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Alimentary Pharmacology & Therapeutics Pharmacokinetics and pharmacodynamic action of budesonidein children with Crohn’s disease K . D I L G E R * , M . A L B E R E R   , A . B U S C H à , A . E N N I N G E R § , R . B E H R E N S – , S . K O L E T Z K O   , M . S T E R Nà , C . B E C K M A N N * * & C . H . G L E I T E R * * Budesonide is effective as initial therapy of mild to moderate Crohn’s disease in adults. Superior tolerability to conventional corticosteroids might be attributed to extensive first-pass metabolism of budesonide by To evaluate biotransformation and pharmacodynamic action of budeso- Hospital Tu¨bingen, Otfried-Mu¨ller-Str.
Drug disposition and effects on endogenous cortisol were evaluated in 12 children with Crohn’s disease (5–15 years) after first intake of 3 mgbudesonide (single dose), and again after 1 week of thrice daily dosing (steady-state). The parent drug and cytochrome P450 3A-dependent metabolites were analysed in blood and urine.
administration (e.g. AUC0)¥ 7.7 Æ 5.1 h ng/mL, Cmax 1.8 Æ 1.2 ng/mL)did not change upon multiple dosing. Overall systemic elimination ofbudesonide reflected by clearance and half-life was not differentbetween children and adults. After 1 week of treatment reversible adre-nal suppression was observed – most pronounced in children agedbelow 12 years.
ConclusionsDisposition of oral budesonide appears to be similar between childrenand adults, but the doctor has to be aware of an increased risk for adre-nal suppression in paediatric patients.
safe dosing and weaning of budesonide in children, effects on endogenous cortisol production have to be Use of drugs in children requires a thorough con- sideration of the pharmacokinetics and pharmaco- Thus, the aim of our trial was to determine the pharmacokinetic profile and pharmacodynamic action Variation in body composition, and maturity of liver of oral budesonide following single dose and steady- and kidney are predominant factors accounting for state dosing in children with Crohn’s disease. A differences in drug disposition between children and profound analysis of metabolite kinetics (formation of adults.1 Simplified dosing approaches for paediatric 6b-hydroxybudesonide and 16a-hydroxyprednisolone patients based on extrapolation from adult data do via CYP3A) and comparison with data in adults will not consider age-associated changes in absorption be provided. This is the first report in children on and drug elimination or pharmacodynamics. Lack of pharmacokinetics of a modified release formulation of comprehensive evaluations of drugs to treat children with inflammatory bowel diseases is a concern.
Inflammatory bowel diseases primarily affect youngadults, but in 15–25% of cases, the initial disease Budesonide is a newer synthetic glucocorticoid with a high ratio of local to systemic anti-inflammatory Twelve female and male children aged below 16 years activity.3 Oral formulations of budesonide are effective with a diagnosis of mild or moderate Crohn’s disease, as initial therapy of mild to moderate Crohn’s disease confirmed by history, endoscopy, or histology evi- of the ileum and ascending colon in adults.4, 5 Two dence, and negative stool culture were enrolled in the recent investigations in paediatric Crohn’s disease study. Disease activity was assessed by the paediatric reported similar remission rates with budesonide and Crohn’s disease activity index (PCDAI) at screening.14 prednisone or prednisolone treatment; budesonide was The patients were eligible if, at the investigator’s dis- suggested as an alternative to conventional cortico- cretion, they had to start treatment with a corticoster- steroids in children because of superior tolerability.6, 7 oid. Exclusion criteria were: (i) severe Crohn’s disease; The decreased risk for adverse drug reactions might be (ii) any other disease of bacterial, fungal