DRUG EVALUATION Drugs 50 (5) 854-872,1995 0012-6667/95/001 l-()854/S19 00/0

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Budesonide A Review of its Pharmacological Properties and Therapeutic Efficacy in Inflammatory Bowel Disease

Caroline M. Spencer and Donna McTavish Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by: S. Bank, Division of Gastroenterology, Long Island Jewish Medical Center, New Hyde Park, New York, USA; G. Bianchi Porro, Gastrointestinal Unit, Ospedale 'L. Sacco', Milan, Italy; V. Binder, Department of Medical Gastroenterology, Herlev Hospital/University of Copenhagen, Herlev, Denmark; M. Campieri, Istituto di Clinica Medica, e Gastroenterologia, Clinica Medica Generale e Terapia Medica, Policlinico S, Orsola, Bologna, Italy; A Danielsson, Section for Gastroenterology & Hepatology, Department of Medicine, Umea University, Umea, Sweden; G.R. Greenberg, Division of Gastroenterology, Mount Sinai Hospital, Toronto, Ontario, Canada; D.P. Jewell, Gastroenterology Unit, Radcliffe Infirmary, Oxford, England; J.E. Kellow, University of Sydney Department of Medicine, Royal North Shore Hospital, St Leonards, New South Wales, Australia; V. Mani, Department of Gastroenterology, Leigh Infirmary, Leigh, England; T. Miwa, School of Medicine, Tokai University, Boseidai, Isehara, Kanagawa, Japan; J.M. Rhodes, University Department of Medicine, Liverpool University, Liverpool, England; P. Rutgeerts, Department of Gastroenterology, Leuven University Hospital, Leuven, Belgium; W. Selby, Royal Prince Alfred Hospital Medical Centre, Newton, New South Wales, Australia; S. Tarpila, The Deaconess Hospital, The Deaconess Institute in Helsinki, Helsinki, Finland_

Contents Summary , , , . . . . . . . . . . . . 1. Pharmacological Properties . . . .

1.1 Pharmacodynamic Properties 1 .1 . 1 Effects on Plasma Cortisol Levels 1.1,2 Effect on Indicators of Inflammation 1.1.3 Other Effects ........ .

1.2 Pharmacokinetic Properties , . . . 1.2.1 Absorption and Distribution 1.2.2 MetabOlism and Elimination 1.2.3 Correlation with Clinical Parameters

2. Therapeutic Efficacy ... 2.1 Budesonide Enema . , ..... . 2.2 Oral Budesonide . , ...... .

2.2,1 As Maintenance Therapy 3, Tolerability ........ , . . . . .. . 4. Dosage and Administration. . . . . . 5. Place of Budesonide in the Management of Inflammatory Bowel Disease

854 857 857 858 860 860 861 861 862 862 862 862 866 867 868 869 870

Summary Synopsis Budesonide is a glucocorticoid with high topical activity, but low systemic bio­

availability which results in reduced systemic effects in comparison with other

Budesonide in Inflammatory Bowel Disease: A Review 855

Pharmacological Properties

glucocorticoids. To date, it has been evaluatedfor use in patients with inflamma­tory bowel disease when administered either orally as a controlled ileal release formulation or rectally as an enema.

In comparative trials, daily treatment with budesonide enema 2 mg/IOOmlfor 4 weeks produced endoscopic remission or improvement in 46 to 84% of patients with active distal ulcerative colitis and/or proctitis and histological remission or improvement in 45 to 68%. In general, this regimen was a effective as regimens of hydrocortisone, methylprednisolone, prednisolone or mesalazine (5-amino­salicylic acid, mesalamine) enemas, but caused less suppression of plasma cor­tisollevels than the other glucocorticoids.

Oral treatment with controlled release budesonide 9 mg/day for 8 weeks pro­duces clinical remission in 42 to 67% of patients with active Crohn s disease of the ileum, ileocaecal region and/or ascending colon and significantly reduces Crohn s disease activity index scores compared with baseline and placebo. Re­sults of a quality-of-life questionnaire reflected these clinical improvements. Budesonide has similar efficacy to prednisolone. Response to budesonide is main­tained after dosage tapering at 8 weeks. Compared with placebo, maintenance treatment with oral budesonide 3 or 6 mg/day increases the duration of remission in patients with Crohn s disease, but does not appear to affect the I -year relapse rate.

Thus, budesonide, administered rectally to patients with distal ulcerative co­litis or proctitis or orally to patients with Crohn s disease of the ileum, ileocaecal region and/or ascending colon, is a favourable option for the treatment of acute exacerbations of inflammatory bowel disease. Because of the low incidence of adverse glucocorticoid-related effects associated with oral budesonide, it may also be a useful agent for longer term maintenance therapy if further clinical trials confirm its efficacy in this indication.

Budesonide is a glucocorticoid used in the treatment of inflammatory bowel disease. It has greater topical anti-inflammatory activity than many other glucocorticoids, but does not reduce cortisol levels (a measure of systemic effect on adrenal function) to the same extent as methylprednisolone, prednisolone or hydrocortisone when administered orally or rectally. In fact, administration of budesonide 2 mg/lOOml enema has no significant effect on basal plasma cortisol levels in patients with ulcerative colitis. Response to corticotrophin (adrenocor­ticotrophic hormone; ACTH) is also impaired to a lesser extent by rectal treatment with budesonide than with prednisolone. Sithilarly, oral budesonide 9 mg/day is associated with less impairment of adrenal function than oral prednisolone 40 mg/day (after 2 weeks tapered to 5 mg/day over 7 weeks), but does cause some adrenal suppression compared with placebo. A I -year placebo-controlled study showed that decreases in ACTH-stimulated plasma cortisol levels induced by oral budesonide did not result in clinically important glucocorticoid-associated ad­verse effects in 105 patients with Crohn's disease.

In general, treatment with oral budesonide 9 mg/day reduced mean erythrocyte sedimentation rate in patients with active Crohn's disease, but did not signifi­cantly alter mean serum orosomucoid, C-reactive protein or albumin levels or plasma haptoglobin level. However, in I trial, budesonide therapy resulted in a 20% decrease in serum C-reactive protein level. Although both budesonide and prednisolone enema therapy induce small decreases in serum osteocalcin level from baseline, changes are greater in prednisolone recipients. Compared with oral

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856

Therapeutic Efficacy

Tolerability

Spencer & McTavlsh

prednisolone 40 mg/day (after 2 weeks tapered to 5 mg/day over 7 weeks), oral budesonide 9 mg/day (after 8 weeks tapered to 6 mg/day) produces smaller de­creases in natural killer cell activity (by 22 to 30% vs 25 to 54%) after 2 and 4 weeks in patients with active Crohn's disease.

Budesonide enema achieves adequate maximum retrograde colonic spread within 15 minutes in patients with distal ulcerative colitis. The drug has a systemic bioavailability of9.3 to 15% and a mean absorption time of about 6 and 1.4 hours, respectively, when administered orally or rectally to healthy volunteers. In healthy volunteers and patients with ulcerative colitis, maximum plasma concen­trations of 2.1 to 3 nmollL are achieved 1.2 to 1.5 hours after rectal administration of budesonide 2 mg/1 OOml. Area under the plasma concentration-time curve in­creased after 28 days' therapy, but other assessments showed that the drug did not accumulate with repeated administration. The controlled ileal release formu­lation of oral budesonide is predominantly absorbed in the ileum and ascending colon. Budesonide undergoes extensive first-pass metabolism via oxidative and reductive pathways in the liver to 2 major metabolites 6P-hydroxy-budesonide and 16a-hydroxy-prednisolone, which have considerably less glucocorticoid ac­tivity than the parent drug.

Budesonide has been incorporated into formulations for oral (controlled release) or rectal (enema) treatment of patients with inflammatory bowel disease, most commonly Crohn's disease (affecting the ileum, ileocaecal region and/or ascend­ing colon) or ulcerative colitis, respectively. Budesonide enema 2 mg/1 OOml gen­erally has similar efficacy to hydrocortisone, methylprednisolone, prednisolone or mesalazine enemas and greater efficacy than placebo after 4 weeks of treat­ment. General well-being is also improved after 2 weeks' treatment with budeson­ide enema in comparison with placebo. Budesonide enema produced endoscopic improvement faster than prednisolone enema in one of the larger studies, but not in another. Endoscopic remission or improvement occurred in 46 to 84% of pa­tients treated with budesonide enema, while histological remission or improve­ment was achieved by 45 to 68% of patients enrolled in comparative trials.

