Effect of single and multiple doses of elobixibat, an ileal bile acid transporter inhibitor, on chronic constipation: A randomized controlled trial

AIMS: Elobixibat is a minimally absorbed ileal bile acid transporter inhibitor. This study aimed to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of elobixibat in Japanese patients with chronic constipation. METHODS: This study consisted of single‐dose and multiple‐dose tests with a dose‐escalating design. Sixty patients including females and males were randomized into five dose levels of elobixibat (2.5, 5, 10, 15 or 20 mg, n = 10 per level) and corresponding placebo (n = 2 per group). A crossover design was used to examine food effect in single‐dose test. Patients received test tablets once daily for 14 days in multiple‐dose test. We assessed pharmacokinetic‐dose proportionality, levels of serum high‐ and low‐density lipoprotein cholesterol and plasma 7α‐hydroxy‐4‐cholesten‐3‐one (C4), food effect and sex‐specific effect. Adverse events and bowel functions such as bowel movements, stool consistency and straining were also evaluated. RESULTS: Food consumption reduced systemic exposure by around 80% [e.g. least squares mean (ratio of breakfast/no breakfast) maximum plasma concentration: 0.2085 (90% confidence interval, 0.1371–0.3172) at 15 mg] while increased plasma C4 level (P < 0.001). In the multiple‐dose test, elobixibat reduced low‐density lipoprotein cholesterol and increased C4 whilst unaltering high‐density lipoprotein cholesterol level. The increased spontaneous bowel movement frequency was correlated with higher dosage and higher C4 level (R(2) = 0.5929 at Week 2). Adverse events were mainly gastrointestinal symptoms, most of which were mild. CONCLUSIONS: Elobixibat should be taken before breakfast. Once‐daily administration of elobixibat was found to be safe and tolerated up to 20 mg in female and male patients with chronic constipation.