or viral ori- attributed to the very low absolute bioavailability of gin; (iii) hepatic or renal disease or other pathological budesonide of about 10% which results from gastroin- findings, which might interfere with pharmacokinetics testinal efflux mediated by P-glycoprotein, the product or drug safety; (iv) administration of corticosteroids of the multidrug resistance 1 (MDR1) gene, and from within 3 months prior to the study drug; (v) concom- extensive biotransformation via cytochrome P450 3A itant treatment with methotrexate, infliximab, antac- (CYP3A) in gut and liver.8, 9 CYP3A enzymes are the ids or colestyramine (cholestyramine); (vi) use of most important enzymes in human drug metabolism.10 drugs during the last week prior to the first adminis- However, changes in CYP3A activity during childhood tration or during the trial, which might influence bio- and adolescence are incompletely characterized.11 Data concerning developmental expression of P-glycopro- azathioprine or mercaptopurine (6-mercaptopurine), tein which is the major drug transporter in human the dose must have been stable prior to study entry intestine are scarce.12 Therefore, clinical studies on for at least 8 weeks. Mesalazine (mesalamine) was disposition of budesonide in children including char- allowed in dosages of 30–50 mg/kg. Intake of grape- acterization of the relevant metabolic pathways are fruit in the week prior to the first study day preclu- Recently, paediatric gastroenterologists discussed a trend to higher incidence of certain steroid-associated side-effects such as moon face in children when com-pared with adults during both prednisolone and budes- The children ingested 3 mg budesonide as a single oral onide treatment.7 Symptoms of adrenal suppression dose on day 1, thrice daily from days 2 to 7, and once are dose-related in adults,13 but may be a special in the morning of day 8. On day 1 and on day 8, problem in childhood and during puberty. To support ª 2006 Blackwell Publishing Ltd, Aliment Pharmacol Ther 23, 387–395 B U D E S O N I D E I N C H I L D R E N W I T H C R O H N ’ S D I S E A S E pharmacodynamic profiling were performed by deter- Pharmacokinetic and pharmacodynamic analysis mination of budesonide, CYP3A-dependent metabolites(6b-hydroxybudesonide, Pharmacokinetic analysis was based on plasma con- and cortisol in plasma and urine before and during centrations above the limit of quantification. Peak 24 h after drug administration. On day 1, one separate plasma concentration (Cmax), trough plasma concentra- blood sample was collected for deoxyribonucleic acid tion (Cmin) and time of Cmax (tmax) were taken directly extraction in order to determine MDR1 single nucleo- from the plasma concentration–time curves. Area tide polymorphisms (2677G>T,A and 3435C>T).16 All under the plasma concentration–time curve (AUC) as children were hospitalized during two study days (days well as terminal elimination half-life (t1/2 ¼ ln[2]/k), 1 and 8). After an overnight fast, a standardized lunch apparent oral clearance (Cl/f ¼ dose/AUC0)¥), and was served but not until 4 h after intake of budeso- nide. Blood samples were taken just before and 1, 2, [AUC0)¥ k]) were calculated using standard non-com- 2.5, 3, 4, 4.5, 5, 6, 8 and 24 h after administration of partmental analysis (WINNONLIN v. 3.1A, Pharsight Cor- the study drug. For safety reasons, in one children poration, Mountain View, CA, USA). Cl/f and Vd/f aged 5 years blood collection for determination of were normalized for body weight. The elimination rate cortisol had to be restricted to two samples (0 and constant (k) was determined by linear regression ana- 24 h). Blood samples (ethylenediaminetetraacetic acid lysis of the terminal log-linear phase of the plasma tubes) were centrifuged immediately. Urine was collec- concentration–time curve. AUC describes the extent of ted in two consecutive samples (0–8 and 8–24 h).
