Uceris (Page 3 of 6)

12.3 Pharmacokinetics

Absorption

Distal Ulcerative Colitis Patients

Based on population pharmacokinetic analysis from sparse PK samples from phase 3 studies, the estimated AUC0-12 following administration of UCERIS rectal foam 2 mg twice a day was 4.31 ng*hr/mL with a CV of 64% in the target patient population.

Distribution

The 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 of 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations is approximately 0.8.

Metabolism

Following absorption, budesonide is subject to first-pass metabolism. 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 16α-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 demonstrate that budesonide has a plasma clearance of 0.9-1.8 L/min. These plasma clearance values approach the estimated liver blood flow, suggesting that budesonide is a high hepatic clearance drug.

Excretion

Budesonide is excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [3 H]-budesonide, approximately 60% of the recovered radioactivity is found in urine. The major metabolites, including 6β-hydroxybudesonide and 16α-hydroxyprednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide is detected in urine.

Specific Populations

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of UCERIS rectal foam has not been studied. In a study in patients with mild to moderate hepatic impairment (Child-Pugh Class A and Child-Pugh Class B) dosed with budesonide 4 mg oral capsules, systemic exposure was similar between patients with mild hepatic impairment (Child-Pugh Class A; n=4) and healthy subjects (n=8), and 3.5-fold higher in patients with moderate hepatic impairment (Child-Pugh Class B; n=4) than in healthy subjects. For the intravenous dose, no significant differences in CL or VSS are observed. Patients with severe liver dysfunction (Child-Pugh Class C) were not studied [see Use in Specific Population (8.6)].

Renal Impairment

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.

Drug-Drug Interactions

Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma concentrations of budesonide. Co-administration of ketoconazole (inhibitor of CYP3A4) results in an 8-fold increase in AUC of oral 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 concentrations. The effect of CYP3A4 inhibitors and inducers on the pharmacokinetics of UCERIS rectal foam have not been studied [see Dosage and Administration (2) and Drug Interactions (7)].

Oral contraceptives containing ethinyl estradiol, which are also metabolized by CYP3A4, do not affect the pharmacokinetics of oral budesonide. Budesonide does not affect the plasma concentrations of oral contraceptives (i.e., ethinyl estradiol).

In vitro interactions studies performed with budesonide showed that budesonide did not inhibit human cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C9, CYP2D6, or CYP2E1 at concentrations ranging from 0.11 to 1130 ng/mL. Isoenzyme CYP3A4 was inhibited at the highest concentration tested but the IC50 was >1130 ng/mL. UCERIS rectal foam is not expected to inhibit these enzymes in clinical use. No significant induction of CYP1A2, CYP2B6, CYP2C9 or CYP3A4/5 expression was observed in human hepatocytes in vitro at budesonide concentrations up to 9000 nM (3.88 mcg/mL).

In an in vitro study, budesonide was not a substrate of human transporters OATP1B3 and may be a weak substrate of OATP1B1. Budesonide at concentrations up to 300 nM (129 ng/mL) did not inhibit OATP1B1 or OATP1B3.

Budesonide was not a substrate of BCRP and was a weak substrate of P-glycoprotein. Budesonide was a weak inhibitor of P-glycoprotein (IC50 9.78 µM or 4.21 mcg/mL) and BCRP (IC50 43.1 µM or 18.6 mcg/mL). UCERIS rectal foam is not expected to inhibit these transporters in clinical use.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Carcinogenicity studies with budesonide were conducted in rats and mice. In a 2-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.06 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area).

In an additional 2-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.24 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area).

Mutagenesis

Budesonide showed no evidence of mutagenic potential in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test or the mouse micronucleus test.

Impairment of Fertility

In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.20 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.05 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No such effects were noted at 5 mcg/kg.

14 CLINICAL STUDIES

The safety and efficacy of UCERIS rectal foam were evaluated in 2 replicate, randomized, double-blind, placebo-controlled, multi-center trials (Studies 1 and 2).

Participants in the trials were adult patients with active mild-to-moderate distal ulcerative colitis with disease extending at least 5 cm but no further than 40 cm from the anal verge (confirmed by endoscopy). To be eligible, patients had to have a Modified Mayo Disease Activity Index (MMDAI) score between 5 and 10, inclusive, a rectal bleeding subscore of 2 or 3, and an endoscopy subscore of 2 or 3. The MMDAI score ranges from 0 to 12 and has 4 subscales that are each scored from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment. An endoscopy subscore of 2 is defined by marked erythema, lack of vascular pattern, friability, and erosions; an endoscopy subscore of 3 is defined by spontaneous bleeding and ulceration.

