively to the colon. Crohn's disease may occurat any
`site in the gastrointestinal tract, but more frequently in
`the terminal ileum and the proximal colon.
`distinct.
`The
`two
`conditions
`are
`pathologically
`Inflammation in ulcerative colitis begins in the anal
`canal,
`is continuous to a variable degree through the
`colon, andis superficial. In contrast, Crohn's disease is
`usually characterized by segmental involvement of the
`colon or small bowel with transmural inflammation.
`Endoscopically, linear ulcerations surrounded by areas of
`normal mucosa are seen. The clinical course of both
`diseases
`is unpredictable,
`and usually consists of
`intermittent exacerbations of symptoms interspersed
`with periods of remission.'
`
`Correspondence to: Dr Brian Feagan, London Health Sciences Centre,
`University Campus, 60F 13, 339 Windermere Road, London, Ontario,
`Canada.
`
`MEDICAL THERAPY FOR INFLAMMATORY BOWEL
`DISEASE
`
`As the cause of inflammatory bowel disease (IBD) is
`unknown,current medical treatmentis directed towards
`suppressing the pathological inflammatory response. The
`most important classes of drugs are 5-aminosalicylates
`(5-ASAs), glucocorticoids and immunosuppressives.?
`Surgeryis used to treat complicationsof either disease or
`as a meansofcontrolling symptomsin thoseindividuals
`whodo notrespondto drug therapy. In the case ofulcera-
`tive colitis, colectomy is curative. Surgery does not cure
`Crohn'sdisease: the inflammation recursfollowing resec-
`tion of a segmentof inflamed bowel.
`Glucocorticoids are the most important class of drugs
`for the treatmentof active ulcerative colitis and Crohn's
`disease. The efficacy of
`steroid therapy has been
`confirmed by randomized, controlled trials.** Gluco-
`corticoids exert their anti-inflammatory effects through
`multiple mechanisms,
`including suppression of both
`humoraland cellular immunity, inhibition of neutrophil
`and macrophage chemotaxis and reduction of cytokine
`production.” However, glucocorticoids also have powerful
`metabolic effects, which include the regulation of carbo-
`hydrate, protein, and mineral homeostasis. As glucocorti-
`coid receptors are ubiquitous in human tissue and the
`
`98
`
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`REVIEW: DRUG DEVELOPMENTIN INFLAMMATORY BOWEL DISEASE
`
`99
`
`acting steroids in patients who have disease elsewhere in
`the colon or small bowel. The developmentof suchfor-
`mulations were pioneered during the 1980s for the
`5-aminosalicylates. Sulfasalazine, which consists of a
`sulfonamide antibiotic (sulfapyridine) linked by an azo
`bond with an anti-inflammatory salicylate (mesalamine)
`is poorly absorbed in the upper gastrointestinal tract.
`Upon entering the colon, bacterial enzymes split the
`sulfasalazine diazo bond,
`liberating 5-ASA./? As the
`efficacy of 5-ASA is dependenton the drug concentration
`in the bowel lumen,this is a highly effective mechanism
`for delivery of the drug to the colon. However,the sulfa-
`pyridine moiety is associated with adverse effects. Newer
`5-ASA delivery systems were designed which did not
`require a sulfur-based carrier molecule. These formula-
`tions prevent proximal absorption of 5-ASA and deliver
`the drugto specific sites of intestinal inflammation. The
`developmentof these compoundsprovide a model which
`can be exploited for use with other classes of drugs,
`including glucocorticoids.‘>
`
`DRUG ABSORPTION: LOCAL AND SYSTEMIC
`
`interaction of these steroids with the glucocorticoid
`receptor is not tissue-specific,® adverse drug effects from
`glucocorticoids are a common occurrence. The cosmetic
`effects that characterize Cushing’s syndrome are almost
`uniform with chronic steroid use. The most commonside-
`effects are moonfaces, acne, swollen ankles, easy bruis-
`ing, and hirsutism.” More serious adverse events, such as
`diabetes mellitus, hypertension and osteoporosis may
`also occur.®:? Thus, glucocorticoid therapy is a two-edged
`sword;its efficacy for the suppression of inflammationis
`coupled to other unwanted metabolic effects. These con-
`siderations have led to a search for new glucocorticoids
`with enhanced anti-inflammatory activity and decreased
`systemic toxicity.