systemic drug exposure; Cl/f characterizes the ability Plasma and urine were stored at )20 °C (<1 month) to remove budesonide from the plasma in a given per- until analysis. To ensure compliance during days 2–7, iod; Vd/f is a function of plasma and tissue protein- patients had to use a dispenser and fill in a medication binding properties of the substance, but does not diary. Any concomitant medication was administered necessarily refer to any physiological compartment in with a difference of at least 2 h to the study medica- the body. Rate of accumulation was obtained by the tion. Adverse drug reactions were recorded in all chil- following ratio:18 Rac ¼ AUCss,0-8h,d8/AUC0-8h,d1. A lin- administration was calculated as the ratio of AUCss,0- AUC0)¥,d1. Ratios of metabolite formation (AUCMet/AUCBudesonide, where Met is the metabolite) Concentrations of budesonide, 6b-hydroxybudesonide, such as AUC0-24h of 6b-hydroxybudesonide to AUC0- and 16a-hydroxyprednisolone in plasma and urine of budesonide were used as indices of CYP3A were determined by validated liquid chromatography metabolic activity. Urinary recoveries of the analytes tandem mass spectrometry.17 After extraction from the were based on the cumulative amount of the analyte matrix, budesonide and its metabolites were quantified excreted during the 24 h collection period (Ae0-24h), using a triple-stage mass spectrometer SCIEX API III and were expressed as percentage of the budesonide PLUS (SCIEX, Thornhill, ON, Canada). The chromatog- dose administered. Clearances to metabolites (ClMet) raphy column was coupled via a heated nebulizer being a measure of elimination of budesonide via bio- interface to an atmospheric pressure ionization cham- transformation were calculated by dividing Ae0-24h of ber of the mass spectrometer. For determination of the respective metabolite by AUC0-24h of budesonide 16a-hydroxyprednisolone a turbo ion spray interface in plasma. Effects of budesonide on endogenous corti- was used instead. The lower limit of quantification in sol production were evaluated in each individual by (i) plasma (urine) was 0.1 ng/mL (0.5 ng/mL) for budeso- measuring morning cortisol plasma levels (8 AM), by (ii) calculating AUC of cortisol in plasma during 24 h (2 ng/mL) for 16a-hydroxyprednisolone. Between-day and by (iii) measuring the cumulative amount of corti- and within-day coefficients of variation of quality sol excreted into urine during 24 h.
controls were below 15%. Cortisol in plasma and inurine was determined using a fluorescence polariza- tion immunoassay (TDx/TDxFLx, Abbott Laboratories,Abbott Park, IL, USA). Sensitivity of the test was It has been demonstrated that in a paediatric pharma- cokinetic study with frequent blood collection a group ª 2006 Blackwell Publishing Ltd, Aliment Pharmacol Ther 23, 387–395 of 12 subjects will provide reliable information on the lines of the Declaration of Helsinki, and International parameters reported.19 The pharmacokinetic and phar- Conference on Harmonization (ICH) guidelines for macodynamic parameters are given as mean Æ s.d. or Good Clinical Practice (GCP). Details of the study drug median with 95% confidence interval in parentheses.
and study design were outlined to the child and the Wilcoxon test was used to compare the parameters on parents by the investigator prior to screening. All par- day 1 (single dose) with the corresponding parameters ents or legal guardians gave written informed consent.
on day 8 (steady-state). Morning concentrations of Children gave either written consent or assented cortisol in plasma were compared across treatment (C0h,d1, C24h,d1, C0h,d8, C24h,d8) by non-parametric ANO-VA. In addition, differences in our results on disposi- tion of budesonide and formation of metabolites in children and our previously published results on phar- macokinetics of oral budesonide in adults were testedfor significance by Mann–Whitney test; in eight Four female and eight male children with Crohn’s dis- ease (PCDAI, 16.9 Æ 11.7) completed the study accord- parameters of budesonide and its metabolites follow- ing single-dose administration of 3 mg of budesonide Individual demographic and clinical characteristics are are available from baseline of a drug interaction study presented in Table 1. The study drug was well toler- using the same methods.20 The P-value of <0.05 was ated. There was no serious adverse drug reaction.