Clinical remission is achieved by 42 to 67% of patients with active Crohn's disease of the ileum, ileocaecal region and/or ascending colon following treat­ment with oral controlled ileal release budesonide 9 mg/day for 8 weeks. This drug regimen also significantly reduces Crohn's disease activity index scores compared with baseline and placebo. Results of a quality-of-life questionnaire reflected these clinical improvements. Oral budt;sonide has a rapid effect in com­parison with placebo, but results of comparisons with prednisolone were equiv­ocal. However, oral budesonide generally has efficacy similar to that of prednisolone. Prior treatment with steroidal agents does not have a detrimental effect on response to oral budesonide. Budesonide dosages were generally tapered after 8 weeks of oral therapy and responses were maintained after dosage reduc­tions. Maintenance treatment with budesonide 3 to 6 mg/day increases the dura­tion of remission in patients with Crohn's disease, but does not appear to significantly reduce the proportion of patients experiencing relapse after I year of treatment.

Budesonide enema is generally well tolerated: the most frequently experienced events (reported in ::;;5 % of patients) are gastrointestinal and include increased bowel frequency and colorectal bleeding. Haematuria, thromboembolism, acne and villous adenoma have been reported in 1 patient each. Laboratory abnormal-

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Budesonide in Inflammatory Bowel Disease: A Review

Dosage and Administration

ities do not usually develop and no signs of significant adrenal suppression have been detected during treatment with budesonide enema.

In a large trial (n = 258) comparing oral controlled ileal release budesonide 3, 9 or 15 mg/day and placebo, similar proportion of patients in the active treatment and placebo groups experienced an adverse event or discontinued treatment be­cause of these events. 41 % of adverse events were gastrointestinal in nature, with dyspepsia and nausea being most commonly reported. Glucocorticoid-associated effects developed in a similar proportion of patients in each group (15 to 38%), but cushingoid facial features were more common with budesonide (7%) than with placebo (2%). Glucocorticoid-associated adverse effects, particularly cushingoid facial features, appear to occur more commonly during prednisolone therapy than during treatment with oral budesonide. Oral budesonide therapy does not appear to affect liver function tests, or to produce haematological and biochemical abnormalities when compared with placebo. In general, 6 to 12 months' maintenance therapy with oral budesonide was not associated with sig­nificant adverse events. However, longer term trials are necessary to fully define the tolerability profile of budesonide.

Budesonide enema 2 mg/l OOml should be inserted rectally once daily at bedtime for the treatment of acute distal ulcerative colitis or proctitis. In most studies treatment was continued for 4 weeks. Clinical studies indicate that oral budeson­ide should be administered at a daily dose of 9mg for about 8 weeks for the treatment of active Crohn's disease of the ileum, ileocaecal region and/or ascend­ing colon.

857

Glucocorticoids are commonly used in the treat­ment of inflammatory bowel disease. However, their usefulness has been limited by systemic ad­verse effects, such as mood changes, osteoporosis, atrophy of connective tissue and suppression of the hypothalamic-pituitary adrenal axis. Budesonide (fig. 1) is a nonhalogenated glucocorticoid which is used for the treatment of inflammatory respira­tory disorders[ll and is now being evaluated as an oral and rectal treatment of patients with inflamma­tory bowel disease. It has greater topical anti­inflammatory activity, but less systemic activity than other glucocorticoids (section 1.1), because of its high first-pass metabolism to metabolites with low glucocorticoid activity (section 1.2). There­fore, budesonide has the potential to be an effective agent for the treatment of inflammatory bowel dis­ease. This article reviews the pharmacological properties and therapeutic efficacy of budesonide in patients with ulcerative colitis or Crohn's dis­ease. Many aspects of the pharmacological profile of budesonide were determined prior to, or during,

its use in patients with asthma and readers are re­ferred elsewhere for a review of these data (for ex­ample, Brogden & McTavish[ll).

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1 . Pharmacological Properties

1.1 Pharmacodynamic Properties

Rectal administration of 3 doses of budesonide enema (O.25ml of budesonide 10 flmollL) im­proved symptoms and reduced colon damage in rats with induced acute colitisJ2l Local population macrophage and dendritic cell numbers and dis­tribution patterns were also normalised and major histocompatibility complex (MHC) Class II expression, which is enhanced in colitis, was re­duced to normal levels, but the local population of lymphocytes was minimally affected. The anti­inflammatory activity of oral budesonide was dem­onstrated to be local, not systemic, in hamsters with induced ileitisPl

In the human skin vasoconstriction assay, budesonide had greater topical potency than

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858

beclomethasone, betamethasone valerate, deson­ide, flunisolide, hydrocortisone butyrate, pre­dnisolone, and fluocinolone, prednacinolone and triamcinolone acetonide and similar activity to betamethasone dipropionateJ4,5]

1.1. 1 Effects on Plasma Cortisol Levels Changes in basal plasma cortisol levels after

treatment with glucocorticoids are often used as a measure of systemic effect on adrenal function. As shown in table I, administration of budesonide 2 mg/100ml enema had little effect on basal plasma cortisol levels in patients with ulcerative colitis, with no significant changes from baseline noted. In contrast, treatment with methylprednisolone, pre­dnisolone or hydrocortisone resulted in a signifi­cant decrease in plasma cortisol levels compared with baseline and/or budesonide therapy after 4 weeks (table I). Oral controlled ileal release bu­desonide 3 to 15 mg/day also had a lesser effect on

Budesonide

Fig. 1. Structural formulae of budesonide and its 2 main metabolites.

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Spencer & McTavish

plasma cortisol levels than prednisolone 20 mg/day, but had a greater effect than placebo, when admin­istered for 5 days to 24 healthy volunteers in a dou­ble-blind crossover study. [1 6] Similar results were obtained in patients with active Crohn's disease when these agents were administered for up to 8 weeks (table I).

Basal plasma cortisol levels only partially re­flect changes in adrenal function. Response to corticotrophin (adrenocorticotrophic hormone; ACTH) can give a more accurate determination of adrenal suppression by measuring the functional reserve of the adrenal gland for cortisol secretion. ACTH testing in 26 patients from the study of Lofberg et aUlO] showed that of 11 budesonide en­ema 2 mg/1 OOml recipients, only one had abnormal test results after 4 weeks' treatment [this patient also had abnormal (30-minute plasma cortisol lev­els <500 nmol/L) baseline results] and all had nor-

CH20H

I c=o

CH3 ·""""",,, ,,,, OH

""""'OH

16a-Hydroxy-predmsolone

OH

6p-Hydroxy-budesonide

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Budesonide in Inflammatory Bowel Disease: A Review 859

Table I. Effect of oral and rectal formulations of budesonlde (B) and other glucocorticoids on basal plasma cortisol levels in patients with ulcerative colitis (enema) or Crohn's disease (oral controlled ileal release)

Reference Dally treatment Mean plasma cortisol level (nmol/L)a Proportion of patients with [no. of evaluable patients] a decrease In cortisol levels

to <150 nmol/L, unless otherwise stated (%)

baseline 2wk 4wk 8wk 2wk 4wk 8wk

Enema Bianchi Porro et a1.l6] B2 mg/100ml 503 [44] 465 [40] 416[21] 25c

MP 20 mg/100ml 447 [44] 315*t [35] 464 [11]b 57ct

Danlelsson et alF] B2 mgl100ml 481 [29] 398 430 7 0

Danlelsson et a1.l8] B2 mg/100ml 411 [21] 389[21] 447[21]

PI 464 [20] 440 [20] 466 [20]

Danlelsson et al [9] B2 mg/100ml 402 [28] 360 [26] 413 [26]

Pr 31.25 mg/100ml 366 [28] 163*t [28] 239*t [24]

Lofberg et a1.l1O] B2 mg/100ml 382 [45] NS NS NS 0 2 0

Pr 25 mgl100ml 402 [55] 133t 206t 221t 65t 50t 44t

Tarplla et al [11] B2 mg/100ml 447 [37] 386 412

H 125 mg/5ml 503 [35] 449 375t

Oral administration Cam pieri et al [12]d B 9mg od 382e J,194 33e 41 e

B 4.5mg bid 374e J,132 38e 36e

Pr 40mg od x 2wk then 375" J,258t 87e 76e

tapered to 5mg

Greenberg et a1.l13] B 15mg In 2 divided doses 3171 [64] 88f** 66f** 72f** 629* 679* 679*

B 9mg in 2 divided doses 326f [61] 138f** 135f** 146f** 669* 709* 699*

B 3mg In 2 divided doses 331f [67] 270f** 259f* 268f* 319* 369* 309*

PI 334f[66] 359f 353f 309f 149 149 149 Lafberg et aJ.[14J B 3mg lid 497[18] 317* [17] 330* [14] 29 Rutgeerts et a1.l15] B9mg 415[88] NR NR NR 37 39

Pr 40mg x 2wk, 30mg x 373 [88] NRt NRt NRt 89t 94t 2wk, 25mg x 2wk, then decreaSing dose

a DIVide values by 27.6 for J.lgldl

b These patients had been sWitched from methylprednisolone to budesonlde after 4 weeks' therapy.

c Proportion of patients with a substantial (>20%) decrease in plasma cortisol levels, 43% of methylprednisolone, and 5% of budesonlde, recIpients had >50% decrease

d A total of 177 patients were randomised to treatment.

e Data on file, Astra Draco AB.

f Median values.

g Proportion of patients with plasma cortisol levels <200 nmol/L.