`
`CHARACTERISTICS OF AN IDEAL GLUCOCORTICOID
`FOR USE IN INFLAMMATORY BOWEL DISEASE
`
`The pharmacologicalprofile of an ideal glucocorticoid for
`use in inflammatory bowel disease (IBD) is shown in
`Table 1. The drug should combine high potencyatthesite
`of inflammation with minimal systemic effects. One way
`offulfilling these criteria is to employ localized therapy.
`Theinitial formulationsof steroids for localized therapy
`utilized rectal
`installation routes. Clinical
`trials have
`shownthattopical formulations (enemas, suppositories,
`foams) of hydrocortisone or betamethasoneareeffective
`for the treatment of ulcerative colitis and infrequently
`cause systemicside-effects. ’””?* However, rectal adminis-
`tration formulations are effective only for those patients
`whose disease is distal to the splenic flexure of the colon.
`The development ofspecific oral drug delivery systems
`involves a newer, alternative approachto deliver locally
`
`Thesite at which an oral drug is absorbed is affected by
`multiple factors (Table 2).'® Differences in absorption
`rates are often notclinically important for systemically
`acting drugs, as the pharmacodynamiceffectis primarily
`determined by the total amountof drug, not the rate of
`absorption. However, this is not the case for compounds
`which act topically in the gastrointestinal tract, because
`the luminal concentration of the drug may be the prim-
`ary determinantof efficacy. Furthermore, thefactors that
`govern drug absorption may vary between healthy indi-
`viduals and those with IBD. This may result in marked
`differences in bioavailability between individuals. The two
`Table 1. Characteristics of an ideal glucocorticoid for treatmentof IBDaeeneeee
`physiological factors that are of primary importance in
`regulating absorption in the gastrointestinal tract are pH
`andintestinal transit time. The site where water-soluble
`compounds are absorbed is dependent upon anionic
`charge, whichis in turn,sensitive to the environmental
`
`e High anti-inflammatory activity
`@ Site selectivity
`e@ Low systemic absorption
`© Rapid degredation of absorbed drugto inactive metabolism
`
`ne
`
`Drug factors
`
`Dosage form factors
`
`Physiological factors
`
`pKa
`
`Disintegration time
`
`Intestinal surface area and transit time
`
`Table 2. Factors affecting the absorption of
`drugs
`
`Dissolution rate
`Solubility
`Enterohepatic cycling first-pass effect
`Type of dosage form
`Partitioning
`
`——_eer:000
`
`pH ofgastrointestinal fluids
`
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`100 R.HAMEDANI, R.D. FELDMAN & B.G. FEAGAN
`
`hydrogen ion concentration. The pH of the stomach in
`the fasting state is approximately 4.0-6.0, but can
`decrease toless than 2.0 after a meal. In the small bowel,
`the pH ranges from approximately 5.0 in the duodenum
`to nearly 8.0 at the ileocaecal valve. The rate of absorp-
`tion of weak acids increases with decreasing pH; con-
`versely, the rate of absorption of weak basesis increased
`with increasing pH. As the pH of the bowel contents
`governsthe proportion of drug whichexists in an ionized
`form, compoundsthat are acidic should, in theory, be
`absorbed to a greater extent in the stomach and com-
`pounds that are basic should be absorbed to a greater
`extentin the distal colon. However, other factors such as
`the much greater surface area available in the small
`bowel for absorption and theintestinal transit time are
`dominant.'” These factors must be considered when
`designing drugs for targeting specific sites in the gastro-
`intestinal tract. The presenceof regionaldifferences in pH
`can be used to either decrease or increase drug absorp-
`tion. However, it should be recognized that the hydrogen
`ion concentration in specific regions of
`the gastro-
`intestinal tract of patients with IBD may not be the same
`as in normalindividuals. Fallingborg et al. have studied
`this question, using a radiotelemetry capsule as a pH
`probe.’” Patients with ulcerative colitis had normal gas-
`tric and small bowel hydrogen ion concentrations.
`However, three of the six individuals evaluated showed
`very low pH values (2.3—3.4) in the proximinal colon.
