Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Antidiarrheals, intestinal anti-inflammatory / anti-infective agents, corticosteroids acting locally, ATC code: A07EA06

Mechanism of action
Budesonide is a non-halogenated glucocorticosteroid, which acts primarily anti-inflammatory via binding to the glucocorticoid receptor. In the treatment of EoE with Jorveza, budesonide inhibits antigen-stimulated secretion of many pro-inflammatory signal molecules such as thymic stromal lymphopoeitin, interleukin-13 and eotaxin-3 in the esophageal epithelium, which results in a significant reduction of the esophageal eosinophilic inflammatory infiltrate.

Clinical efficacy and safety
In a randomised, placebo-controlled, double-blind phase III clinical study (BUL-1/EEA) including 88 adult patients with active EoE (randomisation rate: 2:1), 1 mg budesonide given twice daily as an orodispersible tablet for 6 weeks induced clinico-pathologic remission (defined as both peak of < 16 eosinophils/mm2 high power field in esophageal biopsies and no or only minimal symptoms of dysphagia or pain during swallowing) in 34 out of 59 patients (57.6%) versus 0/29 patients (0%) in the placebo-group. Open- label extension of the treatment with 1 mg budesonide orodispersible tablet twice daily for further 6 weeks in patients without remission in the double-blind phase increased the rate of patients with clinico-pathologic remission to 84.7%.

In a randomised, placebo-controlled, double-blind phase III clinical study (BUL-2/EER) including 204 adult patients with EoE in clinico-pathological remission, patients were randomised to treatment with 0.5 mg budesonide twice daily (BID), 1 mg budesonide BID, or placebo (all given as orodispersible tablets) for 48 weeks. Primary endpoint was the rate of patients free of treatment failure with treatment failure defined as clinical relapse (severity of dysphagia or pain during swallowing of ≥4 points on a 0-10 nummerical rating scale, respectively), and/or histological relapse (peak of ≥ 48 eosinophils/mm2 high power field), and/or food impaction requiring endoscopic intervention, and/or need of an endoscopic dilation, and/or premature withdrawal for any reason. Significantly more patients in the 0.5 mg BID (73.5%) group and the 1 mg BID (75.0%) group were free of treatment failure at week 48 compared to placebo (4.4%).
The most stringent secondary endpoint “deep disease remission”, i.e., deep clinical, deep endoscopic and histological remission showed a clinically relevant higher efficacy in the 1 mg BID group (52.9%) compared to the 0.5 mg BID group (39.7%), indicating that a higher dose of budesonide is of advantage to achieve and maintain deep disease remission.
The double-blind period was followed by an optional 96-week open-label treatment with a recommended dose of 0.5 mg budesonide BID or up to 1 mg budesonide BID. More than 80% of the patients maintained clinical remission (defined as weekly Eosinophilic Esophagitis Activity Index-Pro ≤ 20) over the 96-week period, while only 2/166 patients (1.2%) experienced a food impaction. In addition, 40/49 patients (81.6%) maintained deep histological remission (0 eosinophils/mm2 high power field in all biopsies) from baseline of study BUL-2/EER to the end of treatment of the 96-week open-label period. Over a period of up to 3 years (i.e., 96-week open-label treatment with Jorveza, following a 48-week double-blind maintenance treatment with Jorveza) no loss of efficacy was observed.

For information about the observed adverse reactions, see section 4.8.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Absorption
Following administration of Jorveza, budesonide is rapidly absorbed. Pharmacokinetic data following administration of single doses of 1 mg budesonide to fasted healthy subjects in two different studies show a median lag time of 0.17 hours (range 0.00 – 0.52 hours) and a median time to peak plasma concentration of 1.00 - 1.22 hours (range 0.50 – 2.00 hours).
The mean peak plasma concentration was 0.44 - 0.49 ng/mL (range 0.18 - 1.05 ng/mL) and the area under the plasma-concentration–time curve (AUC0-∞) was 1.50 - 2.23 hr*ng/mL (range 0.81 - 5.14 hr*ng/mL).

Single dose pharmacokinetic data in fasted patients with EoE are available with 4 mg budesonide: Median lag-time was 0.00 hours (range 0.00 – 0.17), median time to peak plasma concentration was 1.00 hour (range 0.67 – 2.00 hours); peak plasma concentration was 2.56 ± 1.36 ng/mL, and AUC0-12 was 8.96 ± 4.21 hr*ng/mL.

Patients showed a 35% increase in peak plasma concentrations and a 60% increase in AUC0-12 compared to healthy subjects.

Dose proportionality of the systemic exposure (Cmax and AUC) from 0.5 mg orodispersible tablets to 1 mg orodispersible tablets has been demonstrated.

Distribution
The apparent volume of distribution following oral administration of 1 mg budesonide to healthy subjects was 35.52 ± 14.94 L/kg and 42.46 ± 23.90 L/kg following administration of 4 mg budesonide to patients with EoE. Plasma protein binding is on average 85-90%.

Biotransformation
Metabolism of budesonide is decreased in EoE patients compared to healthy subjects resulting in increased plasma concentrations of budesonide.

Budesonide undergoes extensive biotransformation by CYP3A4 in the mucosa of the small intestine and in the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α- hydroxyprednisolone, is less than 1% of that of budesonide. CYP3A5 does not contribute significantly to the metabolism of budesonide.

Elimination
The median elimination half-life is 2 - 3 hours in healthy subjects (receiving 1 mg budesonide) and 4-5 hours in EoE patients (receiving 4 mg budesonide). Clearance of budesonide is about 13 –15 L/hour/kg in healthy subjects and 6.54 ± 4.4 L/hour/kg in EoE patients. Budesonide is eliminated only in marginal if any amounts by the kidney. No budesonide, but only budesonide metabolites were detected in urine.

Hepatic impairment
A relevant proportion of budesonide is metabolised in the liver by CYP3A4. The systemic exposure of budesonide is considerably increased in patients with severely impaired hepatic function. No studies have been conducted with Jorveza in patients with impaired liver function.