Abbreviations and symbols: bid = twice dally; H = hydrocortisone; MP = methylprednisolone; NR = actual changes in cortisol levels were not reported, but between-group differences were; NS = no significant change from baseline (actual changes were not reported); od = once daily; PI = placebo, Pr = prednisolone; tid = 3 times daily; * indicates a significant change from baseline (p < 0.01); t Indicates a Significant difference versus budesonide treatment (p < 0 .05); * Indicates a Significant difference versus placebo (p < 0 .05); J, indicates a decrease In cortisol level by the amount specified.

mal results (30-minute cortisol levels >500 nmollL) at 8 weeksJ17] However, budesonide en­ema produced a dose-related decrease in plasma cortisol levels in response to ACTH stimulation

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over the dose range of 0.5 to 8 mg/day, but there was no evidence of adrenal insufficiency after 6 weeks' therapy.[lS] In dosages providing similar efficacy to budesonide enema (section 2), therapy

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860

with prednisolone enema resulted in lower mean plasma cortisol levels 30 minutes after injection of ACTH than did budesonide at 4 and 8 weeks.[17]

Similarly, oral budesonide 9mg once daily or 4.5mg twice daily was associated with a lower in­cidence of adrenal dysfunction than oral pre­dnisolone 40 mg/day, taken for 2 weeks before the dose was tapered over 7 weeks to 5 mg/day (58 vs 50 vs 84%), as assessed by a short ACTH stimula­tion test.[12] Response to ACTH stimulation was preserved after oral budesonide 9 mg/day in an­other study, although basal cortisol levels reached a lower maximum level than before treatment [292 vs 734 nmollL (106 vs 266 j..lglL)].[I9] However, when compared with placebo, oral budesonide 9 mg/day impaired the response to ACTH stimula­tion in significantly more patients (fig. 2). A I-year placebo-controlled study, conducted in 105 pa­tients with Crohn's disease, showed that although oral budesonide 3 or 6 mg/day caused a dose­related decrease in ACTH-stimulated plasma cortisol level when determined 3 months after treatment was started, no clinically important glucocorticoid-associated adverse effects were noted PO]

1. 1.2 Effect on Indicators of Inflammation Treatment with oral budesonide 9 mg/day re­

duced mean erythrocyte sedimentation rate in 21 patients with active Crohn's disease of the distal ileum, ileocaecal region and/or ascending colon.[14] The most notable change occurred during the first 4 weeks, with a decrease from 30 to 20 mmIh (p < 0.01). In a comparative trial, oral prednisolone therapy produced a greater early (4 weeks) reduc­tion in these rates than oral budesonide, but the difference between treatments was not significant at 8 weeks (2 vs 8 mmIh).[I5]

Mean serum orosomucoid,u4,15] C-reactive pro­tein,D4] albumin[14] and plasma haptoglobin lev­els[14] did not significantly change during treatment with oral budesonide 9 mg/day. Similarly, changes in serum orosomucoid and C-reactive protein lev­els were not significantly different in 258 placebo or budesonide 3 to 15 mglday recipients.[13] How­ever, the 20% decrease in serum C-reactive protein

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Spencer & McTavish

o Before treatment

• After treatment

Placebo

*

o 10 20 30 40 50 60

Patients with impaired response (%)

Fig. 2. Effect of budesomde on response to stimulation with

corticotrophin (adrenocorticotrophic hormone) The proportion of pa­

tients with Impaired response to corticotrophin before and after 10

weeks' treatment with oral budesontde 3 to 15 mg/day or placebo is

depicted 258 patients entered thiS tnal. [13] • Signtficant difference

between treatment and placebo (p < 0 006)

level observed in 1 trial was not significantly dif­ferent from the 35% decrease seen in prednisolone recipients.[15]

1. 1.3 Other Effects Although both budesonide and prednisolone en­

ema therapy induced a small decrease in serum os­teocalcin level from baseline, changes were greater in prednisolone recipients, with significant be­tween-group differences at 2 and 8 weeks.[IO] Se­rum osteocalcin levels are correlated with bone turnover, but the clinical relevance of the effect of glucocorticoids on these levels has not been re­solved. Other studies conducted in patients with asthma have shown inhaled budesonide to have a lesser effect on bone metabolism thaI). beclometha­sone or prednisone.l l ] However, longer trials are required to determine the extent of bone loss with budesonide therapy in patients with inflammatory bowel disease.

Neither budesonide nor prednisolone enema therapy significantly altered plasma glucose lev­els.[17] However, oral prednisolone 40 mg/day for 2 weeks then decreased to 5 mg/day over 7 weeks, produced an increase in mean fasting blood glucose level from 8.3 to 9.7 mglL during a lO-week treat-

Drugs 50 (5) 1995

Budesonide in Inflammatory Bowel Disease: A Review

ment period, resulting in hyperglycaemia in 1 pa­tient.[15] In contrast, oral budesonide 9 mg/day

caused a significantly smaller increase in mean

plasma glucose levels (from 8.1 to 8.3 mglL) than prednisolone in this study[15] and did not signifi­cantly affect them in another. [1 4]

Treatment with oral budesonide 9 mg/day (ta­pered to 6 mg/day after 8 weeks) decreased natural

killer cell activity (by 22 to 30%) after 2 and 4

weeks in patients with active Crohn's disease, but

activity had almost returned to baseline levels after 10 weeks' therapy.[21] In contrast, prednisolone 40

mg/day (after 2 weeks tapered to 5 mg/day over 7

weeks) decreased activity by 25 to 54% after 2 and 4 weeks and, after 10 weeks' treatment, activity was significantly higher than pretreatment levels. These changes in natural killer cell activity were caused by a decrease in CD 16+ natural killer cell

numbers and were correlated with changes in plasma cortisol levels, suggesting that budesonide

has a smaller immunosuppressive effect than pre­

dnisolone.

861

1.2 Pharmacokinetic Properties

1.2. 1 Absorption and Distribution

Although budesonide enema is packaged to al­low administration of 2mg of active drug, studies have shown that the actual mean administered dose ranged from 1.88 to 2.06mg.[7,22] After administra­tion of budesonide enema, adequate maximum ret­rograde colonic spread was achieved within 15 minutes in 4 of 5 patients with distal ulcerative colitisJ22] A mean of 94mI from a 100mI dose was administered and this spread over a major portion of the section of the colon between the rectum and the splenic flexure. Budesonide had a mean sys­temic bioavailability of about 15% after rectal ad­ministration (table 11), although considerable inter­individual variation was noted because of variable hepatic bypass .[24] Mean absorption time was 1.4 hours in healthy volunteers, and maximum plasma concentrations (Cmax) of 2.1 to 3 nmollL (table II) were achieved 1.2 to 1.5 hours (tmax) after rectal administration of budesonide 2 mg/l00ml to healthy volunteers or patients with ulcerative coli­tis or proctitis.[7,22-24] Total rectal absorption of

Table II. Pharmacoklnetlc parameters of Single and multiple doses of budesomde enema or oral controlled Ileal release budesomde capsules In healthy volunteers or patients With distal ulcerative colitis (UC), proctitis (P) or Crohn's disease (CD) of the ileum, Ileocaecal region or ascending colon)

Study participants Dally dose Cmax tmax AUC Systemic Mean absorption References (no) (nmoI/L)a (h) (nmoI/L· h) availability time

(%) (h)

Budesonide enema

Healthy volunteers (10) 2 mgl100ml 12 130 1.4 23

Healthy volunteers (15) 2 mgl100ml 3 13 136 152 14 24

Patients With UC or P (24) 2mg/100ml 21 13 97 7

Patients With UC or P (24) 2 mg/100ml x 28db 2.5 12 11.6' 7

Oral budesonide

Healthy volunteers (12) 3mg x 5db 19 23 115 25,26

Healthy volunteers (12) 9mg x 5db 5.3 27 370 25,26

Healthy volunteers (12) 15mg x 5db 80 31 602 25,26

Patients with CD (18) 45mg 41 47 28.5 27

Patients With CD (18) 4.5mg bid x 8wkb 32'* 44 21 1*' 27

a Multiply by 0 431 for ~glL

b Pharmacoklnetlc parameters were measured after the last dose of budesomde, which was admlmstered once dally.