`Increased concentrations of faecal lactate were noted in
`this area. Fallingborg et al. hypothesized that this abnor-
`mally low pH wastheresult of a decreased capacityof the
`epithelium to metabolize butyrate. In normalindividuals,
`butyrate is the primary source of energy for enterocytes;
`however, the presence of inflammation may impair cellu-
`Jar metabolic pathways. This could result in an increased
`production of lactate in the colon.'*'!? Thefinding may
`be important for the design of locally acting therapy
`because the abnormally acidic environment present in
`active ulcerative colitis could significantly alter the phar-
`macokinetics of an orally administered drug. Another
`important determinant of drug absorption is intestinal
`transit time. A drug that is absorbed in the gastro-
`intestinaltract outside of the area of inflammationis not
`available to act as a local therapy. Thus, the absorption of
`a drug whichis intended for this purpose, either proximal
`or distal to a site of inflammation, is undesirable. The
`high degree of variability in intestinal transit time noted
`in normal individuals is more pronounced in patients
`with intestinal diseases. Reddy et al., used both radio-
`
`isotopes and manometry to comparethecolonic motility
`of patients with active ulcerative colitis to healthy con-
`trols.?° In the latter group, an increase in colonic pres-
`sure was demonstrated after eating and was greatest in
`the descending colon. In contrast, patients with ulcera-
`tive colitis had decreased colonic pressure in all areas of
`the colon, and no pressure gradient was observed
`between adjacent colonic segments. Thetransit of intes-
`tinal contents in the control group was reduced in the
`fasting state. However,following the ingestion of a stan-
`dardized meal, both antegrade andretrograde transit of
`intestinal contents were increased. In contrast, intestinal
`transit in the patients with ulcerative colitis was variable
`both before and after a meal. An increase in low ampli-
`tude contractions was associated with a more rapid ante-
`grade transmission of bowel contents into the sigmoid
`colon. Reddy et al. speculated that these findings would
`result in a decreased time for the bowel contents to be in
`contact with the rectal mucosa. Other manometric stud-
`ies are also consistent with the notion that abnormalities
`of motility are commonin patients with IBD. Rao and
`Read studied 62 patients with active ulcerative colitis and
`20 healthy controls using rectal manometry.?! These
`investigators demonstrated that
`the resting motor
`activity was significantly lower in patients with active
`ulcerative colitis than in the healthy controls. Rectal con-
`tractions of higher amplitude than normal were demon-
`strated following infusion of saline into the distal bowel.
`Theinvestigators postulated that the diarrhoea in ulcera-
`tive colitis is a result of both an increase in rectal sensi-
`tivity and more vigorous muscular contractions. These
`abnormalities have important
`implications for drug
`development, as locally acting drugs require adequate
`time to enter the bowel wall compartment. An adequate
`concentration of drug must be delivered to the site of
`inflammation without proximal absorption. Sufficient
`time mustbe available for the drug to be in contact with
`the intestinal epithelium. This presents a challenge for
`time-dependent delivery systems. If a topically active
`drugis released at a site whichis either proximal ordistal
`to the targetsite, efficacy is likely to be compromised.
`
`Drug determinants: implicationsfor gastrointestinal drug-
`delivery systems
`
`For an orally administered, topically active drug to be
`effective, it must be in solution.’® Orally administered
`drugs are usually in the form of capsules or tablets. Free
`drug is released from these products through aninitial
`
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`REVIEW: DRUG DEVELOPMENTIN INFLAMMATORY BOWEL DISEASE
`
`101
`
`process of disintegration. The rate of disintegration is
`governed by the physical formulation of a product.
`Tablets consist of granules of drug in a matrix of inert
`ingredients (excipients). Disintegration results in the
`release of small particles that can provide a large surface
`area for solubilization of the drug. Gelatin capsulesdis-
`solve rapidly (less than 10 min) andreleasefine particles
`of drug that are easily solubilized. Following solu-
`bilization, the drug is available for absorption. Many
`drugsare poorly soluble, so that the rate of dissolution is
`rate-limiting for absorption. Oral drugs maybe altered in
`several ways to modify dissolution and absorption
`characteristics. Prodrugs may be designed to influence
`the site at which absorption takes place. For systemically
`active drugs,
`it is desirable to enhance proximal drug
`absorption. Weak acids whichare poorly absorbed in the
`proximal small bowel may be conjugated with lipophilic
`side-chains to enhance absorption. Following absorption,
`the modified drug is metabolized and the parent com-
`poundis released. Another drug factor which regulates
`absorptionisits lipid solubility. Lipophilic compounds are
`absorbed more rapidly across epithelial cell membranes
`than polar molecules. Absorption occurs in accordance
`with the pH partition coefficient. This value reflects the
`relative concentrations of drug present at an organicsol-
`vent/waterinterface. A drug witha partition coefficient
`of 1 has equal solubility in the organic and liquid phases.