Oral and rectal corticosteroids, and rectal 5-aminosalicylic acid (5-ASA) products were prohibited during the course of the trials, but were allowed as rescue therapy. Oral 5-ASA products were allowed at doses ≤ 4.8 grams/day.

In total, 546 subjects were randomized in these trials: 267 subjects to UCERIS rectal foam and 279 subjects to placebo. In each trial (Study 1 and Study 2), patients received UCERIS rectal foam 2 mg or placebo twice daily for 2 weeks followed by once daily for 4 weeks.

The median age was 41 years and 42 years, 5% and 8% were ≥ 65 years of age, and 43% and 45% were male, in Studies 1 and 2, respectively. In each of these trials, 90% were Caucasian, 7‑8% were African American, and 3% were Asian or Other.

The majority of patients had a baseline diagnosis of proctosigmoiditis (69% and 74%) in Studies 1 and 2, respectively. The remaining patients had a baseline diagnosis of proctitis. Concomitant oral 5-ASA use at baseline was 59% and 51% in Studies 1 and 2, respectively.

Baseline MMDAI total score was 7.8 and 7.9 in the UCERIS rectal foam group and placebo group, respectively, of Study 1; and 7.9 and 8.0 in the UCERIS rectal foam group and placebo group, respectively, of Study 2. The mean stool frequency subscore at baseline was 1.8 and 1.9 in the UCERIS rectal foam group and placebo group, respectively, of Study 1; and 1.7 and 1.8 in the UCERIS rectal foam group and placebo group, respectively, of Study 2.

In each trial (Study 1 and Study 2), the primary endpoint was the proportion of subjects who were in remission after 6 weeks of treatment. Remission was defined as a decrease or no change in the stool frequency subscore from baseline, a rectal bleeding subscore of 0, and an endoscopy score of 0 or 1. (An endoscopy subscore of zero is defined by normal or inactive disease; an endoscopy subscore of 1 is defined by erythema and decreased vascular pattern.)

In each trial (Study 1 and Study 2), a higher proportion of patients in the UCERIS rectal foam group than in the placebo group were in remission at Week 6, and had a rectal bleeding subscore of 0 at Week 6 (Table 4).

Table 4: Efficacy Results: Studies 1 and 2
*
p-values obtained from the Cochran-Mantel-Haenszel (CMH) test.
Remission was defined as an endoscopy subscore of 0 or 1, a rectal bleeding subscore of 0, and a decrease or no change in stool frequency subscore from baseline.

Efficacy Endpoint

Study 1

UCERIS Rectal Foam N = 133

Placebo

N=132

p-value *

Treatment Difference

(95% CI)

Remission at Week 6

38.3%

25.8%

0.032

12.6% (1.5%, 23.7%)

Rectal bleeding subscore = 0 at Week 6

46.6%

28.0%

0.002

18.6% (7.2%, 30%)

Study 2

UCERIS Rectal Foam N = 134

Placebo

N=147

p-value *

Treatment Difference

(95% CI)

Remission at Week 6

44.0%

22.4%

< 0.001

21.6% (10.8%, 32.4%)

Rectal bleeding subscore = 0 at Week 6

50.0%

28.6%

< 0.001

21.4% (10.3%, 32.6%)

CI: Confidence Interval

In Study 1, the percentage of patients with endoscopy subscore of 0 or 1 at Week 6 was 55.6% in the UCERIS rectal foam group versus 43.2% in the placebo group. In Study 2, the percentage of patients with endoscopy subscore of 0 or 1 at Week 6 was 56.0% in the UCERIS rectal foam group versus 36.7% in the placebo group (an endoscopy subscore of 0 is defined by normal or inactive disease; an endoscopy subscore of 1 is defined by erythema and decreased vascular pattern).

In patients that met the primary endpoint of remission in Study 1, the mean (SD) decrease in stool frequency subscore was 1.2 (0.9) in the UCERIS rectal foam group and 1.2 (0.8) in the placebo group. In patients that met the primary endpoint of remission in Study 2, the mean (SD) decrease in stool frequency subscore was 1.3 (0.8) in the UCERIS rectal foam group and 1.1 (0.9) in the placebo group.

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