AbbreVIatIons and symbol: AUC = area under the plasma concentration-time curve; bid = tWice dally, Cmax = maximum plasma concentration, d = days, h = hours, tmax = time to Cmax, wk = weeks, * Indicates a slgmflcant difference versus day 1 value (p = 0 03), '* Indicates a slgmficant difference versus day 1 value (p < 0 05)

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862

budesonide usually occurs within 3 hours.[24] Treatment with budesonide enema for 28 days did not result in significant drug accumulation, as evi­denced by an inability to detect budesonide in plasma 24 hours after the last dose in 23 of 24 pa­tients, or a significant change in Cmax or tmax values in 1 study.[7J However, area under the plasma con­centration-time curve (AVC) values were signifi­cantly increased following repeated administration (table II). Budesonide is 88% bound to plasma pro­teins, which is similar to other glucocorticoids)28]

Cmax and AVC values for oral controlled ileal release budesonide increased linearly over the dos­age range of3 to 15 mg/day for 5 days in 12 healthy volunteers given the drug in a randomised cross­over study (table II). Interestingly, mean Cmax and AVC values were significantly lower (by 21 and 26%, respectively) after repeated administration than after a single dose of the drug in 18 patients with Crohn's disease.[27] Oral administration of this formulation of budesonide (18mg) after a heavy breakfast, compared with the fasting state, increased the mean Cmax (9.1 vs 5.8 nmollL) and mean absorption time (5.4 vs 3.1 hours) of the drug in 8 healthy volunteers (p < 0.05»)29] However, systemic availability (11.5 vs 9.1 %) and site of ab­sorption (69 vs 68% of the dose absorbed in the ileum and ascending colon) were not significantly affected by food.

1.2.2 Metabolism and Elimination 88% of an administered rectal dose was esti­

mated to be available for hepatic first-pass metabo­lismp4] and the low systemic availability of budesonide indicates extensive first-pass metabo­lism (table 11). Budesonide is metabolised via oxi­dative and reductive pathways in the liver to 6 me­tabolites, predominantly 6~-hydroxy-budesonide and 16a-hydroxy-prednisolone (fig. 1).[30,31] These 2 metabolites have considerably less gluco­corticoid activity (one-tenth to one-hundredth) than their parent compound.[28] Metabolism of budesonide occurred 2 to 4 times faster than the metabolism of beclomethasone 17a-propionate (the active metabolite of beclomethasone 17a,21-dipropionate)[28,32] and 2 to 3 times faster than tri-

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Spencer & McTavish

amcinolone acetonide[28] in human liver homoge­nate in vitro. The plasma elimination half-life of unchanged budesonide was 2.8 hours, while plasma clearance was 83.7 Lih after intravenous administration. [28]

7.2.3 Correlation with Clinical Parameters Therapeutic efficacy was not correlated with

pharmacokinetic parameters of budesonide enema, whereas changes in plasma cortisol levels were negatively correlated with Cmax, although the clin­ical significance of this is unclear. There was no such correlation with AVC, but this parameter showed large interpatient variationP]

Similarly, cortisol suppression was correlated with plasma concentrations of budesonide after re­peated oral administration of the controlled ileal release formulation of the drug. No correlation between therapeutic efficacy, as measured by Crohn's disease activity index and van Hees index, and pharmacokinetic parameters of oral budeson­ide or cortisol suppression were detected.[27]

2. TherapeutiC Efficacy

Budesonide formulations have been developed for the oral or rectal treatment of patients with in­flammatory bowel disease. Because of the differ­ing absorption and activity profiles of the budeson­ide formulations, all comparative trials which evaluated use of the enema enrolled patients with distal ulcerative colitis or proctitis, whereas oral controlled release formulations were used in stud­ies of patients with Crohn's disease involving the ileum, ileocaecal region and/or ascending colon.

2.1 Budesonide Enema

In all but 2 dose-ranging trials,[18,33) budesonide enema was formulated and administered at a strength of 2 mg/lOOmI.

In initial, noncomparative trials, budesonide 2 mg/l OOrnl enema produced remission «3 formed stools per day without blood or mu~us, plus pale rectal mucosa with clearly visible blood vessels on endoscopy) or improvement after 10 weeks in 16 of 22 patients with active distal ulcerative colitis un-

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Budesomde in Inflammatory Bowel Disease: A Review 863

Table III. Comparison of the efficacy of budesonlde enema and other therapies or placebo Clinical efficacy of 4 weeks' (unless otherwise stated) treatment with budesonlde 2 mg/l OOml (B), administered once dally at bedtime, in patients with active ulcerative colitis (UC) enrolled In comparative trials EndoscopIc scores were measured uSing a 0- to 3-polnt scale and histological scores were measured on a 1- to 5-polnt scale

Reference Site of disease Additional medications, Study medications, Clinical [trial design] administered at administered dally outcomea

constant oral dosages (no of pts) (no of pts) (no of pts) [%]

Bianchi Mild to moderate S (22) or B(44) R 17[39] Porro et al [6] distal UC or ASA (45) I 16 [36]

proctosigmOldltls NI 11 [25] [r,sb,mc]

MP 20 mgll00ml (44)b R 16 [36] I 10 [23] NI 18[41]

Danlelsson Distal UC or proctitis S (10) B (20) I' 16 [80]e* et al [8] [r,db,mc] NI4[20]

PI (21)b I 5 [24]e* NI 16 [76]

Danlelsson Distal UC S(21) B (31) B=Pf'l et al [9] [r,sb,mc]

Pr 31 25 mg/l00ml (33)b

Danish Distal UC S (22) or B (37)e B= Pr Budesonlde [r,sb,mc] ASA(45) Pr25 mgll00ml (31)9 Study Group[33]

Hanauer et Distal UC B (54)9 10 [19]h* al [18]1 [r,db] PI (57)9 2 [4]h*

Lamers et Proctitis , B(32) B=A'SA' al [36]1 proctoslgmoidltlS

[r,mc] ASA 4 g/60ml (30)b

Lemann et Distal UC B (48) a1.l37]1 [sb,mc] ASA 19 1100ml (49) Lofberg et Distal UC S,ASAorO B (45) R 7 [16]h al [10] [r,sb,mc]

Pr 25 mgll00ml (55)b R 14 [24]h

Tarplla et Distal UC S (32) or B (37) B=H al [11 ] [r,sb,mc] ASA(8)

H 125 mg/5ml (35)

a Measured subjectively uSing diary cards andlor a visual analogue scale, unless otherwise stated b Administered once dally at bedtime

c Clinical response was based on endoscopIc (sigmoidoscopIc) plus histological scores.

Endoscopic Histological outcome outcome (no of pts) (no of pts) [%] [%]

R 6[14] R 5 [11] I 14 [32] I 15 [34] NCNV 20 [45] NCNV 20 [45] NE 4[9] NE 4[9] R 8 [18] R 6[14] I 12 [27] I 14 [32] NCNV 17 [39] NCNV 15 [34] NE 7[16] NE' 9 [20] B> PI B > PI

R 16 [52]' I/R 21 [68]* 1' 10 [32]

R 8[24]' I/R 12 [36]* I 13 [39] B = Pr NC from baseline

Significant Improvement from baseline

R 11 [34] I 12 [37 5]

R 11 [37] I 15 [50] R/I 36 [75] R/I. 30 [63] R/I 40 [81] R/I 33 [67] R 7[16] R 4[9] 1-[54] I 21 [56] R 13[25] R 8 [15] 1 - [42] I 22 [40] R 22[61] R/I 16 [46] I 3 [8] NI 19[54] NI 11 [31] R 17[49] R/I 16 [47] I 2 [6] NI 18[53] NI 16[46]

d Significant advantage for budesonlde for decrease In frequency of blood In stools and Improvement In social function ; there was no significant difference between treatments for other parameters.

e Administered for 2 weeks f Published as an abstract g Administered for 6 weeks h Clinical remission required endoscopIc remiSSion plus no more than 3 bowel movements per day Without blood. I ASA treatment reduced the number of formed loose stools With blood more than budesonide therapy.

