Clinical Gastroenterology and Hepatology 2015;13:701–708
A Randomized Trial of 5-Hydroxytryptamine4–Receptor Agonist, YKP10811, on Colonic Transit and Bowel Function in Functional Constipation Andrea Shin,*,a Andres Acosta,*,a Michael Camilleri,* Amy Boldingh,* Duane Burton,* Michael Ryks,* Deborah Rhoten,* and Alan R. Zinsmeister‡ *Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Department of Medicine, ‡Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, Minnesota BACKGROUND & AIMS:
YKP10811, a selective agonist of the serotonin 5-hydroxytryptamine-4 receptor, increases gastrointestinal (GI) motility. We investigated the safety and effects of YKP10811 on GI and colonic transit and bowel movements (BMs) in patients with functional constipation in a randomized, double-blind, placebo-controlled study.
METHODS:
Patients with functional constipation, based on the Rome III criteria, were assigned randomly to groups given YKP10811 10 mg (n [ 15), 20 mg (n [ 16), 30 mg (n [ 15), or placebo (n [ 11) daily for 8 days. Transit of solids was measured by validated scintigraphy at baseline and on days 7 to 9. Patients kept diaries on days 1 to 9, recording time to first BM, number of BMs/day, and stool consistency (based on the Bristol Stool Form Scale). To evaluate safety, we collected data on adverse events and clinical laboratory test and electrocardiograms results. The primary efficacy end points were determined from an intent-to-treat analysis assessing colonic transit at 24 hours and the half-time (t1/2) of gastric emptying, using analysis of covariance models. Secondary efficacy end points included measures of colonic transit (geometric center at 4 and 24 hours), small-bowel transit (based on colon filling at 6 hours), t1/2 of ascending colon emptying, and bowel functions. We used the Dunnett test to compare the effects of each dose with placebo. A per-protocol analysis (PPA) assessed the t1/2 of gastric emptying and time to first BM using proportional hazards models.
RESULTS:
Fifty-five participants completed the study. YKP10811 was associated with a significant acceleration in colon filling at 6 hours (P < .05), t1/2 of ascending colon emptying, and colonic transit at 24 and 48 hours, as well as increased stool consistency over 8 days (based on intent-to-treat analysis). In general, the 10-mg and 20-mg doses were the most effective in accelerating colonic transit. No serious adverse events were observed.
CONCLUSIONS:
YKP10811, a selective agonist of the serotonin receptor 5-hydroxytryptamine-4, accelerates GI and colonic transit and improves bowel functions in patients with functional constipation, compared with placebo. ClinicalTrial.Gov: NCT01523184.
Keywords: Prokinetic; Clinical Trial; Drug; Benzamide.
he prevalence of functional constipation (FC) is 16% in adults and almost double that number (33.5%) in people older than age 60 years.1,2 Functional constipation can be subclassified as normal colonic transit, slow colonic transit, and/or defecatory disorder.1,3 Better understanding of the mechanisms of FC has led to insights on receptors, neurotransmitters, fluid and electrolyte secretion and reabsorption, and novel targets. Recently approved medications for the treatment of FC include the secretagogues lubiprostone and linaclotide.4 These medications do not appear to activate gastrointestinal muscle contraction directly.5,6 The
T
5-hydroxytryptamine (5-HT)4 receptor is an established target for increasing smooth muscle contractility. Thus, when stimulated by 5-HT4–receptor ligands, there are a
Authors share co-first authorship.
Abbreviations used in this paper: AC, ascending colon; ANCOVA, analysis of covariance; EC50, median effective concentration; FC, functional constipation; GC, geometric center; GE, gastric emptying; GI, gastrointestinal; 5-HT, 5-hydroxytryptamine; IC50, median inhibitory concentration; ITT, intent-to-treat. © 2015 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2014.08.012
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increased levels of intracellular cyclic adenosine monophosphate facilitating cholinergic neurotransmission in the myenteric plexus, thereby inducing contractions in the gastrointestinal tract.7 There is a subgroup of patients who do not achieve satisfactory relief of FC. Such patients appear to receive benefit from treatment with 5HT4–receptor agonists such as prucalopride,8 which is approved for prescription and marketing in several countries; however, it is not yet approved in the United States. YKP10811 (C24H30ClFN4O4 HCl) is a novel benzamide derivative with high binding affinity to the 5-HT4 receptor. The aim of this phase II, single-center, randomized, parallel-group, multiple-dose, double-blind, placebo-controlled study was to evaluate the effects of 8 days of treatment with 10, 20, and 30 mg YKP10811, once daily, on gastrointestinal and colonic transit, and on bowel functions in patients with FC. In addition, we aimed to assess the safety and tolerability of multiple doses of YKP10811.
