Aliment PharmacolTher 1997: 11 (Suppl. 3): 98-108.
`
`Review article: Drug development in 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
`The use of non-specific anti-inflammatory drugs such as
`the glucocorticoids is the foundation of medical therapy
`for inflammatory bowel disease. 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
`
`nucleus and the use of new drug delivery systems that
`target the bowel wall as the pharmacokinetic
`compartment of interest. Budesonide is a novel
`glucocorticoid compound that illustrates the potential of
`this approach to identify effective and safe new
`treatments. Regional therapy for inflammatory bowel
`disease is an important pharmacological concept for the
`future development of the new glucocorticoids and
`other classes 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 symptoms of diarrhoea, bleeding and abdominal
`pain. In ulcerative colitis, the inflammation is confined
`exclusively to the colon. Crohn’s disease may occur at any
`site in the gastrointestinal tract, but more frequently in
`the terminal ileum and the proximal colon.
`The
`two conditions are pathologically distinct.
`Inflammation in ulcerative colitis begins in the anal
`canal, is continuous to a variable degree through the
`colon, and is 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.’
`
`Cormspondence to: Dr Brtan Feaflan. London Health Sciences Centre,
`University Campus. 60F13. 339 Windermere Road. London. Ontarto.
`Canada.
`
`MEDICAL THERAPY FOR INFLAMMATORY BOWEL
`DISEASE
`As the cause of inflammatory bowel disease (IBD) is
`unknown, current medical treatment is directed towards
`suppressing the pathological inflammatory response. The
`most important classes of drugs are 5-aminosalicylates
`( 5-ASAs), glucocorticoids and immunosuppressives.2
`Surgery is used to treat complications of either disease or
`as a means of controlling symptoms in those individuals
`who do not respond to drug therapy. In the case of ulcera-
`tive colitis, colectomy is curative. Surgery does not cure
`Crohn’s disease: the inflammation recurs following resec-
`tion of a segment of inflamed bowel.
`Glucocorticoids are the most important class of drugs
`for the treatment of active ulcerative colitis and Crohn’s
`disease. The efficacy of steroid therapy has been
`confirmed by randomized, controlled trials. 3*4 Gluco-
`corticoids exert their anti-inflammatory effects through
`multiple mechanisms, including suppression of both
`humoral and 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
`
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`REVIEW: DRUG DEVELOPMENT IN INFLAMMATORY BOWEL DISEASE 99
`
`interaction of these steroids with the glucocorticoid
`receptor is not tissue-specifk6 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 common side-
`effects are moon faces, acne, swollen ankles, easy bruis-
`ing, and hirs~tism.~ More serious adverse events, such as
`diabetes mellitus, hypertension and osteoporosis may
`also
`Thus, glucocorticoid therapy is a two-edged
`sword; its efficacy for the suppression of inflammation is
`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.
`
`CIIARACTERISTICS OF AN IDEAL GLOCOCORTICOID
`FOR USE IN INFLAMMATORY BOWEL DISEASE
`The pharmacological profile of an ideal glucocorticoid for
`use in inflammatory bowel disease (IBD) is shown in
`Table 1. The drug should combine high potency at the site
`of inflammation with minimal systemic effects. One way
`of fulfilling these criteria is to employ localized therapy.
`The initial formulations of steroids for localized therapy
`utilized rectal installation routes. Clinical trials have
`shown that topical formulations (enemas, suppositories,
`foams) of hydrocortisone or betamethasone are effective
`for the treatment of ulcerative colitis and infrequently
`cause systemic side-effects."b12 However, rectal adminis-
`tration formulations are effective only for those patients
`whose disease is distal to the splenic flexure of the colon.
`The development of specific oral drug delivery systems
`involves a newer, alternative approach to deliver locally
`
`Table 1. Characteristics of an ideal glucocorticoid for treatment of IBD
`
`0 High anti-inflammatory activity
`0 Site selectivity
`0 Low systemic absorption
`0 Rapid degredation of absorbed drug to inactive metabolism
`
`acting steroids in patients who have disease elsewhere in
`the colon or small bowel. The development of such for-
`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.I3 As the
`efficacy of 5-ASA is dependent on 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 drug to specific sites of intestinal inflammation. The
`development of these compounds provide a model which
`can be exploited for use with other classes of drugs,
`including glucocorticoids.'