AbbreVIatIOns and symbols: ASA = mesalazlne, db = double-blind; H = hydrocortisone, I = Improved (reduction In score from baseline), mc = multlcentre; MP = methylprednisolone, NC = no change, NE = not evaluable, NI = no Improvement, 0 = olsalazine, PI = placebo, Pr = prednisolone, pts = patients, r= randomlsed; R = remission (score of 0 or 1), S = sulfasalazlne, sb = Single (Investigator) blind, W = worsened, * Indicates a Significant difference between treatments (p < 0 05), > Indicates statistically Significant Improvement in favour of the former agent (p < 0 05), = Indicates no Significant difference between treatments (p > 0 05)

© Ad,s International Limited All rights reserved. Drugs 50 (5) 1995

864

35 • Budesomde D Hydrocortisone

3

2.5

05

EndoscopiC flndmgs Histological findings

Fig. 3. Comparison of the efficacy of treatment with budesonlde enema and hydrocortisone enema Change in endoscopIc and histological scores In 72 patients with active distal ulcerative colitis treated with budesonide enema 2 mg/1 OOml or hydrocor­tisone enema 125 mg/5ml; a decrease In score reflects Improve­ment [11] * Slgmficant change In score from baseline (p < a 01).

successfully treated with conventional therapies[34] and, after twice-daily administration for 6 weeks, in 7 of 8 patients with active distal colonic Crohn's dis­ease.[34] Endoscopic remission or improvement oc­curred in 7 patients in the latter study. Another non­comparative trial showed the same dose of budesonide, administered once daily at bedtime, to significantly improve endoscopic and histological scores and the variables 'urgency' and 'well-being' at 4 weeks in 28 patients with active distal ulcerative colitis or proctitisP] These latter 2 variables were measured daily by patients using a visual analogue scale. Significant reductions in both the number of formed stools with blood and diarrhoea with blood were also seen. A retrospective analysis of 110 pa­tients with active ulcerative colitis and/or Crohn's disease who received budesonide enema once or twice daily (as 3 different enema formulations) on a compassionate use basis in clinical practice showed that 66% of patients improved, 16% were unchanged and 4.5 % deteriorated; data from 14 patients (13.5 % ) were incomplete)35]

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Spencer & McTavish

A number of trials have been published which compared the efficacy of once-daily budesonide en­ema with placebo, other glucocorticoids (hydrocorti­sone, methylprednisolone and prednisolone) or mesalazine in patients with active distal ulcerative colitis (table III). Disease had been diagnosed a mean of 5.1 to 7.6 years[6,8,1O] or median of 2.8 to 4 years[Il,33] before study entry. Many patients (24 to 98.5%) received concomitant treatment with sul­fasalazine, mesalazine or olsalazine; this was allowed only if these drugs were being taken prior to study entry and if daily doses were kept constant for the study duration. In general, budesonide enema dem­onstrated similar efficacy to other active therapies and greater activity than placebo after 4 weeks of treatment. Endoscopic remission or improvement was noted in 46 to 84% of budesonide-treated pa­tients, although the greatest response rate was ob­served using a preliminary formulation of the en­ema.[9] Histological remission or improvement was achieved in 45 to 68% of budesonide recipients. Pa­tients treated with budesonide had improved general well-being, as measured by visual analogue scale, at 2 weeks compared with placebo recipients)8] In 1 study, although 50% of patients with mild disease in each group achieved clinical remission, patients with moderate disease tended to be more likely to improve clinically when treated with budesonide en­ema than with methylprednisolone enema (81 vs 64% improved)J6] Budesonide enema produced endo­scopic improvement faster than prednisolone enema in 1 study,[9] but not in anotherJIO] Endoscopic and histological signs were significantly less severe in pa­tients treated with budesonide enema than in those treated with prednisolone enema after 2 and 4 weeks' treatrnent.[9] In a 6-week study, budesonide 2mg en­ema had similar efficacy to hydrocortisone 100mg enema, as shown by improvements in endoscopic and histological scores from baseline at weeks 4 and 6, in 184 patients with active distal ulcerative colitis)38]

Greater endoscopic and/or histological im­provement was observed after 4 weeks' treatment with budesonide than after 2 weeks[8,9,1l] (fig. 3), and these improvements were maintained during 8 weeks of treatment)lO] Indeed, the proportion of

Drugs 50 (5) 1995

Budesonide in Inflammatory Bowel Disease: A Review 865

Table IV. Clinical efficacy of oral budesonlde In patients with active Crohn's disease treated with a controlled Ileal release formulation of

budesonlde (8 CIR) or pH-modified release formulation of budesonlde (8 mod), measurements were made at 8 weeks unless otherwise stated

Reference Clinical Decrease in Crohn's Site of disease

[tnal design]

Study medications

(no. of pts) remission" disease activity Index from (%) baseline (no. of pomts)

Caesar et a1,[39] lIeocaecal region [nc]

Camplen et a1,[12]c Ileum ± ascendmg colon

(177 patients randomised)

[r,db,mc]

Greenberg et al [1 3] Ileum ± colon up to hepatic

flexure [r,db,mc]

Gross et al,[40jc

Lofberg et al [14)

Roth et al [19]

Rutgeerts et al,(15)

NS [r,db,mc]

Distal Ileum, Ileocaecal region and/or ascending colon [nc]

NS[nc]

Ileum or Ileocaecal region [r,db,mc]

8 mod 9 mg/day x 6wk (30)

8 CIR 9mg od x 8wk, 6 mg/day x 2wk, 3 mg/day x 2wk

67b

60

8 CIR 4 5mg bid x 8wk, 42 6 mg/day x 2wk, 3 mg/day x 2wk

Pr 40mg od x 2wk, 60 30 decreased to 5 mg/day x 7wk, then 5 mg/day x 3wk

8 CIR 15mg m 2 divided doses x 8wk, 43t 6 mg/day x 2wk (64)

8 CIR 9mg in 2 divided doses x 8wk, 6 mg/day x 2wk (61)

8 CIR 3mg m 2 divided doses x 8wk, PI x 2wk (67)

PI bid x 10wk (66)

8 mod 9 mg/day x 8wk (34)

MP 48 mg, decreased to 8 mg/day, x 8wk (33)

8 CIR 3mg tid x 12wk, 2mg tid x 6wk, 1 mg tid x 6wk (21 )e

8 mod 9 mg/day x 6wk (9)

8 CIR 9mg od x 8wk, 6 mglday x 2wk (86)

Pr 40mg od x 2wk, 30mg od x 2wk, 25mg od x 2wk, then decreaSing dose x 4wk (86)

33

20

56

73

67d

52, 539

65,669

a Defined as a decrease m the Crohn's disease activity Index to $150

b Measured at 6wk

c Published as an abstract.

d Measured at 2wk

167b* (responders only)

121t

21

145

168

130d, 1439

e Concurrent therapy with other non-steroidal medication for Crohn's disease (such as sulfasalazme or metronidazole) was allowed, provided the dose remained constant throughout the study

Measured at 12wk The modified Crohn's disease activity mdex was used

9 Measured at 10wk

AbbrevIatIOns and symbols: bid = tWice dally; db = double-blind; mc = multlcentre, MP = methylprednisolone; nc = noncomparative, NS = not specified, od = once daily, PI = placebo, Pr = prednisolone, r= randomised; tid = 3 times dally, wk = weeks; * Indicates a Significant difference compared with baseline (p < 0 001), t Indicates a Significant difference between active therapy and placebo (p < 0 01), t indicates a significant difference versus prednisolone (p = 0 001 )

patients with clinical remission at S weeks (non­inflamed mucosa as shown by endoscopy plus no more than 3 bowel movements per day without blood) increased compared with the proportion at 4 w eeks (36 vs 16%).[10] Daily administration of budesonide enema 1 mg/lOOml for 2 weeks tended

© Adis International limited All rights reseNed .

to be less clinically and endoscopically effective than doses of 2 mg/lOOml or 4 mg/lOOml in 1 dose­ranging study, although the lowest dose demon­strated some efficacyJ33] Similarly, daily doses of 2 or Smg were significantly superior to placebo, but budesonide 0.5 mg/day was not, after 6 weeks'

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866

treatment in 233 patients with distal ulcerative colitis.[l8]

2.2 Oral Budesonide

Two oral formulations of budesonide have been evaluated in clinical trials (table IV). The most ex­tensively studied formulation is a controlled ileal release coated capsule, which was designed to facilitate delivery of the drug to the terminal ileum and proximal colon.[12-15] These are areas of the

intestine commonly affected in patients with Crohn's disease.[41]

In most of the trials, patients were required to have a score of ~200 on the Crohn' s disease activity index to be eligible for enrolment or, in 1 study each, an erythrocyte sedimentation rate >25 mmIh, serum orosomucoid level > 1.2 giL or plasma haptoglobin level >2.5 glL,[14] or a score of >150 on the Crohn's disease activity index was neces­sary.[40] Clinical remission (a decrease in Crohn's disease activity index to S;150 with or without a 60-point decrease in score from baseline) was de­fined in 5 trials.l 12,13,15,39.40]

Treatment with oral budesonide 9 mg/day for up to 8 weeks resulted in clinical remission in 42 to 67% of patients with active Crohn's disease of the ileum, ileocaecal region and/or ascending colon and often produced significant reductions in Crohn's disease activity index scores compared with baseline or placebo (table IV). It should be noted that a large number of patients did not com­plete a dose-finding study, predominantly because of inefficacy in the placebo or budesonide 3mg group (fig. 4).[13] Inflammation, as measured by

mean erythrocyte sedimentation rate, was also re­duced during treatment with budesonide (see sec­tion 1.1.2). Clinical improvement was reflected in the results of a quality-of-life questionnaire (the inflammatory bowel disease questionnaire), which showed that patients who received budesonide 9 or 15 mg/ day had greater mean increases in score than placebo recipients (p S; 0.01).l13] A dosage of 9 mg/day was also significantly more effective than the higher dosage of 15 mg/day. In 1 study, a long history of Crohn's disease at study entry (12.3 vs

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60

50

10

o Placebo

o Budesonide 3mg/day

o Budesonide 9mglday Budesonide 15mglday

Spencer & McTavish

Fig. 4. Reasons for discontinuation of study medication In 119 patients with active Crohn's disease treated with oral budeson­Ide 3, 9 or 15 mg/day or placebo, administered in 2 divided doses before meals for 8 weeks 258 patients were randomised to receive treatment in this studyJ13] * Significant difference in the proportion of patients affected, as compared with the placebo or budesomde 3 mg/day groups (p = 0.014).

