Goofice Mechanism of Action

ATC code: A06AX09.
Pharmacology: Pharmacodynamics: Mechanism of action: Elobixibat inhibits bile acid reabsorption via ileal bile acid transporter (IBAT) expressed on the epithelial cells of the terminal ileum and thereby increases the amount of bile acid passing into the large intestinal lumen. Bile acid promotes the secretion of water and electrolytes into the large intestinal lumen and enhances the colonic motility. Therefore, GOOFICE induces the therapeutic effect on constipation.
Effect on constipation induced by loperamide in rats: In rats of loperamide-induced constipation model, a single oral administration of elobixibat demonstrated the effect of improving constipation.
Clinical Studies: Phase III Double-blind, Placebo-controlled Comparative Study: In patients with chronic constipation (n = 132), placebo or GOOFICE 10 mg was orally administered once daily before breakfast. The change from baseline in the spontaneous bowel movement frequency on treatment period Week 1 with GOOFICE was significantly greater than that with placebo, confirming the superiority of GOOFICE to the placebo (p <0.0001). (See Figure 1.)

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The frequency of adverse reactions was 30% (21/69 patients). Major adverse reactions included abdominal pain 19% (13/69 patients) and diarrhoea 13% (9/69 patients).
Long-term Treatment Study: In patients with chronic constipation (n = 340), GOOFICE 10 mg was orally administered once daily (adjusted in a range of 5 mg to 15 mg depending on the patient's symptoms) before breakfast for 52 weeks. The mean weekly spontaneous bowel movement frequency increased from baseline on treatment period Week 1, and maintained the similar level until Week 52. (See Figure 2.)

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The frequency of adverse reactions was 48% (163/340 patients). Major adverse reactions included abdominal pain 24% (82/340 patients), diarrhoea 15% (50/340 patients), abdominal pain lower 5% (17/340 patients), abdominal distension 3% (11/340 patients), nausea 3% (10/340 patients), liver function test abnormal 3% (10/340 patients), abdominal discomfort 2% (7/340 patients).
Pharmacokinetics: Absorption: A single oral dose of GOOFICE 5 mg, 10 mg or 15 mg was administered to patients with chronic constipation before breakfast and the pharmacokinetic parameters were noted as follows: See Table 2.

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A single oral dose of ¹⁴C-elobixibat 5 mg (approx. 2.75 MBq) was administered to healthy adult male subjects (n = 6) before breakfast and the pharmacokinetic parameters were noted as follows: See Table 3.

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Distribution: In vitro human plasma protein binding rate of elobixibat was in excess of 99% with human blood to plasma concentration ratio less than 5%.
Metabolism: No metabolites were observed in plasma of healthy adult male subjects (n = 6) following a single oral dose of 14C-elobixibat 5 mg (approx. 2.75 MBq). Unchanged and monohydroxy forms of elobixibat were found in feces pooled over 24 to 48 hours post-dose, while the percentages of radioactivity were 96.06% and 3.16%, respectively, indicating that the majority was unchanged form.
Excretion: When a single oral dose of GOOFICE was administered to patients with chronic constipation under fasting conditions, the cumulative urine drug excretion rate up to 144 hours post-dose was approximately 0.01% of the amount of dose, indicating that drug excretion into urine was almost absent.
When a single oral dose of 14C-elobixibat 5 mg (approx. 2.75 MBq) was administered to healthy adult male subjects (n = 6), 103.1% of radioactivity dosed was excreted in feces while 0.00 to 0.02% excreted in urine up to 144 hours post-dose.
Drug-drug interactions: IC₅₀ of elobixibat towards digoxin (P-glycoprotein substrate) transport was 2.65 μmol/L in Caco-2 cells, indicating the inhibitory effect of elobixibat on P-glycoprotein.
In healthy adult male and female subjects (n = 25), GOOFICE 10 mg was orally administered once daily for 5 days with coadministration of both dabigatran etexilate 150 mg/dose/day on Day 1 and midazolam 2 mg/dose/day on Day 1 and Day 5 to compare with monoadministration of each drug. The results showed that AUC_0-t and C_max of dabigatran (P-glycoprotein substrate) were 1.17 fold greater (90% confidence interval: 1.00-1.36) and 1.13 fold greater (90% confidence interval: 0.96-1.33), respectively, compared with those under monoadministration and both the upper limit of 90% confidence intervals were above 1.25 as the reference value. AUC_0-t and C_max of midazolam on Day 5 were 0.78-fold greater (90% confidence interval: 0.73-0.83) and 0.94-fold greater (90% confidence interval: 0.87-1.01), respectively, compared with those under monoadministration and the lower limit of 90% confidence intervals of AUC_0-t was below 0.80 as the reference value.
Food effects: In patients with chronic constipation (n = 60), the effect of food intake on pharmacokinetics was evaluated following a single oral dose of GOOFICE in a crossover design. C_max and AUC_0-∞ under fed condition were approximately 20 to 30% of those under fasting one.
Toxicology: Preclinical safety data: Serious toxicity or toxicity limiting the use of elobixibat to the intended indication was not observed in toxicological studies performed.
Single-dose toxicity: In single-dose toxicity studies in mice, rats, and dogs, elobixibat was well tolerated, and the approximate lethal dose was determined to be >2000 mg/kg in mice and rats and >140 mg/kg in dogs.
Repeat-dose toxicity: In a 13-week repeat-dose oral toxicity study in mice, there were treatment-related findings associated with the liver at a very high dose. Since these findings were observed at very high exposures compared with clinical exposure, there seems to be no concern about safety in clinical practice. The frequent vomiting observed in the 4- and 13-week oral toxicity studies in dogs was considered to be a toxic change. However, there was a reduction in the number of vomiting in the 52-week oral toxicity study, and there were no findings suggesting deterioration in general conditions. Thus, vomiting was not considered seriously toxic. A wide safety margin is supported by no observed adverse effect level (NOAEL), and there seems to be no concern about safety in clinical practice. All other findings are considered to be changes related to pharmacological effects of elobixibat, changes of no toxicological importance, or secondary effects associated with administration of elobixibat.
Genotoxicity and carcinogenicity: Elobixibat was not genotoxic or carcinogenic.
Reproductive and developmental toxicity: Evaluation of reproductive and developmental toxicity showed that elobixibat had no effect on fertility or embryo-fetal development. In the study for effects on pre- and postnatal development including maternal function, maternal toxicity and effects on survivability, growth, or development were observed in F1 pups at very high exposure. However, a wide safety margin is supported by NOAEL, and there seems to be no concern about safety in clinical practice.