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Mechanism of Action
Budesonide has a high topical glucocorticosteroid (GCS) activity and a substantial first-pass elimination. The formulation contains budesonide in an extended release tablet core. The tablet core is enteric coated to protect dissolution in gastric juice which delays budesonide release until exposure to a pH ≥ 7 in the small intestine. Upon disintegration of the coating, the core matrix provides extended release of budesonide in a time dependent manner.
Budesonide has a high glucocorticoid effect and a weak mineralocorticoid effect, and the affinity of budesonide to GCS receptors, which reflects the intrinsic potency of the drug, is about 200-fold that of cortisol and 15-fold that of prednisolone.
Treatment with systemically active GCS, including UCERIS, is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. Markers, indirect and direct, of this are cortisol levels in plasma or urine and response to ACTH stimulation.
In a study assessing the response to ACTH stimulation test in patients treated with Uceris 9 mg once daily, the proportion of patients with abnormal response was 47% at 4 weeks and 79% at 8 weeks.
Following single oral administration of UCERIS 9 mg in healthy subjects, peak plasma concentration (Cmax) was 1.35 ± 0.96 ng/mL, the time to peak concentration (Tmax) on average was 13.3 ± 5.9 hours, although it varied across different individual patients, and the area under the plasma concentration time curve (AUC) was approximately 16.43 ± 10.52 ng·hr/mL. The pharmacokinetic parameters of UCERIS 9 mg have a high degree of variability among subjects. There was no accumulation of budesonide with respect to both AUC and Cmax following 7 days of UCERIS 9 mg once daily dosing.
A food-effect study involving administration of UCERIS to healthy volunteers under fasting conditions and with a high-fat meal indicated that the Cmax was decreased by 27% while there was no significant decrease in AUC. Additionally, a mean delay in absorption lag time of 2.4 hours is observed under fed conditions.
The mean volume of distribution (VSS) of budesonide varies between 2.2 and 3.9 L/kg in healthy subjects and in patients. Plasma protein binding is estimated to be 85 to 90% in the concentration range 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations is about 0.8.
Following absorption, budesonide is subject to high first-pass metabolism (80-90%). In vitro experiments in human liver microsomes demonstrate that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16αhydroxy prednisolone. The glucocorticoid activity of these metabolites is negligible ( < 1/100) in relation to that of the parent compound.
In vivo investigations with intravenous doses in healthy subjects are in agreement with the in vitro findings and demonstrate that budesonide has a high plasma clearance, 0.9-1.8 L/min. These high plasma clearance values approach the estimated liver blood flow, and, accordingly, suggest that budesonide is a high hepatic clearance drug.
The plasma elimination half-life, t½, after administration of intravenous doses ranges between 2.0 and 3.6 hours.
Budesonide is excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [3H]-budesonide, approximately 60% of the recovered radioactivity is found in urine. The major metabolites, including 6β-hydroxy budesonide and 16α-hydroxy prednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide is detected in urine.
In patients with liver cirrhosis, systemic availability of orally administered budesonide correlates with disease severity and is, on average, 2.5-fold higher compared with healthy controls. Patients with mild liver disease are minimally affected. Patients with severe liver dysfunction were not studied. Absorption parameters are not altered, and for the intravenous dose, no significant differences in CL or VSS are observed.
The pharmacokinetics of budesonide in patients with renal impairment has not been studied. Intact budesonide is not renally excreted, but metabolites are to a large extent, and might therefore reach higher levels in patients with impaired renal function. However, these metabolites have negligible corticosteroid activity as compared with budesonide ( < 1/100).
Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma levels of budesonide several-fold. Co-administration of ketoconazole results in an eight-fold increase in AUC of budesonide, compared to budesonide alone. Grapefruit juice, an inhibitor of gut mucosal CYP3A, approximately doubles the systemic exposure of oral budesonide. Conversely, induction of CYP3A4 can result in the lowering of budesonide plasma levels [See DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].
Oral contraceptives containing ethinyl estradiol, which are also metabolized by CYP3A4, do not affect the pharmacokinetics of budesonide. Budesonide does not affect the plasma levels of oral contraceptives (ie, ethinyl estradiol).
Induction of Remission in Active Mild to Moderate Ulcerative Colitis
Two similarly-designed, randomized, double-blind, placebo-controlled studies were conducted in a total of 970 adult patients with active, mild to moderate ulcerative colitis (UC) which was defined as an Ulcerative Colitis Disease Activity Index (UCDAI of ≥ 4 and ≤ 10). Eight-hundred ninety-nine of these patients had histology consistent with active UC; this was considered the primary analysis population. UCDAI is a four-component scale (total score of 0 to 12) that encompasses the clinical assessments of stool frequency, rectal bleeding, mucosal appearance and physician's rating of disease activity (score of 0 to 3 for each of the components).
The baseline median UCDAI score in both studies was 7.
In Study 1, 56% of patients were male, and the median age was 42 years. In Study 2, 57% of patients were male, and the median age was 44 years. In Study 1, 50% of patients were Caucasian, 7% were African American, and 34% were Asian. In Study 2, more than 99% were Caucasian.
Both studies compared UCERIS 9 mg and 6 mg with placebo and included an active reference arm (a mesalamine 2.4 g in Study 1; and a budesonide* 9 mg not approved for the treatment of UC in Study 2). The primary endpoint was induction of remission after 8 weeks of treatment. Remission was defined as a UCDAI score of ≤ 1, with subscores of 0 for rectal bleeding, stool frequency, and mucosal appearance and with a ≥ 1 point reduction in an endoscopy-only score.2 In both studies, UCERIS 9 mg extended release tablets demonstrated superiority to placebo in inducing remission (Table 4).
Table 4: Induction of Remission in Studies 1 and 2
|Treatment Group||Study 1
|UCERIS 9 mg||22/123 (17.9)||19/109 (17.4)|
|UCERIS 6 mg||16/121 (13.2)||9/109 (8.3)|
|Reference Arm*||15/124 (12.1)||13/103 (12.6)|
|Placebo||9/121 (7.4)||4/89 (4.5)|
|Treatment Difference between UCERIS 9 mg and Placebo (95% CI)†||10.4% (2.2%, 18.7%)||12.9% (4.6%, 21.3%)|
|Remission is defined as a UCDAI score of ≤ 1, with
subscores of 0 for rectal bleeding, stool frequency, and mucosal appearance and
with a ≥ 1 point reduction in an endoscopy-only score.2
The primary analysis population included only patients that had histology consistent with active UC. CI=Confidence Interval
*The reference arm in Study 1 is a delayed release mesalamine 2.4 g; the reference arm in Study 2 is a budesonide 9 mg not approved for the treatment of UC.
†p < 0.025 for UCERIS 9 mg vs. placebo in both Studies 1 and 2 based on the Chi-square test (alpha = 0.025)
1. Falt A, Bengtsson T, Kennedy B, et al. Exposure of infants to budesonide through breast milk of asthmatic mothers. J. Allergy Clin Immunol. 2007;120(4):798-802.
2. Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial. BMJ. 1989;298: 82-6.
Last reviewed on RxList: 1/28/2013
This monograph has been modified to include the generic and brand name in many instances.
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