`Drugs that are well absorbed have partition coefficients of
`10:1 (octanol/water) or greater. For drugs which act
`locally in the gastrointestinal
`tract, proximal drug
`absorption is undesirable. Carrier molecules can be
`attached to the active compound, which, because of their
`polar nature, are poorly absorbed in the proximal small
`bowel. As discussed previously, sulfasalazine is a proto-
`typic example of a drug that exploits this concept.
`Osalazineis an example of a 5-ASA prodrug thatexploits
`a similar approach.” Anotherapproachis to design spe-
`cific gastrointestinal transport systems which are based
`on physical strategies. These drugs may be designed to
`maintain more constant drug levels for systematically
`acting drugs. Natural polymers are available which
`release a drug according to zero-order(i.e. a constant rate
`of release) orfirst-order kinetics. The result is lower drug
`absorption andless variability in serum concentrations.
`Osmotic mini-pumps have been used recently in the oral
`formulation of several drugs, including nifedipine.?? In
`this system, water enters the drug tablet by osmosis. This
`results in an increase in pressure within the tablet. The
`drugis slowly forced outofa laser-drilled outlet, which
`
`yields a constantrate of drugrelease. Similar systems can
`be designed to deliver drug to specific regions of the
`gastrointestinal
`tract
`in a time-dependent
`fashion.
`Eudragit coatings are commonly used.?* Eudragit is a
`synthetic polymer which has pH-dependent dissolution
`properties. Two forms of Eudragit; R and L, have signifi-
`cantly different dissolution properties. Eudragit L dis-
`solves at pHs of greater than 7.0, whereas EudragitS is
`optimally released at under pH 6.0.
`
`Determinants of systemic absorption: implicationsfor
`toxicity
`
`Systemic toxicity is dependent both on the degree of
`absorption and the extent to which the drug is metabo-
`lized in theliver as it passes from the portal circulation.
`The liver is the primary site of drug metabolism.2°
`Hepatic enzymesystemsfacilitate the excretion of lipid-
`soluble drugs by converting them to more polar meta-
`bolites. However,it has recently been recognized that the
`intestine
`also plays an important
`role in drug
`metabolism.?° The epithelial cells of the small bowel
`express cytochrome P450 (CYP)3A enzymes, which
`metabolize glucocorticoids and other drugs. A wide vari-
`ation exists amongindividuals in the expression of these
`enzymes.”’ Thus, the intestinal phase of drug meta-
`bolism in a population may be highly heterogeneic.
`Commonly prescribed drugs may interact with these
`enzyme systems. Rifampicin is a potent
`inducer of
`CYP3<Aexpression in enterocytes.?* Erythromycin”? and
`grapefruit juice*° inhibit these enzymes. Some impor-
`tant clinical correlates of these pharmacokinetic consid-
`erations have beenidentified. Drugs such as cyclosporin
`and felodipine
`are highly sensitive
`to intestinal
`metabolism. Cytochrome P450 enzymes may be impor-
`tant to the pharmacokinetics of regionally active gluco-
`corticoids, however. no data are currently available
`which address this issue. Following transport across the
`epithelial cell, orally administered drugs are transported
`to theliver via the portal circulation. The absorption and
`subsequent metabolism of drugs is sensitive to changes
`in mesenteric blood flow. Bolondi et al., using Doppler
`ultrasound measurements, have demonstrated a signifi-
`cant increase in splanchnic venous return in patients
`with active IBD, in comparison to healthy individuals.?!
`In patients with Crohn's disease, the mean velocity of
`portal venous blood was 28.2 + 7.7 cm/sec in compari-
`son to 19.4+2.2 cm/sec in healthy individuals (P <
`0.001). Accordingly, the values in patients with ulcera-
`
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`102. R.HAMEDANI, R.D. FELDMAN & B.G. FEAGAN
`
`tive colitis were 27.7+5.8 cm/sec as compared with
`19.4+2.2 cm/sec (P< 0.05) for the control group. The
`increased flow in these patients with IBD normalized
`following treatment.
