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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, and a change in the spontaneous bowel movement frequency from baseline on treatment period Week 1 with GOOFICE was significantly higher than that with placebo, verifying the superiority of GOOFICE to the placebo (p < 0.0001). (See Figure 1.)
Click on icon to see table/diagram/imageThe 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, and 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.)
Click on icon to see table/diagram/imageThe 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: 1. 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.)
Click on icon to see table/diagram/image2. 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.)
Click on icon to see table/diagram/imageDistribution: 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: 1. 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.
2. 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: 1. 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.
2. 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 AUC0-t and Cmax 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. AUC0-t and Cmax of midazolam on Day5 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 AUC0-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. Cmax and AUC0-∞ under fed condition were approximately 20 to 30% of those under fasting one.