5.3 years) correlated with unsuccessful budesonide therapy. [39]

The only study to compare single and multiple daily doses of budesonide showed that a once-daily dosage regimen of budesonide 9mg tended to be more effective than daily administration of two 4.5mg doses.l12] Response to oral budesonide was

similar in patients who had received treatment with steroidal agents prior to study entry and in those who had received no such previous therapy.[14] In­

deed, in a study which enrolled 17 patients with active Crohn's disease who were refractory to or intolerant of glucocorticoid therapy and were con­sidered candidates for surgery, budesonide 9 mg/day reduced , mean Crohn's disease activity index score from 371 to 195 after 4 weeks, which was sufficient to obviate the need for surgery, in 9 patients. [42] Mean scores were also reduced in the remaining 8 patients, from 390 to 250 at 4 weeks, but all these patients later required surgery. Treatment with oral

Drugs 50 (5) 1995

Budesonide in Inflammatory Bowel Disease: A Review

budesonide allowed postponement of surgery by at least 6 months in 3 of 4 patients who were potential candidates for surgery at enrolment in another trial. [14]

Oral budesonide produced a rapid effect, with significant reductions in Crohn's disease activity index, compared with placebo,[13] noted after only 2 weeks of therapy. In comparisons with pred­nisolone, contrasting results were obtained. In 1 study, early remission was achieved by more pa­tients treated with oral budesonide 9mg once daily than with oral prednisolone 40mg once daily (dos­age was then reduced after 2 weeks) [48 vs 37% at 2 weeks], although both drugs were equally effec­tive at 8 weeksJ12] However, treatment with pre­dnisolone was more effective than budesonide therapy after 4 (remission rate of 67 vs 40%), but not 2, 8 or 10, weeks in another triaU15] In this latter trial, prednisolone recipients also had a greater decrease in the number of liquid or soft stools and a greater increase in body weight and general well-being at most time points than budesonide recipients. There was no significant difference in efficacy between treatment with the modified pH release formulation of budesonide

867

and treatment with methylprednisolone in 67 pa­tients with active Crohn's diseaseJ40]

Budesonide doses were generally tapered after 8 weeks of therapy. Although responses were maintained after these dose reductions, mean Crohn's disease activity scores tended to in­creaseJ14]

A slow-release formulation of budesonide has also been evaluated in patients with ulcerative co­litis extending proximally beyond the sigmoid co­lonJ43] At a dose of 5mg twice daily for 4 weeks (then tapered to 2mg twice daily), this formulation had similar efficacy to prednisolone 40 mg/day for 2 weeks (then tapered to 5 mg/day) after 9 weeks of therapy. Endoscopic scores decreased by 1.20 points in the 34 budesonide recipients and by 1.36 points in the 38 prednisolone recipients.

2.2.1 As Maintenance Therapy Four studies have specifically evaluated the ef­

ficacy of oral budesonide as maintenance therapy for patients with Crohn's disease. In these trials, relapse was defined as an increase in Crohn's dis­ease activity index to ;:::150[20,44] or ;:::200[45] or by ;:::60 points from baseline[20,44,45] or therapy with-

Table V. Efficacy of oral budesomde (B) for maintenance of remission In patients With Crohn's disease, ali studies were published as abstracts except that of Novacek et al [45]

Reference Site of PrevIous (study deSign) disease treatment Greenberg et aU20] Ileum ± proximal ND (r,db,mc) colonb

Gross et al [46]

L6fberg et aU44] (r,db,mc)

ND

lIeocaecal region

Predmsolone or eqUivalent B or predmsolone x 10 wkc

Treatment (no of pts) [mglday] B6 B3

Study duration (mo) 12

Time to disease relapsea (days)

178 124

Relapse rate at 12mo(%) 61 70

Placebo 39* 67 B3(85) 12 35 Placebo (95) 29 B 6 (32) 12 258dt 5ge

B3(31) 139dt 74e

Placebo (27) 92dt 63e

Novacek et al [45] (nc) Ileum and/or colon Prednisolone x 6mo B 3 (9) or 6 (11) 6 ~105 75d!

a Relapse was defined as an increase m Crohn's disease activity Index to ~150 or ~200 or by ~60 pOints from baseline or therapy Withdrawal because of disease detenoratlon that reqUIred alternative treatment

b 105 patients were enrolled In thiS tnal. c Probably respondmg patients from the study of Rutgeerts et al [15] d Treatment dlscontmuatlon or relapse e Data on file, Astra Draco AB

Rate at 6mo AbbreViations and symbols. db = double·blind, mc = multlcentre, mo = months, nc = noncomparatlve, ND = not defined, r = randomlsed, * Indicates slgmflcant difference compared With active treatment (not speCified which budesonlde dose was more effective) [p = 0026], t Indicates a slgmflcant difference between all treatments (p = 0 017)

© Adls International Limited All nghts reserved. Drugs 50 (5) 1995

868

drawal because of disease deterioration that re­quired alternative treatment.[20]

Although 75% of patients relapsed after 6 months in 1 study and similar proportions of budesonide and placebo recipients relapsed after 12 months in another trial (61 to 70%), treatment with controlled ileal release budesonide 3 or 6 mg/day significantly increased the duration of re­mission (table V). Mean reductions in Crohn's dis­ease activity index were also maintained for 6 months in 9 patients who responded to therapy with oral budesonide 9 mg/day[42] and in 18 patients who received a decreasing dose of the drug in an­other triaPl4] Crohn's disease activity index was 195,206,183 and 184, respectively, after 4, 12, 18 and 24 weeks of therapy in the former study.[42]

Most patients treated with pH-modified release budesonide 3 mg/day or placebo relapsed within 6 months of achieving remission (66 vs 62% of pa­tients), with no significant differences between therapies noted.[46]

3. Tolerability

Few of the studies reviewed in section 2.1 re­ported budesonide enema to be associated with adverse events. Those which did noted that gastro­intestinal symptoms, such as increased bowel fre­quency and colorectal bleeding, were the most fre­quently experienced (~5% of patients[35]) adverse events of budesonide enema therapy) 10.35] Al­though most events were mild, 1 patient discon­tinued budesonide therapy because of perianal pain)lO] However, these gastrointestinal events are also associated with inflammatory bowel disease, making a causal relationship with therapy difficult to determine. Haematuria,[35] thromboembolism[35] and acne[lO] were also reported in 1 patient each. In addition, one patient developed a villous adenoma; a causal relationship with budesonide was not es­tablished.[35] There was a slight tendency for more budesonide, than prednisolone, recipients to de­velop adverse events in 1 study, although the pro­portions of patients affected and the nature of these events was not specifiedJIO] In another trial, a sim­ilar proportion of budesonide (22%) and hydro-

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Spencer & McTavish

cortisone (26%) enema recipients developed non­serious adverse events that were not thought to be treatment-related)"] Laboratory abnormalities did not usually develop and no signs of significant adrenal suppression were detected during treat­ment with budesonide enema (see also section 1.1.1).

Like the enema formulation, oral budesonide was generally well tolerated in the clinical trials reviewed in section 2.2, with no serious adverse effects reported by some investigators.[I4.19,42] In a large trial (n = 258), which compared budesonide 3,9 or 15 mg/day and placebo, a similar proportion of patients withdrew from active or placebo treat­ment because of adverse events (5.2 vs 4.5%; see also fig.4).D 3] 215 patients experienced a total of 744 adverse events in this study, with no significant difference in incidence between groups (range 76 to 90%). 41 % of adverse events were gastrointes­tinal in nature, with dyspepsia and nausea being most commonly reported, and 16% were consid­ered to be glucocorticoid-associated effects. Al­though these latter effects occurred in a similar pro­portion of patients in each group (15 to 38%) and there was no difference in the incidence of symp­toms and signs such as acne, ankle oedema, hirsut­ism and · buffalo hump, cushingoid facial features were more common in budesonide-treated patients (7%) than in placebo recipients (2%).

