Budesonide has a high topical glucocorticosteroid (GCS) activity and a substantial first pass elimination. The formulation contains granules which are coated to protect dissolution in gastric juice, but which dissolve at pH >5.5, ie, normally when the granules reach the duodenum. Thereafter, a matrix of ethylcellulose with budesonide controls the release of the drug into the intestinal lumen in a time-dependent manner.

Pharmacokinetics

Absorption

The absorption of ENTOCORT EC seems to be complete, although C_max and T_max are variable. Time to peak concentration varies in individual patients between 30 and 600 minutes. Following oral administration of 9 mg of budesonide in healthy subjects, a peak plasma concentration of approximately 5 nmol/L is observed and the area under the plasma concentration time curve is approximately 30 nmol hr/L. The systemic availability after a single dose is higher in patients with Crohn's disease compared to healthy volunteers, (21% vs 9%) but approaches that in healthy volunteers after repeated dosing.

Distribution

The mean volume of distribution (V_ss) 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.

Metabolism

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, 6b-hydroxy budesonide and 16a- hydroxy 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. Similarly, high plasma clearance values have been shown in patients with Crohns disease. 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, t_1/2, after administration of intravenous doses ranges between 2.0 and 3.6 hours, and does not differ between healthy adults and patients with Crohn s disease.

Excretion

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 6b-hydroxy budesonide and 16a-hydroxy prednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide is detected in urine.

Special Populations

No significant pharmacokinetic differences have been identified due to sex.

Hepatic Insufficiency

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 V_ss are observed.

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