regarded as statistically significant. Statistical compar-ison was carried out by use of the software package GRAPHPAD INSTAT (GraphPad Software, Inc., San Diego, Pharmacokinetic parameters of oral budesonide and twoCYP3A-dependent metabolites are given in Table 2 forcomparison of single-dose administration and steady- state dosing. Plasma concentration–time curves of The study protocol was approved by the Institutional budesonide, 6b-hydroxybudesonide and 16a-hydroxy- Ethics Committees of the respective centres. The trial prednisolone are illustrated in Figures 1–3. Mean Cl/f of was conducted in accordance with the ethical guide- budesonide describing the ability of the body to remove Table 1. Demographic and clinical features of the paediatric population 5-ASA, mesalazine; AZT, azathioprine.
* Not on the study days (days 1 and 8).
ª 2006 Blackwell Publishing Ltd, Aliment Pharmacol Ther 23, 387–395 B U D E S O N I D E I N C H I L D R E N W I T H C R O H N ’ S D I S E A S E kinetic parameters of budeso-nide and two CYP3A- Data are given as mean Æ s.d. or as median with 95% confidence interval in paren-theses.
Cmax, peak plasma concentration; tmax, time of peak plasma concentration; AUC0)¥,area under the plasma concentration–time curve extrapolated to infinity; t1/2, terminalelimination half-life; Cl/f, apparent oral clearance; Vd/f, apparent volume of distribu-tion; Ae0-24h, amount excreted into urine during 24 h; Css,max, peak plasma concentra-tion at steady-state; tss,max, time of peak plasma concentration at steady-state; Css,min,trough plasma concentration at steady-state; AUCss,0-8h, area under the plasma concen-tration–time curve at steady-state during the dosing interval of 8 h; CYP3A, cytochromeP450 3A.
Figure 1. Plasma budesonide concentration–time curves Figure 2. Plasma 6b-hydroxybudesonide concentration– in 12 children with Crohn’s disease following a single time curves in 12 children with Crohn’s disease following oral dose of 3 mg budesonide on day 1 (solid circle) and a single oral dose of 3 mg budesonide on day 1 (solid cir- on day 8 (open circle) after thrice daily dosing during cle) and on day 8 (open circle) after thrice daily dosing days 2–7. Data are presented as mean Æ s.d.
during days 2–7. Data are presented as mean Æ s.d.
the drug from plasma was 0.18 L/min/kg in children drug accumulation (1.5 Æ 0.6, budesonide; 2.2 Æ 0.8, following a single oral dose of 3 mg. Median t1/2 of 6b-hydroxybudesonide; 1.5 Æ 0.4, 16a-hydroxypredn- budesonide was 1.9 h on day 1, and it was not signifi- isolone; Rac). The linearity factor based on AUC was cantly longer on day 8 (2.5 h, 95% CI: 2.0–4.3 h).
1.0 Æ 0.5 for budesonide, 0.9 Æ 0.2 for 6b-hydroxybu- Steady-state dosing did not result in relevant systemic desonide and 1.1 Æ 0.3 for 16a-hydroxyprednisolone, ª 2006 Blackwell Publishing Ltd, Aliment Pharmacol Ther 23, 387–395 Figure 3. Plasma 16a-hydroxyprednisolone concentra- Figure 4. Ratios of cytochrome P450 3A (CYP3A)- tion–time curves in 12 children with Crohn’s disease fol- dependent metabolite formation (AUCMet/AUCBudesonide lowing a single oral dose of 3 mg budesonide on day 1 where Met is the metabolite) following a single oral dose (solid circle) and on day 8 (open circle) after thrice daily of 3 mg budesonide in 12 children with Crohn’s disease dosing during days 2–7. Data are presented as (black) and eight healthy adults20 (white). Data are pre- sented as mean values and s.d. (*P < 0.05).