`
`the treatmentof skin disease becauseof poortissue pen-
`etration. The introduction of lipophilic constituents at
`the 17-a and 16-a positions enhances tissue penetra-
`tion. The resultant compound,
`triamcinolone ace-
`tonide, is a highly effective drug for the treatment of
`dermatoses.?? Similar modifications resulted in the
`developmentof budesonide.
`Budesonideis a 17-o substituted steroid that has many
`Only a small fraction of a systematically administered,
`desirable
`characteristics
`for
`use
`as
`a_
`regional
`absorbed drugisinitially exposed to hepatic metabolism.
`anti-inflammatory drug. Budesonide has a_topical
`In contrast, all of an orally administered, absorbed drug
`anti-inflammatory effect approximately five times that
`whichis absorbed is susceptible to hepatic metabolism.
`of prednisone. This increase in potency was achieved
`This occurs because the venousblood from the gastro-
`by modifying the 6-a-hydroxy-prednisolone nucleus
`intestinal
`tract
`returns to the systemic circulation
`through the addition of 16a and 17a acetyl groups.
`throughthe portal system andtheliver. In contrast, only
`Budesonide has a systemic bioavailability of 9.3-15%
`25-30% of blood in the systemic circulation passes
`when administered orally as a controlled, ileal-release
`through the liver with each transit of the circulation.
`capsule orrectally as an enema.** The drug undergoes
`Thus,there is approximately a four-fold increase in expo-
`extensive first-pass metabolism in the liver and possibly
`sure to the effects of hepatic metabolism in orally admin-
`the intestinal epithelium. The two major metabolites, 6B-
`istered drugs compared to those given parenterally. In
`hydroxy-budesonide
`and
`16a-hydroxy-prednisolone,
`order to minimize the undesirable systemic effects of
`have minimalglucocorticoid activity.** The highest con-
`glucocorticoids,
`topically actings drugs should have a
`centration of metabolites are excreted via the kidneys. A
`high,
`first-pass metabolism. Hepatic CYP3A enzyme
`smaller amountof conjugated metabolites are eliminated
`systems are primarily responsible for glucocorticoid
`through the bile. Formulations of budesonide have been
`metabolism.?° This family of enzymesis involved in the
`designed to target specific regions of the gastrointestinal
`metabolism of many other commonly used drugs. Thus,
`tract that are of relevance to the treatment of IBD. An
`interactions with drugsthateither induceor inhibit these
`enemaformulationis available for the treatmentofdistal
`enzymes maybeclinically important.
`ulcerative colitis or proctosigmoiditis.**3° The develop-
`ment of a budesonide enterocapsule (budesonide con-
`trolled ileal release) hasfacilitated delivery of the drug to
`the distal small bowel and proximal colon for use as a
`treatment in Crohn's disease. This formulation contains
`acid-stable micro-granules of budesonide whichare sus-
`pended in ethy! cellulose. The enterocapsule is coated
`with a layer of metho-acrylic acid copolymer that dis-
`solves at a pH above 5.5. Approximately 50-79% of the
`absorption of budesonide occursin the distal small bowel
`and proximal colon.'* Recently, a colonic preparation of
`budesonide has been described, which consists of bude-
`sonide capsules containing acid-resistant pellets of
`drug.*” This formulation has a sustained-release profile
`whichdelivers active drug during passage of the capsule
`throughthe colon.
`
`First pass metabolism
`
`Pharmacokinetic properties of budesonide
`
`Chemical modification to the glucocorticoid nucleus
`can enhance anti-inflammatory effects while minimiz-
`ing undesirable mineralicorticoid activity. Two methods
`are available for the assessmentof the potency of gluco-
`corticoid drugs. Oneis the in vitro measurement of the
`binding affinity for the glucocorticoid receptor.° To
`achieve optimalanti-inflammatoryactivity, a candidate
`drug should have a high affinity for this receptor. The
`other measureis a bioassay in which a range of concen-
`trations of a candidate compoundis applied to the skin
`of a healthy volunteer. Blanching of the skin from
`steroid-induced vasoconstriction is assayed visually in
`comparison with a laboratory standard, fluocinolone
`acetonide. This bioassay evaluates both the anti-inflam-
`matory activity and tissue penetration of a drug.
