Pharmacokinetics of Budesonide (Entocort??? EC) Capsules for Crohn???s Disease

Abstract

This overview summarises available pharmacokinetic data on budesonide capsules (Entocort EC), approved for the treatment of mild-to-moderate active Crohn's disease involving the ileum and/or ascending colon and for prolongation of symptom control. Budesonide is a locally-acting glucocorticosteroid with an extensive, primarily hepatic, metabolism after oral administration. It is rapidly absorbed and biotransformed by cytochrome P450 (CYP) 3A to metabolites with negligible glucocorticoid activity. Entocort EC, a pH- and time-dependent oral formulation of budesonide, was developed to optimise drug delivery to the ileum and throughout the colon. Pharmaco-scintigraphic studies have confirmed that the Entocort EC formulation delays budesonide absorption and prolongs the rate of elimination but maintains complete absorption. This improves the delivery of budesonide to the intestinal lumen relative to a plain formulation. A low systemic availability of 9-21% indicates extensive first-pass elimination. Food appears to have little impact on the absorption of budesonide from Entocort EC capsules and the pharmacokinetics are dose-proportional between 3 and 15 mg. On average, systemic availability was 2.5-fold higher in patients with cirrhosis compared with healthy controls; however, mild liver impairment had little effect on systemic exposure. Pharmacokinetics appear unaffected by gender and age, although this has not been tested in younger children. Renal impairment is not expected to have an impact on the kinetics of Entocort EC. Budesonide is unlikely to inhibit the metabolism of other drugs, including CYP3A4 substrates, mainly because of the very low plasma concentrations obtained with the compound even after high doses of Entocort trade mark EC capsules. Strong CYP3A4 inhibitors, such as ketoconazole, will inhibit the metabolism of budesonide, resulting in several-fold increases in the area under the concentration-time curve of budesonide. Also, grapefruit juice intake may increase systemic availability of budesonide, probably by inhibition of intestinal CYP3A4 activity. Unlike prednisolone, oral contraceptives do not alter plasma budesonide concentrations. An increased pH obtained by gastric acid inhibitory drugs, such as omeprazole, does not affect the pharmacokinetics of budesonide. In summary, budesonide capsules (Entocort EC) possess many pharmacological features that make the formulation well adapted for a targeted treatment of inflammatory disorders, such as Crohn's disease involving the ileum and ascending colon.

Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation

“…The systemic availability of budesonide from MMX®-tablets matches that of marketed formulations [3]. However, the time to reach maximum plasma concentrations for the MMX®-tablets was prolonged from 6 h [10] to 14 h, which might be a measure of the projected slow and graded budesonide release throughout the colon.…”

“…This time-and pH-dependent delivery system consists of enteric coated (Eudragit L) pellets with a rate-limiting polymer containing the active drug. This formulation releases 70% of budesonide in the distal ileum and right sided colon [3], the main location of Crohn's disease lesions. In the present study, the release, absorption and plasma pharmacokinetics of budesonide were evaluated after administration of newly patented MMX®-tablets to healthy subjects.…”

“…Venous blood samples (10 mL) were collected from an arm vein at predose on days 2, 4, 6 and 7, and at the following time points after the last dose on the 7th treatment day: 0 (predose), 2,3,4,5,6,7,8,10,12,16,20,24,30,36 and 48 h. Plasma samples, obtained by centrifugation were stored at ≤ − 20 ° C until analysis.…”

“…For the treatment of IBD, budesonide has been evaluated either as oral controlled-ileal-release formulation targeting the distal ileal and right-sided colonic region in Crohn's disease [3], or as enema for the treatment of left-sided ulcerative colitis or sigmoiditis [4]. However, there are no budesonide formulations available for the oral treatment of distally located IBD.…”

The Role of Corticosteroids in Celiac Disease

“…Budesonide has been formulated as an entericcoated controlled-release capsule used primarily in the treatment of inflammatory bowel disease. It has low systemic bioavailability while delivering active glucocorticoid to the distal small intestine and colon; as such, it is appropriate for Crohn's disease patients [11][12][13]. Recent studies have confirmed its efficacy in patients with celiac disease.…”