3435 TT genotype (patient 9) was carrier of MDR1 behaviour of budesonide might be well predicted by 2677 TT. Looking over the plasma concentration–time curves in these children, absorption of budesonide was There were no significant differences in the pharma- not found to be lower in MDR1 3435 CC with puta- cokinetic parameters following a single dose of 3 mg tively high intestinal expression of P-glycoprotein21 than in MDR1 3435 TT. Remarkably delayed absorp- ease and healthy adults20 (e.g. Cmax, 1.76 Æ 1.17 ng/ tion of budesonide was observed in a boy (patient 10) mL vs. 1.07 Æ 0.63 ng/mL; Cl/f, 0.18 Æ 0.08 L/min/kg vs. 0.22 Æ 0.11 L/min/kg; Vd/f, 40.1 Æ 23.2 L/kg vs.
12 days) until the evening before first administration 46.7 Æ 27.9 L/kg; children vs. adults). In accordance of budesonide. On day 1 but not on day 8, budesonide with results in adults,20 mean urinary recovery of in plasma was below the limit of quantification during budesonide (sum of budesonide and both metabolites) in children was about 12% of the dose administered.
The amount of unchanged budesonide excreted into urine is negligible. Ratios of metabolite formation(AUCMet/AUCBudesonide) reflecting activity of CYP3A Effects of budesonide on endogenous cortisol are were not different between single-dose administration summarized in Table 3. After 1 week of thrice daily and steady-state dosing in children. Formation of dosing of 3 mg budesonide, morning cortisol levels 6b-hydroxybudesonide was significantly increased in in plasma decreased significantly (17 Æ 13 lg/dL vs.
children when compared with recent data in adults20 9 Æ 12 lg/dL, day 1 vs. day 8, P < 0.01). Likewise, (2.9 Æ 1.0 vs. 1.9 Æ 0.9, P ¼ 0.0373, Figure 4). In the areas under the effect curves (AUC0-24h) were lower paediatric population, ClMet were 0.24 Æ 0.12 L/h/kg on day 8 when compared with day 1 (P < 0.05). On for 6b-hydroxybudesonide, and 1.2 Æ 1.2 L/h/kg for day 8, in five of 12 children (the three youngest 16a-hydroxyprednisolone; comparison with adults20 patients, and two older children; patients 1, 3, 8, 10 and 12) plasma cortisol at 8 AM was below the limit To assess a pharmacogenetic impact on disposition of detection. In each subject, withdrawal of budeso- of budesonide, we contrasted opposite homozygous nide resulted in a return to normal values of morn- MDR1 genotypes. All children with MDR1 3435 CC ing plasma cortisol within 24 h (C24h,d8). Urinary genotype (patients 1–3) were also carriers of MDR1 excretion of cortisol was not affected by intake of 2677 GG, and one patient with the variant MDR1 ª 2006 Blackwell Publishing Ltd, Aliment Pharmacol Ther 23, 387–395 B U D E S O N I D E I N C H I L D R E N W I T H C R O H N ’ S D I S E A S E lites amounts to only 1–10% of the parent drug.9 Table 3. Effect of budesonide on endogenous cortisol in Overall systemic elimination of budesonide reflected by Cl/f and t1/2 was not different between children and (AUC ratio) was found to be 1.5-fold higher in children than in adults. Difference in formation of Met/AUCBudesonide) has been proven to be a good measure of CYP3A activity.20 However, it is difficult to gain insight into age-related differences in CYP3A activity comparing children with Crohn’s disease and healthy adults. Consistent with our data, absolute bio- availability of a different delivery system of oral budesonide was similar (9 Æ 5% vs. 11 Æ 7%) in eight children with Crohn’s disease (12.4 Æ 1.8 years) and six adults with Crohn’s disease (33.2 Æ 12.6 years).22 The trend to lower bioavailability of oral budesonide in the paediatric population observed by those investi-gators might now be explained by enhanced biotrans- On day 1 and on day 8, a single oral dose of 3 mg budeso-nide was given after thrice daily dosing during days 2–7.
formation via CYP3A enzymes in children. However, metabolic pathways of budesonide were not analysed C0h, predose cortisol plasma concentration (8 AM); C24h, cort- isol plasma concentration at 24 h (8 AM); AUC0-24h, area CYP3A is the most abundant human CYP enzyme under the cortisol plasma concentration–time curve during accounting for approximately 30% of the total CYP 24 h; Ae0-24h, amount of cortisol excreted into urine during content in adult liver.23 Clinical trials with substrates 24 h; LOQ, limit of quantification (0.77 lg/dL).
