Correspondence to: Dr S. Edsbäcker, Experimental Medicine, AstraZeneca LP, 1800 Concord Pike, PO Box 15437, Wilmington, DE, USA. E-mail: Staffan.Edsbacker@astrazeneca.com
Aim : To investigate whether omeprazole affects the pharmacokinetics and systemic effects of budesonide controlled-release capsules when the two medications are taken together.
Methods : Thirteen healthy volunteers were enrolled into a randomized, double-blind, placebo-controlled, cross-over study. Participants received omeprazole, 20 mg/day, or placebo every morning for 5 days, with three 3-mg budesonide controlled-release capsules being given with omeprazole or placebo on day 5. After a 12-day washout period, participants were switched from omeprazole to placebo, or vice versa, and the trial was repeated. Blood samples for pharmacokinetic evaluation and urine samples for cortisol assessments were collected before and after the budesonide doses.
Results : No statistically significant differences were seen between omeprazole and placebo treatment with regard to any of the parameters analysed, including the maximum budesonide plasma concentration, time to concentration maximum, area under the concentration–time curve, mean residence time and urinary excretion of cortisol. Very few adverse events were reported during the trial, and the majority were of mild to moderate severity.
Conclusion : Omeprazole treatment does not affect the pharmacokinetics or systemic effects of budesonide controlled-release capsules when the two medications are taken simultaneously.
Budesonide, a glucocorticoid with high topical anti-inflammatory activity and little or no systemic effect, has been used for many years in the treatment of inflammatory airway diseases.1 The low systemic activity of budesonide is a result of its rapid metabolism to biologically inactive metabolites — budesonide undergoes around 90% first-pass metabolism in the liver.2 Thus, long-term treatment with budesonide is less likely to cause the systemic adverse effects, such as reduced bone density and disturbed adrenal function, that are associated with traditional glucocorticoid treatment.3
The improved safety profile of budesonide compared with conventional agents has led to its use as a locally acting agent in the treatment of inflammatory bowel diseases, such as Crohn's disease and collagenous colitis. Oral budesonide, however, is readily absorbed by the gastrointestinal tract, limiting the amount of agent delivered to the ileum and colon.4 Budesonide controlled-release capsules (Entocort, AstraZeneca, Lund, Sweden) contain small pellets (1.0–1.4 mm in diameter) that are designed to resist gastric acid up to pH 5.5. Above this pH, the pellets release the drug in a time-dependent manner, with more than 60% of the budesonide dose being absorbed in the ileum and colon.5 The effectiveness of budesonide controlled-release capsules in the treatment of Crohn's disease affecting the ileum and colon has been demonstrated in a number of studies.6–9 Budesonide controlled-release capsules also appear to be effective in collagenous colitis, a disease commonly associated with an increased gastrointestinal transit.10,11
Omeprazole (Losec, AstraZeneca, Mölndal, Sweden) is a selective, non-competitive inhibitor of the gastric proton pump (H+,K+-ATPase) located in the secretory membrane of parietal cells. The duration of the antisecretory effect is not dependent on sustained plasma concentrations of omeprazole.12 Omeprazole is metabolized by cytochromes P450 2C19 and P450 3A4.13
The release of budesonide from controlled-release capsules is pH dependent, and it is possible that the increased stomach pH caused by omeprazole may lead to early budesonide release. Furthermore, the two agents are metabolized via a common pathway involving cytochrome P450 3A4,13,14 and thus it is possible that there may be a competitive interaction between the two drugs. In this study, we investigated whether the kinetics of budesonide are affected when omeprazole and budesonide are taken together.
Materials and methods
This was a randomized, cross-over, placebo-controlled study that was double blind with regard to omeprazole. Healthy adults received omeprazole, 20 mg, or placebo in the morning for 5 days. After a washout period of 12 weeks, the procedure was repeated with participants switching treatment group. On the fifth day of each 5-day period, the participants received budesonide controlled-release capsules (3 × 3 mg) together with the omeprazole or placebo (Table 1).
Table 1. Treatment schedule
Omeprazole 20 mg
Omeprazole 20 mg + budesonide 3 × 3 mg
Placebo + budesonide 3 × 3 mg
Omeprazole 20 mg
Placebo + budesonide 3 × 3 mg
Omeprazole 20 mg + budesonide 3 × 3 mg
All participants were judged to be healthy by the investigator. Participants were excluded if they had a history of glucocorticoid intolerance, were pregnant or breast feeding, were using oral contraceptives, smoked, were human immunodeficiency virus or hepatitis B virus positive or had donated blood within 12 weeks of the start of the study. The study was carried out in accordance with the Declaration of Helsinki and all volunteers provided written informed consent.