`Esterification at the 17-a position markedly enhances
`the potency of a glucocorticoid. However, despite potent
`anti-inflammatory
`effects,
`compounds
`such
`as
`betamethasone and dexamethasoneare unsuitable for
`
`Budesonide: results of clinical studies
`
`A large numberofclinical trials have evaluated the use of
`budesonide enemas in patients with distal ulcerative
`colitis or proctosigmoiditis. The oral controlled,
`ileal-
`
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`REVIEW: DRUG DEVELOPMENTIN INFLAMMATORY BOWELDISEASE
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`103
`
`release formulation has been assessed in patients with
`Crohn’s disease involving the ileum and/or ascending
`colon. A single study has evaluated the use of an oral
`formulation of budesonidefor the treatmentof ulcerative
`colitis.
`
`Enematherapy for ulcerativecolitis
`
`Budesonide enemas have been evaluated extensively in
`patients with distal ulcerative colitis, and a similar
`efficacy to conventional glucocorticoid enemashas been
`demonstrated. **:*? However, budesonide-treated patients
`are less likely to show suppression of morning plasma
`cortisol concentration, or have abnormal adreno-
`corticotrophic hormone (ACTH) stimulation tests than
`those receiving hydrocortisone enemas or oral pred-
`nisolone. As abnormalities of these measures of hypo-
`thalamic-pituitary-adrenal
`(HPA)
`axis
`function are
`markers of systemic glucocorticoid exposure, the chronic
`administration of budesonide enemas maybe lesslikely to
`cause glucocorticoid-related toxicities, such as osteoporo-
`sis, than conventionalsteroid preparations.
`
`ORAL BUDESONIDE FOR CROHN'S DISEASE
`
`Induction of remission
`
`Three randomized, controlled trials have evaluated the
`efficacy of oral budesonide for the treatment ofpatients
`with active Crohn's disease. Two of these studies were
`reported in 1994. A multicentre study performed in
`Canada evaluated three different doses of budesonide
`(3mg, 9mg/day and 15 mg/day) in comparison to a
`placebo for 8 weeks of treatment.*” A European study
`compared theefficacy of 9 mg/day of budesonide admin-
`istered once daily to a conventional, tapering-dose regi-
`men ofprednisolone (40 mg/day to 5 mg/day).*' These
`studies were of similar design and used an identical
`measure of response, remission (a minimum of a 60-
`point decrease in the Crohn's disease activity index
`(CDAI), and a CDAIscore of <150 after week 8 of treat-
`ment). In both trials, the patients were required to have
`disease confined to the ileum and/or right colon, and a
`minimum CDAIscore of 200 at the entryvisit.
`The Canadian dose-finding study identified that
`9 mg/day of budesonide wasthe mosteffective dose and
`that no additional benefit was conferred by a 15 mg/day
`dose. A 51% rate of remission was observed following 8
`weeks of budesonide therapy, in comparison to a 20% res-
`ponse rate in the placebo group (P < 0.001). An almost
`
`© 1997 Blackwell Science Ltd, Aliment Pharmacol Ther 11 (Suppl. 3), 98-108
`
`[__] Placebo
`Ea Budesonide
`‘ Prednisolone
`
`70
`
`%Remissionweek8 S
`
`Figure 1, The proportionofpatients in remission following treatment
`with budesonide, prednisoloneorplacebo is shown (composite data
`from Refs 40 & 41).
`
`identical response rate (52%) was observed for bude-
`sonide 9 mg/day in the European study, in which no sig-
`nificant difference was observed between the budesonide
`and prednisolone groups (52% budesonide vs. 66% pred-
`nisolone, P = 0.12). Figure 1 shows the composite
`efficacy data from these trials.
`Both studies demonstrated that budesonide therapy was
`well tolerated. No significant difference in the proportion
`of patients experiencing glucocorticoid-related adverse
`events was observed between the treatment groupsin the
`placebo-controlled Canadianstudy. Significantly fewer of
`these events were seen in the budesonide-treated patients
`in the European study in comparison to those who
`received prednisolone (33% vs. 55%, P = 0.003). Figure 2
`showsthe composite toxicity data. Budesonide therapy
`did cause a dose-related depression in mean morning
`plasma cortisol concentrations, and an increase in the
`proportion of patients with an abnormal ACTH-stimula-
`tion test. However, these findings were morelikely to
`occur in patients who received prednisolone, and were
`not correlatedwith the presenceofclinical signs of gluco-
`corticoid toxicity.
