AimsElobixibat 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.MethodsThis 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.ResultsFood 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 (R2 = 0.5929 at Week 2). Adverse events were mainly gastrointestinal symptoms, most of which were mild.ConclusionsElobixibat 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.

Aims AJM300 is an oral antagonist of α4‐integrin that reduces inflammation by blocking leucocyte trafficking. This study aimed to investigate safety, tolerability, pharmacokinetics and pharmacodynamics of AJM300 in healthy male subjects. Methods A total of 23 subjects were randomised to receive 240 mg (n = 6), 480 mg (n = 5), 960 mg (n = 6) of AJM300 or the corresponding placebo (n = 2 per group). The study drugs were taken orally 3 times daily after each meal on the first day followed by a 4‐day washout period. Thereafter, multiple‐dose administration was conducted for 6 consecutive days. The pharmacokinetic parameters of AJM300 and its active metabolite (HCA2969) were assessed, and total white blood cells and the differential cell count were used to determine the pharmacodynamic effects. Adverse events (AEs) were also monitored. Results The plasma AJM300 and HCA2969 concentration–time curves displayed a triphasic pattern on Day 1 (single‐day administration) and Day 10 (last day of multiple dosing), whereas the concentration of HCA2969 was much higher than that of AJM300. A significant but transient increase in lymphocyte count was observed after AJM300 dosing at all dosages tested compared with the placebo. The increase was sustained over a 24‐h period only at the 960‐mg dosage. In particular, a significant increase in the lymphocyte count compared to placebo (mean, 50.58%; 95% confidence intervals, 20.40–80.76) was observed at the first 960‐mg dose on Day 10. Six (26.1%) subjects reported ≥1 AEs, all of which were mild and resolved spontaneously. Conclusion The maximal and 24‐h sustained pharmacodynamic effects were demonstrated at the 960‐mg dosage after oral administration of AJM300 3 times daily for 6 days, which was also found to be safe and well tolerated.

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Background and Objectives Carotegrast methyl, a novel prodrug, oral antagonist of α4-integrin, is in development for the treatment of active ulcerative colitis. This randomised, placebo-controlled, double-blind, crossover study evaluated the effect of food on the pharmacokinetics and pharmacodynamics as well as the safety profile after a single dose of carotegrast methyl in healthy male subjects. Methods Subjects were randomised to receive a single dose of carotegrast methyl (240, 480 or 960 mg) or placebo in a 6:2 ratio and received the study drug under both fed and fasted conditions separated by an 8-day washout. The pharmacokinetic profiles of carotegrast methyl and its active metabolite, carotegrast, were assessed. The pharmacodynamic profile was evaluated according to a change in the peripheral lymphocyte count. Safety was monitored throughout. Results Based on the area under the time curve from zero to the time of the last quantifiable concentration (AUC last ), food reduced systemic exposure to both carotegrast methyl and carotegrast by 21-57% and 5-29%, respectively. The fed-to-fasted ratio of least square means for the increase in the lymphocyte count was almost at unity in each dose, indicating no food effect on pharmacodynamics. The time ≥ 90% of maximum effect was prolonged dose dependently, suggesting that a 960 mg-dose can provide a long-lasting effect. Reported adverse events were all mild. Conclusions Despite the reduced systemic exposure to both carotegrast methyl and carotegrast, food had no effect on the increase in lymphocyte count. A single administration of carotegrast methyl up to 960 mg was found to be safe. Day 240 mg n=4 (active, 3; placebo,1) 480 mg n=4 (active, 3; placebo,1) Group A: Fed (with breakfast) 240 mg n=4 (active, 3; placebo,1) 480 mg n=4 (active, 3; placebo,1) Group B: Fed (with breakfast) 240 mg n=4 (active, 3; placebo,1) 480 mg n=4 (active, 3; placebo,1) Group A: Fasted (without breakfast) 240 mg n=4 (active, 3; placebo,1) 480 mg n=4 (active, 3; placebo,1) Group B: Fasted (without breakfast) 960 mg n=4 (active, 3; placebo,1) Group A: Fed (with breakfast) 960 mg n=4 (active, 3; placebo,1) Group B: Fed (with breakfast) 960 mg n=4 (active, 3; placebo,1) Group A: Fasted (without breakfast) 960 mg n=4 (active, 3; placebo,1) Group B: Fasted (without breakfast)

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