Adverse effects associated with glucocorticoid therapy were more common among prednisolone­treated patients than among budesonide recipients in 1 trial which enrolled 176 patients (33 vs 55% of patients affected) [fig. 5].l15] However, the inci­dence of these effects was similar between treat­ments in another study, although cushingoid facial features more commonly developed in pre­dnisolone recipients than among those receiving budesonide 9mg once daily or 4.5mg twice daily (38 vs 14 vs 11 %»)12] Methylprednisolone was as­sociated with a greater incidence of glucocorticoid­related effects than was budesonide (70 vs 29% of patients affected) in 1 trial which enrolled 67 pa­tients with Crohn's Disease)40]

Drugs 50 (5) 1995

Budesonide in Inflammatory Bowel Disease: A Review

40

35

30

10

• Budesonide

o Prednisolone

869

Adverse effect

Fig. 5. Percentage of patients who experienced glucocorticoid-related adverse effects dUring oral treatment with budesonide or prednisolone. Patients received dally doses of budesonide 9mg for 8 weeks then 6mg for 2 weeks (n = 88) or prednisolone 40mg for 2 weeks, 30mg for 2 weeks, 25mg for 2 weeks then a dose which decreased by 5 mg/week for 4 weeks (n = 88).115] Some patients experienced more than 1 adverse effect.

Oral budesonide therapy did not alter liver func­tion tests in 1 noncomparative study[l4] and haematological and biochemical abnormalities of equivalent severity were reported in a similar pro­portion of patients treated with budesonide 3 to 15 mg/day or placebo.[l3] In comparison with pre­dnisolone, budesonide was associated with a sig­nificantly smaller increase in mean serum creati­nine levels and a significantly greater decrease in serum potassium levelsJl5]

Studies evaluating the efficacy of oral budeson­ide for 6 to 12 months as maintenance therapy have currently been published only as abstracts and have not adequately discussed the adverse effect profile of budesonide during longer treatment periods. Additional trials of increased duration are needed before the long term (> 12-month) tolerability pro­file of budesonide can be defined. In 1 trial, oral budesonide 3 or 6 mg/day was not associated with any clinically important glucocorticoid-related or other adverse effects over a I-year period.[20] An-

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other 12-month study reported that 2 patients de­veloped renal concretions during treatment with the same dosages of oral budesonide and that mild glucocorticoid effects, such as acne and cushingoid facial features, were more likely in budesonide, than in placebo, recipients.[44] However, most of these events were correlated with previous pre­dnisolone therapy.

4. Dosage and Administration

Budesonide enema is prepared such that 2.3mg budesonide is contained in 115ml of vehicle. This allows patients with distal ulcerative colitis or proctitis to administer 100ml of enema, which con­tains the recommended dose of budesonide 2mg. The enema should be inserted rectally once daily before bedtime and should be retained overnight if possible. In most studies reviewed in section 2.1, this dosage was administered for 4 weeks, although increasing the duration of treatment to 8 weeks may improve remission rates.[lO]

Drugs 50 (5) 1995

870

From the studies evaluated in section 2.2, it ap­pears that oral budesonide should be administered at a daily dose of 9mg for about 8 weeks for the treatment of patients with active Crohn's disease of the ileum, ileocaecal region and/or ascending co­lon. The dosage should then be tapered before treat­ment is stopped to reduce the risk of possible re­bound effects following adrenal suppression. A large dose-ranging study, which randomised 258 patients to oral treatment with budesonide 3, 9 or 15 mg/day or placebo, showed 9 mg/day to be the optimal dosage of budesonide in patients with Crohn's disease)l3] Clinical studies also suggest that an oral dosage of budesonide 6 mg/day is in­dicated for maintenance treatment in these patients.

5. Place of Budesonide in the Management of Inflammatory Bowel Disease

Inflammatory bowel disease comprises 2 dis­tinct, although similar, conditions: Crohn's disease and ulcerative colitis. Ulcerative colitis affects the colon from the rectum proximally. The length of colon affected varies, but the disease always occurs in continuity in the mucosal layer only. In contrast, Crohn's disease does not usually affect the rectal area and lesions involve, not only the mucosa, but the entire bowel wall. Both conditions are chronic, and, although symptoms may spontaneously re­solve, most patients will relapse. Of interest, non­smoking is a risk factor for ulcerative colitis, whereas smoking is a risk factor for Crohn's dis­ease)41,47]

The incidence of inflammatory bowel disease appears to be increasing in north-western Europe, where both Crohn's disease and ulcerative colitis have an annual incidence of 4 to 10 per 100 000 of population depending on country)48-50] However, in part because of the use of glucocorticoids, the mortality rate of this disease is <1 %,[51] although patients with ulcerative colitis have an increased risk of colonic cancer.[41]

Glucocorticoid enemas are accepted as being among the most effective therapies for patients with active distal ulcerative colitis or proctitis. Oral

© Adls International Limited. All nghts reserved

Spencer & McTavish

formulations of these agents are also commonly used in the treatment of Crohn's disease and more extensive ulcerative colitis. However, gluco­corticoid therapy is associated with some poten­tially serious adverse effects, such as Cushing's syndrome, hypertension, osteoporosis and diabetes mellitus. Because suppression of pituitary-adrenal function can occur during long term treatment with glucocorticoids and recovery of endogenous corti­sol release is slow in patients who have received such therapy, adrenal insufficiency can result when treatment is discontinued. The other agents most commonly used in the treatment of patients with inflammatory bowel disease are mesalazine and the mesalazine-delivering drugs sulfasalazine and olsalazine. Many other therapies, including azathio­prine, mercaptopurine, cyclosporin, methotrexate, metronidazole and 1eukotriene inhibitors have also shown varying degrees of efficacy in the treatment of these patients)47]

The ideal glucocorticoid for the treatment of in­flammatory bowel disease should have high local activity, but few systemic effects. One approach to achieving this goal is to develop an agent with high topical activity, which, when absorbed, is rapidly and extensively metabolised to inactive metabo­lites. The oral and rectal formulations of budeson­ide have been developed to meet these objectives.

B udesonide has a systemic bioavailability of 9.3 to 15% when administered orally in a controlled ileal release capsule or rectally as an enema. Com­pared with other glucocorticoids, budesonide has high topical activity, but low systemic activity. It causes less suppression of plasma cortisol levels than methylprednisolone, prednisolone or hydro­cortisone when administered orally or rectally.

In clinical trials, oral and rectal formulations of budesonide demonstrated superior efficacy to pla­cebo and similar efficacy to other glucocorticoids used in the treatment of inflammatory bowel dis­ease. Nevertheless , additional trials conducted in patients with Crohn's disease are necessary to fully define the role of the oral formulation for treatment acute disease and as maintenance treatment to fa­cilitate disease remission. Further clarification of

Drugs 50 (5) 1995

Budesonide in Inflammatory Bowel Disease: A Review

the comparative efficacy of budesonide versus mesalazine and mesalazine-delivering drugs is also necessary, as only a small number of trials have assessed this issue to date. In general, budesonide caused few adverse effects when ad­ministered for up to 12 months. However, because budesonide may be taken for longer periods, addi­tional trials are necessary to determine the extent to which longer term therapy supresses the pitu­itary-adrenal axis or causes osteoporosis and to further define the efficacy of the drug for mainte­nance therapy.

Although longer term trials are needed, current evidence suggests that budesonide administered orally or rectally does not produce the systemic effects often associated with the administration of some other glucocorticoids. It should therefore be considered as an important option for the short term treatment of selected patients with acute ex­acerbations inflammatory bowel disease. Because of its tolerability profile, the oral formulation may also prove useful for maintenance therapy in pa­tients with Crohn' s disease of the ileum, ileocaecal region and/or ascending colon.