*P < 0.05 vs. day 1; **P < 0.01 vs. day 1.
of CYP3A are needed to evaluate precisely if develop-   No profiling in one children aged 5 years.
mental changes necessitate dose adjustments across thespan of childhood and adolescence. The CYP3A sub-family, CYP3A4, CYP3A5 and CYP3A7, is variably expressed at different stages of life. CYP3A4 is the major isoform This study provides comprehensive data on the pharma- in the adult liver, whereas expression of CYP3A5 is low in adult Caucasians due to a genetic polymorph- budesonide in children with Crohn’s disease. The phar- ism.24 CYP3A7 is expressed in the fetal liver, peaks macokinetic parameters of budesonide following single- shortly after birth and then declines rapidly to levels dose administration did not change significantly upon that are undetectable in most adults.25 Clearly, the multiple dosing. We observed no relevant drug accumu- most dramatic developmental changes occur during the lation during steady-state dosing. Therefore, in the pae- first year of life.26 The few data available comparing diatric population plasma concentration of budesonide duodenal and hepatic expression of CYP3A in older at steady-state may be predicted from single-dose data.
children and adolescents with that in adults are con- After short-term treatment with budesonide, 3 mg thrice flicting.12, 25, 27, 28 Many healthy children of different daily during 1 week, reversible adrenal suppression was ages would be needed in a clinical trial aiming at an observed in the paediatric patients; morning plasma accurate examination of matural changes of CYP3A.
cortisol below the limit of detection in each patient It remains to be determined if Crohn’s disease affects duodenal CYP3A activity. Mean absolute bioavailabili- Budesonide is a high extraction drug. It undergoes ty of a high dose of oral budesonide (18 mg) was extensive first-pass metabolism by CYP3A enzymes reported to be significantly increased (21% vs. 12%, P < 0.05) in six adult patients with Crohn’s disease in prednisolone. Glucocorticoid activity of the metabo- comparison with eight healthy adults.29 Therefore, it ª 2006 Blackwell Publishing Ltd, Aliment Pharmacol Ther 23, 387–395 might be speculated that the difference in formation reactions. Vigilance of healthcare professionals is the of metabolites we observed between children with Cro- most important factor in avoiding adverse drug reac- hn’s disease and healthy adults is further enlarged tions. Plasma cortisol concentrations are a sensitive between children with Crohn’s disease and adults with measure of systemic corticosteroid effects in children.33 Crohn’s disease. Inflammatory bowel diseases might The method is used to detect adrenal suppression not only affect intestinal CYP3A but also intestinal before the appearance of clinical symptoms. Therefore, drug efflux by P-glycoprotein. To date, investigations the finding that morning plasma cortisol was not in Crohn’s disease addressing the interplay between detectable on day 8 in five of 12 children including all drug-metabolizing enzymes and transporter proteins children below 12 years of age needs special attention.