For the first 4 days of each treatment period, patients received omeprazole, 20 mg, or placebo at 07.00 h. On the fifth day at 07.00 h, after fasting for at least 10 h, the participants received omeprazole, 20 mg, or placebo followed by three 3-mg budesonide controlled-release capsules. The study medication was taken with 200 mL of water and was immediately followed by a breakfast of three slices of white bread, two with cheese and one with ham, 300 mL of coffee, tea or water, and 100 mL of orange juice. After breakfast, participants were not allowed to eat for 4 h after the dose, at which time they received a lunch of baked fish with potatoes and tomatoes, one slice of bread and cheese, and liquids. Participants were allowed to eat freely 2 h after lunch.
Blood samples for pharmacokinetic assessment were drawn from an indwelling catheter inserted into an arm vein or taken by venepuncture. Two 10-mL samples were taken immediately before the budesonide dose and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h afterwards.
The assay of budesonide was based on a combination of liquid chromatography and mass spectrometry that is capable of measuring budesonide concentrations down to 0.10 nmol/L.15
The maximum plasma concentration of budesonide (Cmax) and the time to this concentration (Tmax) were estimated from the concentrations of budesonide at each sampling time, C(T). The time taken for the plasma concentration to rise above the lower limit of quantification (LOQ) was recorded (Tapp), and the estimated time for budesonide to appear in plasma (Tlag) was calculated by linear extrapolation using the first two concentrations above LOQ (if extrapolation gave a negative value, zero was used). The terminal elimination rate (k) was estimated by linear regression of the time vs. ln[C(T)] curve during the last phase of the curve. The oral half-life (T1/2) was estimated as ln(2)/k. The area under the plasma concentration–time curve (AUC) was calculated using the trapezoidal rule up to the last measured point that was above LOQ, plus the extrapolated part, which was calculated by dividing the last concentration above LOQ by k. The area under the first moment curve (AUMC) was calculated by integrating the function T × C(T) using the trapezoidal method as described for AUC. The mean residence time (MRT) was calculated as AUMC/AUC.
Urine was collected in two 24-h fractions. Twenty-four hours before the budesonide dose, each participant emptied their bladder, and urine was then collected for 24 h in pre-weighed polythene bottles. Collection of the second 24-h fraction started immediately before the budesonide dose.
Assay of urine free cortisol was based on a combination of gas chromatography and mass spectrometry. The LOQ for cortisol in urine was 10 nmol/L, with a between-run variation of 18% at 10 nmol/L and 15% at 150 nmol/L.
The amount of cortisol excreted in urine was calculated assuming a urine density of 1.02 g/cm3. Concentrations below LOQ were estimated as LOQ/2.
Pharmacokinetic and pharmacodynamic parameters were analysed using analysis of variance (anova). AUC, Cmax, T1/2 and urine cortisol excretion were analysed using a multiplicative model, whereas MRT, Tmax, and Tlag were analysed using an additive model.
The study involved 13 healthy Caucasian volunteers (six men, seven women) with a mean age of 27 years (range, 21–42 years). Eleven participants completed the study; one participant became pregnant during the omeprazole washout period, and another developed a urinary tract infection during the placebo washout period.
The mean plasma concentrations of budesonide were similar in the omeprazole and placebo groups (Figure 1). The time taken for the plasma concentration of budesonide to rise above LOQ (Tapp) did not differ significantly between omeprazole and placebo treatments (52 vs. 44 min, respectively). Tmax was also similar during omeprazole and placebo treatments (3.2 vs. 2.9 h, respectively). In fact, no significant differences were observed between omeprazole and placebo treatments with regard to any of the pharmacokinetic parameters (Table 2).
Table 2. Pharmacokinetic parameters for budesonide. Values are given as means (95% confidence intervals)
AUC , area under the plasma concentration–time curve; Cmax , maximum plasma concentration of budesonide; MRT, mean residence time; T1/2 , oral half-life of budesonide; Tlag , time for budesonide to appear in plasma.
The administration of budesonide reduced urine cortisol excretion by 51% (95% confidence interval, 26–67%) in patients receiving omeprazole and 50% (95% confidence interval, 26–67%) in patients receiving placebo (not significant between treatments or vs. baseline). Cortisol excretion whilst receiving omeprazole was slightly higher than that whilst receiving placebo, both at baseline (94 vs. 76 nmol) and after the budesonide dose (47 vs. 38 nmol), but this difference was not significant.