References 1. Brogden RN, McTaVish D. Budesomde: an updated review of

Its pharmacological properlies, and therapeulic efficacy III

asthma and rhlllilis Drugs 1992,44 (3) 375-407 2. van Rees EP, Soesatyo M, Palmen MJH, et al. Effect of local

hudesomde treatment III expenmental Illflarnmatory bowel disease [abstract] Neth J Med 1993 Aug; 43: A24

3. Boyd AJ, Sherman lA, 5mbll FG Budesomde reduces mflam­mation III a hamster model of Ileitis [abstract] Gastroenterol­ogy 1994 Apr; 106 (4) Suppl: 1019

4. Chssold SP, Heel RC Budesonide. a prehminary review of Its pharmacodynamiC properlies and therapeulic efficacy III

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systemic glucocortlcosterOid potencies of budesonide, beclomethasone diproplOnate and predmsolone m man Eur J Resp DIS 1982,63 Suppl 122.74-82

6. Bianchi Porro G, Prantera C, Camplen M, et al Comparative tnal of methylpredmsolone and budesomde enemas m aclive distal ulceralive cohlis Eur J Gastroenterol Hepatol 1994, 6: 125-30

7 Danielsson A, Edsbacker S, Lofberg R, et al. Pharmacokmetlcs of budesomde enema in patients with distal ulceralive colills or proclitls. Ahment Pharmacol Ther 1993,7 401-7

8 Damelsson A, LOfberg R, Persson T, et al. A steroid enema, budesomde, lackmg systemic effects for the treatment of diS­tal ulcerallve cohlls or proCtitiS Scand J Gastroenterol1992, 27' 9-12

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9 Damelsson A, Hellers G, Lyrenas E, et al. A controlled random­Ized tnal ofbudesomde versus prednisolone retention enemas III active distal uIcerallve cohtis. Scand J Gastroenterol 1987 Oct, 22: 987-92

10. Lofberg R, 0stergaard Thomsen 0, Langholz E, et al. Budeson­Ide versus predmsolone retentIOn enemas III active distal ul­cerallve cohtls Ahment Pharmacol Ther 1994 Dec; 8. 623-9

11 TarpJia S, Turunen U, Seppala K, et al. Budesomde enema III active haemorrhaglc proctitis - a controlled trIal agaillst hy­drocortisone foam enema Ahment Pharmacol Ther 1994; 8. 591-5

12. Campleri M, Ferguson A, Doe W, et al. Oral budesomde com­petes favourably With predmsolone III acllve Crohn's disease [abstract]. Gastroenterology 1995; 108 (4) Supp!.. A790

13. Greenberg GR, Feagan BG, Marlin F Oral budesomde for ac­tive Crohn's disease N EngIJ Med 1994 Sep 29; 331' 836-41

14. Lofberg R, Danielsson A, Salde L Oral budesomde III acllve Crohn's disease. Ahment Pharmacol Ther 1993 Dec, 7 611-6

15. Rutgeerts P, Lofberg R, Malchow H, et al. A companson of budesomde with predlllsoione for active Crohn's disease. N Engl J Med 1994 Sep 29; 331: 842-5

16. Edsbacker S, Larsson P, Nilsson M, et al. Budesomde controlled Ileal release (CIR) capsules affect plasma cortisol less than prednisolone [abstract]. Gastroenterology 1995; 108 (4) Supp!.: A814

17. Thomsen 0, Andersen T, Langholz E, et al. Lack of adrenal gland suppressIOn With budesonide enema III active distal ul­cerative cohtis: a predmsolone-controlled 8-week study. Eur J Gastroenterol Hepatol 1994 Jun; 6: 507-1 I

18. Hanauer S, Robillson M, for the US Budesomde Enema Study Group. Dose ranging study of budesomde enema III active distal ulcerative colitis [abstract] Gastroenterology 1995, 108 (4) Suppl. A832

19. Roth M, Gross V, Scholmench J, et a!. Treatment of acllve Crohn's disease wllh an oral slow-release budesollide formu­latIOn [letter] . Am J Gastroenterol 1993 Jun; 88: 968-9

20 Greenberg GR, Feagan BG, Martlll F, et al. Oral budesomde as mailltenance treatment for Crohn's d,sease a placebo-con­trolled, dose-rangmg study. Gastroenterology In press

21 van Ierssel AJHM, van der Sluys Veer A, Verspaget HW, et al Budesomde and predmsolone suppress penpheral blood nat­ural killer cells m Crohn's dlsese. Aliment Pharmacol Ther 1995; 9' 173-8

22 Nyman-Pantelidls M, Nilsson A, G-Wagner Z, et al. Pharma­cokinetiCS and retrograde colomc spread of budesonide ene­mas in patients With distal ulcerative colitis. Aliment Pharmacol Ther 1994 Dec; 8: 617-22

23. Edsbacker S, Johansson s-A. Correlation between kmetlc prop­erties and chmcal safety of budesomde enema [abstract no. PD 561]. World Congress of Gastroenterology. Sydney, Aus­traha 1990.

24. Dahlstrom K, Edsbacker S, Conradson T-B Rectal and oral blOavahablhty ofbudesonide in man [abstract no. 297]. Hell J Gastroenterol 1992; 5 Suppl.

25. Nilsson M, Edsbacker S, Larsson P, et al Dose-proportIOnal kmetlcs of budesollide controlled Ileal release (CIR) capsules. Lund, Sweden' Astra Draco AB, 1995. (Data on file).

26. Nilsson M, Edsbacker S, Larsson P, et al Dose-proportIOnal kmelics of budesomde controlled ileal release capsules [ab­stract]. Gastroenterology 1995, 108 (4) Suppl A885

27. SJodahl R, Jansen J, Nilsson M, et al Pharmacokmelics of budesollide CIR capsules in pallents after smgle dose and after repeated administration of 4 5 mg tWice daily Lund,

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30. Edsbacker S, Andersson P, Lmdberg C, et al. Liver metabohsm of budesomde in rat, mouse, and man. Comparative aspects. Drug Metab Dlspos 1987; 15: 403-11

31. Edsbacker S, Jonsson S, Lindberg C, et al. MetabolIc pathways of the topical glucocortICOId budesonide 10 man. Drug Metab Dispos 1983; 11 (6): 590-6

32. Andersson P, Ryrfeldt A. BIOtransformation of the topical glucocortICOlds budesomde and beclomethasone l7a,21-dipropionate 10 human liver and lung homogenate. J Pharm Pharmacol1984; 36: 763-5

33. Damsh Budesomde Study Group. Budesonide enema 10 distal ulcerative colitis. A randoffilzed dose-response trial with pre­dmsolone enema as positive control. Scand J Gastroenterol 1991; 26: 1225-30

34. Lofberg R. Budesomde enema 10 therapy-resistant distal UC and colomc CD [abstract]. New aspects of the treatment of IOfiammatory bowel disease. Chester: Adis International, 1991: 14.

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36. Lamers C, Meijer J, Engels L, et al ComparatIve study of the topically actmg glucocorticosteroid budesomde and 5-aminosalicyhc aCid enema therapy of proctitIs and pro­ctoslgmoiditls [abstract]. Gastroenterology 1991; 100 (5): A223

37. Lemann M, Rutgeerts P, van HeuvertzwIJn R, et al. ComparIson of budesonide enema and 5-ASA enema 10 the treatment of actIve distal ulcerative colitIs [abstract]. 1st Umted European Gastroenterology Week, Athens, Sep 25-27,1991.

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Spencer & McTavish

39 Caesar I, Gross V, Roth M, et al. Treatment of aclive Crohn's ileocohlis with oral pH-modified budesomde. Z Gastroenterol 1995; 33. 247-50

40. Gross Y, Andus T, Caesar I, et al. Oral pH-modified release budesomde vs 6-methylpredmsolone in active Crohn's Dis­ease [abstract]. Gastroenterology 1995; 108 (4) Suppl: A828

41 Katz J. The course of IOfiammatory bowel disease Med Clin North Am 1994; 78 (6): 1275-80

42. Wolman SL, Greenberg GR. Oral budesomde 10 active Crohn's disease: an mitial expenence [abstract]. Gastroenterology 1991 May; 100 Suppl.: 263

43. L6fberg R, Danlelsson A, Nilsson A, et al. Oral budesomde is comparable to predmsolone in active ulcerative colitIs but causes no suppression of plasma cortisol [abstract 1787P]. 10th Congress of Gastroenterology October 207, 1994.

44. Lofberg R, Rutgeerts P, Malchow H. Budesomde CIR for mainte­nance of remission in ileocecal Crohn's disease. A European mullicenter placebo controlled Inal for 12 months [abstract no. 90]. 10th World Congresses of Gastroenterology 1994: 13.

45. Novacek G, Kleinberger M, Vogelsang H, et al. Budesonide 10

glucocorticoid dependent chromc active Crohn's disease; a pilot study. Z Gastroenterol1995; 33: 251-4

46. Gross Y, Andus T, Ecker KW, et al. Oral pH-modified release budesonide for maintenance of steroid mduced reffilSSlon 10

Crohn's Disease - an antenm analysIs [abstract]. Gastroen­terology 1995; 108 (4) Suppl: A828

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48. Bmder V. The current understandlOg of mflammatory bowel disease. Res ClIn Forum 1993; 15 (5): 11-6

49 Ekbom A, Helmick C, Zack M, et al. The epideffilology of 10-

flammatory bowel disease: a large, populalion-based study in Sweden. Gastroenterology 1991; 100' 350-8

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51. Jewell DP The new sterOIds: climcal experience in ulceralive colItis Mt Sinai J Med 1990 Oct; 57 293-6

Correspondence: Carolme M. Spencer, Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand.

Drugs 50 (5) 1995