`
`DRUG ABSORPTION: LOCAL AND SYSTEMIC
`The site at which an oral drug is absorbed is affected by
`multiple factors (Table 2).16 Differences in absorption
`rates are often not clinically important for systemically
`acting drugs, as the pharmacodynamic effect is primarily
`determined by the total amount of 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 determinant of efficacy. Furthermore, the factors that
`govern drug absorption may vary between healthy indi-
`viduals and those with BD. This may result in marked
`differences in bioavailability between individuals. The two
`physiological factors that are of primary importance in
`regulating absorption in the gastrointestinal tract are pH
`and intestinal transit time. The site where water-soluble
`compounds are absorbed is dependent upon an ionic
`charge. which is in turn, sensitive to the environmental
`
`Drug factors
`
`PKa
`Solubility
`Partitioning
`
`Dosage form factors
`
`~
`
`Disintegration time
`Dissolution rate
`Type of dosage form
`
`~
`
`Physiological factors
`. - .
`..
`.
`-. . .
`Intestinal surface area and transit time
`pH of gastrointestinal fluids
`Enterohepatic cycling first-pass effect
`
`0 1997 Blackwell Science Ltd. A h e n t Phurmucd Ther 11 (Suppl. 3), 98-108
`
`Table 2. Factors affecting the absorption of
`drugs
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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 to less 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 bases is increased
`with increasing pH. As the pH of the bowel contents
`governs the proportion of drug which exists in an ionized
`form, compounds that 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
`extent in the distal colon. However, other factors such as
`the much greater surface area available in the small
`bowel for absorption and the intestinal transit time are
`dominant.' These factors must be considered when
`designing drugs for targeting specific sites in the gastro-
`intestinal tract. The presence of regional differences 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 normal individuals. Fallingborg et al. have studied
`this question, using a radiotelemetry capsule as a pH
`probe. l7 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 was the result of a decreased capacity of the
`epithelium to metabolize butyrate. In normal individuals,
`butyrate is the primary source of energy for enterocytes;
`however, the presence of inflammation may impair cellu-
`lar metabolic pathways. This could result in an increased
`production of lactate in the ~ o l o n . ' ~ * ' ~ The finding 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-
`intestinal tract outside of the area of inflammation is not
`available to act as a local therapy Thus, the absorption of
`a drug which is 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 compare the colonic motility
`of patients with active ulcerative colitis to healthy con-
`trols.20 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. The transit 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 and retrograde 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 common in patients with IBD. Rao and
`Read studied 62 patients with active ulcerative colitis and
`20 healthy controls using rectal manometry.21 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.
`The investigators 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 must be 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
`drug is released at a site which is either proximal or distal
`to the target site, 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.16 Orally administered
`drugs are usually in the form of capsules or tablets. Free
`drug is released from these products through an initial
`
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`REVIEW DRUG DEVELOPMENT IN 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 capsules dis-
`solve rapidly (less than 10 min) and release fine particles
`of drug that are easily solubilized, Following solu-
`bilization, the drug is available for absorption. Many
`drugs are poorly soluble, so that the rate of dissolution is
`rate-limiting for absorption. Oral drugs may be 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 which are 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-
`pound is released. Another drug factor which regulates
`absorption is its 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 organic sol-
`vent/water interface. A drug with a partition coefficient
`of 1 has equal solubility in the organic and liquid phases.
`Drugs that are well absorbed have partition coefficients of
`10:l (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.
`Osalazine is an example of a 5-ASA prodrug that exploits
`a similar approach.22 Another approach is 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) or first-order kinetics. The result is lower drug
`absorption and less variability in serum concentrations.
`Osmotic mini-pumps have been used recently in the oral
`formulation of several drugs, including nifedi~ine.~ In
`this system, water enters the drug tablet by osmosis. This
`results in an increase in pressure within the tablet. The
`drug is slowly forced out of a laser-drilled outlet, which
`
`yields a constant rate of drug release. Similar systems can
`be designed to deliver drug to specific regions of the
`gastrointestinal tract in a time-dependent fashion.
`Eudragit coatings are commonIy used.’* Eudragit is a
`synthetic polymer which has pHdependent 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 Eudragit S 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 the liver as it passes from the portal circulation.