There were few adverse events in the study and the majority were of mild to moderate severity. Most adverse events occurred whilst participants were receiving omeprazole with budesonide and during the subsequent washout period. Adverse events included dizziness, headache, gastroenteritis, fever and pharyngitis. No adverse events were reported during treatment with placebo and budesonide, and no single adverse event was reported in more than two patients.
One individual experienced a urinary tract infection of severe intensity during the placebo washout period. A causal relationship to either of the study medications was judged to be unlikely.
In this study, there was no interaction between omeprazole and budesonide controlled-release capsules with regard to pharmacokinetics and systemic effects.
Glucocorticoids are one of the most commonly used treatments for inflammatory bowel diseases, such as Crohn's disease. The high systemic activity of traditional agents is, however, associated with long-term side-effects.3,16 Budesonide is rapidly metabolized by the liver to produce metabolites with little or no glucocorticoid activity, and therefore poses less risk of inducing systemic glucocorticoid effects.2,4 The acid-resistant controlled-release formulation of budesonide has been developed to ensure greater delivery of the agent to the regions of the intestine most commonly affected by Crohn's disease.
Medications that reduce stomach acid levels, such as proton pump inhibitors and histamine 2-receptor antagonists, may affect drug formulations that are pH dependent, such as the budesonide controlled-release formulation. However, when omeprazole was given simultaneously with budesonide controlled-release capsules, its effects on the pharmacokinetics and pharmacodynamics of budesonide were no different from those of placebo. These data are consistent with results from previous studies of mesalazine, in which omeprazole (at doses of 20 mg and 40 mg) did not affect the pharmacokinetics of a delayed-release formulation of mesalazine coated with pH-resistant Eudragit S.17
Interactions resulting from the inhibition or induction of drug-metabolizing enzymes can also be important when giving different agents simultaneously. Omeprazole has an inhibitory effect on drugs metabolized via the cytochrome P450 2C subfamily, and it induces the metabolism of those metabolized via the 1A subfamily.18 Although omeprazole is partly metabolized via cytochrome P450 3A4, it does not appear to affect the activity of this isoenzyme at clinically relevant doses. Budesonide is solely metabolized by enzymes of the cytochrome P450 3A pathway.14 The lack of an effect of omeprazole on budesonide pharmacokinetics, demonstrated in this study, suggests that there is no metabolic interaction between budesonide and omeprazole.
The results of this study were based on a small number of healthy individuals. When extrapolating these results to larger populations, it should be noted that there are certain patient groups, such as those with achlorhydria or other pH abnormalities, in whom the results may not be applicable. Care also needs to be taken when applying the results to patients with Crohn's disease. A study by Press et al. has shown that patients with Crohn's disease have a slightly increased stomach pH compared with healthy individuals, which may limit the applicability of the results to these patients.19 The pH in the study of Press et al. did not, however, rise above pH 5.5, the level at which budesonide release may be affected. The dose of omeprazole used in the present study was 20 mg/day — the recommended clinical dose for patients with peptic ulcer. Previous studies have shown that the maximum effect of omeprazole on gastric acid production occurs with a dose of 20–30 mg/day in both healthy individuals20–22 and those with peptic ulcer.20,23,24 Moreover, it has been shown that the effects of antisecretory agents are less in patients with ulcers than in healthy individuals.25 Thus, pH-dependent pharmacokinetic interactions between omeprazole and budesonide are even less likely to occur in individuals with peptic ulcers than in the healthy individuals examined in this study.
It has been observed previously that peaks in gastric pH are related to meals.26 Several studies have shown that doses of 10–80 mg of omeprazole in conjunction with food can raise the gastric pH above 5.5,20,27–30 potentially leading to the early release of budesonide from controlled-release capsules. Although we did not measure gastric pH in the present study, the lack of a significant difference between the effects of omeprazole and placebo on the kinetics of budesonide, when given in association with food, suggests that the increased gastric pH does not affect the controlled release of budesonide. These results are supported by studies showing that the intake of food does not affect budesonide release from Entocort controlled-release capsules.5,31
Omeprazole is a commonly prescribed drug for the treatment of gastric disorders, and there are at least four published studies relating to the clinical benefit of proton pump inhibitors for gastro-duodenal ulcers in patients with Crohn's disease.32 It has been suggested that gastro-duodenal involvement in Crohn's disease may be more prevalent than previously thought.32 Hence, combination treatment with omeprazole and budesonide may be relevant in patients experiencing both gastric disorders and inflammatory bowel disease.
In conclusion, omeprazole had no significant impact on the pharmacokinetics and systemic effects of budesonide controlled-release capsules. This drug combination may be appropriate for patients with inflammatory bowel disease who may also have gastro-duodenal ulcers.
This study was supported by AstraZeneca, Lund, Sweden.