The extent of adrenal suppression in adults is known to MDR1 genotyping was performed due to the partic- be related to the dose of budesonide.13 Using the stand- ular relevance of intestinal P-glycoprotein for oral ard dosage of oral budesonide in Crohn’s disease which drug therapy.30 It has been shown that a 2677G>T,A is 9 mg/day, our children with a mean body weight of single nucleotide polymorphism in exon 21 and a 48 kg received obviously a higher dose per kilogram 3435C>T single nucleotide polymorphism in exon 26 body weight than adults. The observation that young- of the MDR1 gene affect expression of P-glycoprotein est but not most light-weighted children displayed and thereby pharmacokinetics of commonly used highest adrenal suppression might indicate particular drugs.31 There was no hint for a pharmacogenetic sensitivity in the subset of young children. Although effect on absorption of budesonide in our study popu- all children recovered from adrenal suppression within lation. Considering the small number of children, our 24 h, a prolonged effect cannot be excluded after lon- preliminary results of MDR1 genotyping should be ger treatment with budesonide. Thus, it seems advisable to reduce the dose gradually at the end of treatment The finding that in one child receiving metronidaz- with budesonide and monitor morning plasma cortisol ole the lag time of enteric-coated budesonide was con- siderably prolonged is interesting and warrants further In conclusion, our pharmacokinetic and pharmaco- investigation. Unfortunately, repetition of the study in dynamic data may be used to ensure effective and safe that subject (boy) was impossible because of resection treatment with budesonide in children with Crohn’s of the ileum a short time later. One might consider an disease. Disposition of oral budesonide appears to be unexpected drug interaction of budesonide and met- similar between children (5–15 years) and adults.
ronidazole in this case. Alternatively, absorption on However, the doctor has to be aware of an increased the first study day might have been affected by altered risk for adrenal suppression during and after intake of intraluminal pH, delayed gastric emptying or intestinal budesonide in paediatric patients. It is important to transit independent of a concomitant drug.
note that in children corrections in dosing made for Both in adults and in children with Crohn’s disease, body weight or body surface may not accurately the frequency of adverse drug reactions following reflect differences in pharmacodynamics.
effective doses of budesonide has been found to belower than that following effective doses of conven- tional steroids.32 From the pharmacodynamic analysisof our study it is apparent that children with Crohn’s The study was supported by Dr Falk Pharma GmbH, disease who are prescribed budesonide have to be Freiburg, Germany. Genotyping was performed by monitored very carefully for steroid-related adverse Dr G. Schaeffeler, Stuttgart, Germany.
3 Fedorak RN, Bistritz L. Targeted deliv- ery, safety, and efficacy of oral enteric- patients: clinical, therapeutic, and psy- ª 2006 Blackwell Publishing Ltd, Aliment Pharmacol Ther 23, 387–395 B U D E S O N I D E I N C H I L D R E N W I T H C R O H N ’ S D I S E A S E 4 Bar-Meir S, Chowers Y, Lavy A, et al.
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5 Papi C, Luchetti R, Gili L, Montanti S, http://medicine.iupui.edu/flockhart. Last CYP3A5 and its possible consequences.
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25 Lacroix D, Sonnier M, Moncion A, Cher- 6 Levine A, Weizman Z, Broide E, et al. A Gastroenterol Nutr 2003; 36: 248–52.
26 Oesterheld JR. A review of developmen- lone for the treatment of active Crohn’s ble-blind, controlled, multicentre trial.
18 Rowland M, Tozer T. Clinical Pharmaco- 28 Stevens JC, Hines RN, Gu C, et al.
19 CDER. General Considerations for Pedi- 20 Dilger K, Denk A, Heeg MHJ, Beuers U.
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30 Zhang Y, Benet LZ. The gut as a barrier 11 de Wildt SN, Kearns GL, Leeder JS, van tiple sequence variations and correlation 31 Marzolini C, Paus E, Buclin T, Kim RB.
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22 Lundin PDP, Edsbacker S, Bergstrand M, controlled ileal release capsules in chil- dren and adults with active Crohn’s dis- et al. Oral budesonide for active Crohn’s lishment of reference ranges for cortisol 14 Hyams JS, Ferry GD, Mandel FS, et al.
ª 2006 Blackwell Publishing Ltd, Aliment Pharmacol Ther 23, 387–395

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