`The liver is the primary site of drug metaboli~rn.’~
`Hepatic enzyme systems facilitate 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.26 The epithelial cells of the small bowel
`express cytochrome P450 (CYP)3A enzymes, which
`metabolize glucocorticoids and other drugs. A wide vari-
`ation exists among individuals in the expression of these
`enzymes.27 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
`CYPSA expression in enterocytes.” Erythromycin2’ and
`grapefruit juice3” inhibit these enzymes. Some impor-
`tant clinical correlates of these pharmacokinetic consid-
`erations have been identified. 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 the liver 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 individual^.^'
`In patients with Crohn’s disease, the mean velocity of
`portal venous blood was 28.2 f 7.7 cm/sec in compari-
`son to 19.4 f 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
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`tive colitis were 2 7.7 f 5.8 cm/sec as compared with
`1 9 . 4 f 2 . 2 cmlsec (P< 0.05) for the control group. The
`increased flow in these patients with IBD normalized
`following treatment.
`
`First pass metabolism
`Only a small fraction of a systematically administered,
`absorbed drug is initially exposed to hepatic metabolism.
`In contrast, all of an orally administered, absorbed drug
`which is absorbed is susceptible to hepatic metabolism.
`This occurs because the venous blood from the gastro-
`intestinal tract returns to the systemic circulation
`through the portal system and the liver. In contrast, only
`25-30% of blood in the systemic circulation passes
`through the liver with each transit of the circulation.
`Thus, there is approximately a four-fold increase in expo-
`sure to the effects of hepatic metabolism in orally admin-
`istered drugs compared to those given parenterally. In
`order to minimize the undesirable systemic effects of
`glucocorticoids, topically actings drugs should have a
`high, fist-pass metabolism. Hepatic CYP3A enzyme
`systems are primarily responsible for glucocorticoid
`
`m e t a b ~ l i s m . ~ ~ This family of enzymes is involved in the
`metabolism of many other commonly used drugs. Thus,
`interactions with drugs that either induce or inhibit these
`enzymes may be clinically important.
`
`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 assessment of the potency of gluco-
`corticoid drugs. One is the in vitro measurement of the
`binding affinity for the glucocorticoid receptor.6 To
`achieve optimal anti-inflammatory activity, a candidate
`drug should have a high affinity for this receptor. The
`other measure is a bioassay in which a range of concen-
`trations of a candidate compound is 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 17-01 position markedly enhances
`the potency of a glucocorticoid. However, despite potent
`anti-inflammatory
`effects, compounds
`such
`as
`betamethasone and dexamethasone are unsuitable for
`
`the treatment of skin disease because of poor tissue 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
`d e r m a t o ~ e s . ~ ~ Similar modifications resulted in the
`development of budesonide.
`Budesonide is a 17-a substituted steroid that has many
`desirable characteristics
`for use as a
`regional
`anti-inflammatory drug. Budesonide has a topical
`anti-inflammatory effect approximately five times that
`of prednisone. This increase in potency was achieved
`by modifying the 6-a-hydroxy-prednisolone nucleus
`through the addition of 16a and 17a acetyl groups.
`Budesonide has a systemic bioavailability of 9.3-1 5%
`when administered orally as a controlled, ileal-release
`capsule or rectally as an enema.33 The drug undergoes
`extensive fist-pass metabolism in the liver and possibly
`the intestinal epithelium. The two major metabolites, 6p-
`hydroxy-budesonide and 1 6a-hydroxy-prednisolone,
`have minimal glucocorticoid activity.34 The highest con-
`centration of metabolites are excreted via the kidneys. A
`smaller amount of conjugated metabolites are eliminated
`through the bile. Formulations of budesonide have been
`designed to target specific regions of the gastrointestinal
`tract that are of relevance to the treatment of IBD. An
`enema formulation is available for the treatment of distal
`
`ulcerative colitis or procto~igmoiditis.~~*~~ The develop-
`ment of a budesonide enterocapsule (budesonide con-
`trolled ileal release) has facilitated 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 which are sus-
`pended in ethyl cellulose. The enterocapsule is coated
`with a layer of metho-acrylic acid copolymer that dis-
`solves at a pH above 5.5. Approximately 50-7996 of the
`absorption of budesonide occurs in the distal small bowel
`and proximal colon.'4 Recently, a colonic preparation of
`budesonide has been described, which consists of bude-
`sonide capsules containing acid-resistant pellets of
`drug. 37 This formulation has a sustained-release profile
`which delivers active drug during passage of the capsule
`through the colon.