`It should be noted that the two studies used different
`dosing regimens;for the European trial, budesonide was
`administered once daily, as compared to the twice daily
`regimen employed in the Canadianstudy.
`To define the optimum dosing regimen,a third trial was
`performed, in which budesonide 9 mg/day administered
`either once or twice daily was compared to a standard
`
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`Cosmo Ex. 2004-p. 6
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`

`104
`
`R.HAMEDANI, R.D. FELDMAN & B.G. FEAGAN
`
`70
`
` fa Prednisolone %ofpatientswithglucocorticoid-relatedADRs
`
`[| Placebo
`[J Budesonide
`
`55%
`
`
`
`
`
`conclusion was based on a subgroup analysis. No over-
`all benefit was demonstrated in the primary analysis of
`that trial. Three maintenance studies**~*° were per-
`formed as follow-up protocols to each of thetrials in
`active Crohn’s disease, which were previously described.
`The design of these studies was identical. Patients who
`were in remission at the end of the active treatment
`phase (CDAI < 150 points) were re-randomized to
`receive continued therapy with either budesonide
`6 mg/day, budesonide 3 mg/day or placebo. The total
`duration of treatment was 1 year. The primary outcome
`in these studies was the time to a relapse of Crohn's
`disease, which wasdefined by the presenceofeither: a)
`a CDAIincrease of 60 points and a minimum CDAI
`value of 150; or b) the introduction of therapyfor active
`Crohn's disease.
`An overview analysis was recently performed using
`individual patient data from the three trials (unpubl.
`observ.). Glucocorticoid-related adverse effects occurred
`no more frequently in patients who received 6 mg/day
`budesonide for periods of up to 1 year than in those
`assigned to the placebo. Budesonide 6 mg/day signifi-
`cantly prolonged the median duration of
`remission
`in comparison to placebo (263 days vs, 154 days,
`P=0.011). However, at 1 year following randomization,
`no Clinically significant difference existed between the
`treatment groups in the proportion of patients who
`remained free of a relapse.
`These results are both gratifying and at the same time
`disappointing. The data show that the chronic adminis-
`tration of budesonide is safe and modifies the natural
`history of Crohn’s disease following a medically induced
`remission of the disease. These findings contrast with the
`negative results of
`the previous maintenance trials
`which evaluated conventional glucocorticoids for this
`indication. However,
`the effect of budesonide is not
`durable. For most patients, a relapse of the disease is
`prevented but not delayed. Despite these findings, bude-
`sonide might be of value as a chronic treatment in
`selected patients at high risk of relapse. In addition, the
`efficacy of budesonide used in combination with other
`potentially effective maintenance treatments (i.e. 5-
`ASA,fish oil) should be assessed. Such a combination
`maintenance regimen might yield a moreeffective and
`tolerable long-term therapy for the disease. The chronic
`administration of
`a higher dose of budesonide
`(9 mg/day) or the use of a flexible dosing regimen also
`requires evaluation, Clinical trials are currently under-
`wayto assess thesestrategies.
`
`© 1997 Blackwell Science Ltd, Aliment Pharmacol Ther 11 (Suppl. 3), 98-108
`
`Cosmo Ex. 2004-p. 7
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`Figure 2. The proportion of individuals with glucocorticosteroid-related
`adverse events was greatest with prednisolone.No significant difference
`was noted between the budsonide and placebo groups (composite data
`from Refs 40 & 41). ADR = adverse drugreactions.
`
`regimen. After 8 weeks of
`prednisolone treatment
`therapy, the response rate in the once-daily budesonide
`group and prednisolone group wereidentical (60%), as
`compared to the 42% remission rate observed in the
`twice-daily budesonide dose group (P = >0.05).** These
`studies confirmed that 9 mg/day oral budesonide admin-
`istered once daily is the optimum dose for the treatmentof
`active Crohn's disease. The most important advantage of
`budesonide over conventional glucocorticoids is a lower
`risk of adverse events. This is an important consideration
`in selecting a therapy for patients who are intolerant of
`prednisoneor prednisolone.
`
`MAINTENANCEOF REMISSION
`
`The promising results of the clinical trials which evalu-
`ated budesonide for the treatment of active Crohn's
`disease have led to further studies which evaluated the
`role of the drug as a maintenancetherapy. Previous
`studies which evaluated conventional glucocorticoids
`for this indication did not sho