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Effects on Bile Acid Transporters in Transfected Cells: Elobixibat showed strong inhibitory effect on intracellular uptake of 14C-glycocholic acid (a substrate for bile acid transporters) on human IBAT with IC50 of 0.53 nmol/L in HEK293 cells transfected with human IBAT gene, while IC50 for human LBAT (liver bile acid transporter) was 240 nmol/L in HEK293 cells transfected with human LBAT gene. Elobixibat showed inhibitory effect on intracellular uptake of 14C-α-aminoisobutyric acid at the human neutral amino acid transporter in HEK293 cells by 35%, 79%, and 93% at 3.125, 12.5, and 50 μmol/L, respectively. These studies showed that elobixibat is a selective inhibitor for IBAT compared to LBAT and neutral amino acid transporter.
Effects on Bile Acid Absorption in Mice: Elobixibat was administered orally to ApoE gene knockout female C57BL/6 mice thirty minutes before 75SeHCAT, a tracer of bile acid absorption, was orally given. Twenty-four hours later, elobixibat inhibited absorption of 75SeHCAT in a dose-dependent manner (ED50 = 0.274 mg/kg), indicating orally administered elobixibat was shown to inhibit bile acid absorption in the ileum in mice.
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.
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 1.)
Click on icon to see table/diagram/imageA 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 2.)
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%.
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 3.)
Click on icon to see table/diagram/imageLacteal transfer in rat (See Precautions).
14C-Elobixibat was administered to male pigmented (Long Evans) rats at a single oral dose of 2.5 mg/kg, and then, whole-body autoradiograms were prepared. Distribution sites of radioactivity after oral administration were limited, and most of the radioactivity was observed in the gastric mucosa and in small intestinal contents. Radioactivity concentrations in heart blood were less than the detection limit at any time point. Radioactivity was also found in bile, cecum contents, liver, renal cortex, prostate gland, urine and skin by 4 hours after administration but detected only in gastrointestinal contents 24 hours after administration. No radioactivity was detected in the body 2 days after administration.
Metabolism: No metabolites were observed in plasma of healthy adult male subjects (n = 6) following a single oral dose of 14Celobixibat 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 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 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 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.
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.)
Click on icon to see table/diagram/imageLong-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.)
Click on icon to see table/diagram/image