`
`Budesonide: results 01 clinical studies
`A large number of clinical trials have evaluated the use of
`budesonide enemas in patients with distal ulcerative
`colitis or proctosigmoiditis. The oral controlled, ileal-
`
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`52% 1 Placebo
`
`Budesonide
`Prednisolone
`
`70
`
`30 -
`
`20
`
`10
`
`20% L
`
`REVIEW DRUG DEVELOPMENT IN INFLAMMATORY BOWEL DISEASE
`
`1 0 3
`
`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 budesonide for the treatment of ulcerative
`colitis.
`
`Enemu therupg for ulcerutive colitis
`Budesonide enemas have been evaluated extensively in
`patients with distal ulcerative colitis, and a similar
`efficacy to conventional glucocorticoid enemas has been
`demonstrated. 38.3y 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 may be less likely to
`cause glucocorticoid-related toxicities, such as osteoporo-
`sis, than conventional steroid preparations.
`
`ORAL BUDESONIDE FOR CROHN'S DISEASE
`Induction of remission
`Three randomized, controlled trials have evaluated the
`efficacy of oral budesonide for the treatment of patients
`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
`( 3 mg, 9 mg/day and 15 mg/day) in comparison to a
`placebo for 8 weeks of treatment.40 A European study
`compared the efficacy of 9 mgiday of budesonide admin-
`istered once daily to a conventional, tapering-dose regi-
`men of prednisolone (40 mgiday to 5 m g / d a ~ ) . ~ ' 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 CDAI score 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 CDAI score of 200 at the entry visit.
`The Canadian dose-finding study identified that
`9 mg/day of budesonide was the most effective dose and
`that no additional benefit was conferred by a 15 mg/day
`dose. A 5 1% 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
`
`8 1997 Blackwell Science Ltd, A h e n t Pharmucol Ther 11 (Suppl. 3). 98-108
`
`Figure 1. The proportion of patients in remission following treatment
`with budesonide. prednisolone or placebo is shown (composite data
`fromRefs40&41).
`
`identical response rate (52%) was observed for bude-
`sonide 9 mglday 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 groups in the
`placebo-controlled Canadian study. 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. 5 5%, P = 0.003). Figure 2
`shows the 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 more likely to
`occur in patients who received prednisolone, and were
`not correlated with the presence of clinical 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 Canadian study.
`To define the optimum dosing regimen, a third trial was
`performed, in which budesonide 9 mglday administered
`either once or twice daily was compared to a standard
`
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`104 R. HAMEDANI, R.D. FELDMAN & B.G. FEAGAN
`
`a 60
`B Z
`J
`p! 50
`
`
`
`55%
`
`Placebo
`
`Budesonide
`
`Prednisolone
`
`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 = adversedrug reactions.
`
`prednisolone treatment regimen. After 8 weeks of
`therapy, the response rate in the once-daily budesonide
`group and prednisolone group were identical (60%), as
`compared to the 42% remission rate observed in the
`twice-daily budesonide dose group (P = >0.0S).44 These
`studies confirmed that 9 mg/day oral budesonide admin-
`istered once daily is the optimum dose for the treatment of
`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
`prednisone or prednisolone.
`
`MAINTENANCE OF 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 maintenance therapy. Previous
`studies which evaluated conventional glucocorticoids
`for this indication did not show a benefit of chronic,
`low-dose steroid treatment. The National Cooperative
`Crohn’s Disease Study demonstrated that the chronic
`administration of prednisone (1 3.5 mg/kg) was ineffec-
`tive4 and although the results of
`the European
`Cooperative Crohn’s Disease
`have been inter-
`preted by many as showing a modest benefit for contin-
`uation of 6-rnethylprednisolone treatment in patients
`who had previously responded to that drug, this
`
`conclusion was based on a subgroup analysis. No over-
`all benefit was demonstrated in the primary analysis of
`that trial. Three maintenance
`were per-
`formed as follow-up protocols to each of the trials 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 was defined by the presence of either: a)
`a CDAI increase of 60 points and a minimum CDAI
`value of 1 SO: orb) the introduction of therapy for 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 = 0.01 1). 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