Materials and Methods Participants Participants with functional constipation were recruited by public advertisement. Eligible participants provided their written consent before initiation of the study. Each subject completed a validated bowel disease questionnaire9 and was evaluated for functional constipation by Rome III criteria10; in addition, there was no evidence of a rectal evacuation disorder as assessed by physical examination11 conducted by the study investigators. All participants met eligibility criteria, including the following: age 18 through 65 years, body mass index of 18 through 40 kg/m2, reported fewer than 3 bowel movements per week by daily bowel questionnaire, baseline colonic transit by scintigraphy geometric center (GC) of 2.7 or less at 24 hours, failed available constipation medications including laxatives and fiber, and had a negative qualitative urine drug or alcohol test at screening. The study was approved by the Mayo Clinic Institutional Review Board.
Study Design We conducted a single-center, randomized, parallelgroup, multiple-dose administration over 8 days, double-blind, placebo-controlled study. Allocation of study drug was concealed from the clinical research team. We evaluated the effects of YKP10811 (10, 20, and 30 mg once daily, approximately n ¼ 15 each) on gastrointestinal (GI) and colonic transit, and bowel function, safety, and tolerability in patients with FC. The study was conducted in accordance with the Declaration of Helsinki and with Good Clinical Practice guidelines. Written informed consent was obtained from all patients
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before participation. The study was registered at ClinicalTrial.Gov (NCT01523184). Treatment allocation and concealment were conducted by an independent Mayo statistician who otherwise was not involved in the study. The randomization was communicated to and retained by the study research pharmacist, and was concealed from all study investigators until completion of the study and locking up of the data. Randomization was performed within blocks of consecutive patients. Only the independent Mayo statistician and pharmacist knew the block size being used. All randomized patients and study center and contract research organization personnel were blinded to study treatment allocation until data analyses. In addition, participant eligibility was based on the baseline measurement of colonic transit (GC measured over 24 hours [GC24] 2.7) using scintigraphy (which also assessed baseline gastric emptying [GE]). The baseline colonic transit at 24 hours of 2.7 or less (indicating that the average location of the isotope was in the lower part of the descending colon) was selected for eligibility to ensure that the patients had a similar spectrum of colonic transit, and it corresponded to the average colonic transit in healthy volunteers.12,13 Patient randomization was stratified on sex and the baseline GC24 value ( 1.6 vs >1.6) to ensure that there was balance in the number of patients with slow colonic transit (GC24 < 1.6), which was the average colonic transit measurement in 61 patients with slow-transit constipation in our laboratory.14 Patients underwent scintigraphic assessment of gastric, small-bowel, and colonic transit of solids over the 48-hour period from days 7 to 9. A bowel function diary was kept from days 1 to 9; participants recorded the time to first bowel movement after dosing, number of stools per day, average stool consistency (Bristol Stool Scale), ease of passage, and completeness of evacuation.
Study Medication Pharmacology. YKP10811 (C24H30ClFN4O4 HCl) is a novel substituted benzamide derivative, small molecule with high binding affinity to the 5-HT4 receptor (Ki ¼ 4.96 nmol/L). In cellular functional assays conducted with the 5-HT4 receptor, YKP10811 showed weak agonist activity that was dose dependent and reproducible (median effective concentration [EC50] ¼ 0.78 nmol/L). These results indicated that YKP10811 acts as a partial agonist of the 5-HT4 receptor. YKP10811 did not show any significant off-target binding to any other receptors, enzymes, or serotonin-receptor subtypes at 1 mmol/L, except for binding to the 5-HT2A receptor (Ki ¼ 600 nmol/L) and the 5-HT2B receptor (Ki ¼ 31 nmol/L). Thus, YKP10811 has 120-fold and 6-fold lower affinity, respectively, for 5-HT2A and 5-HT2B receptors than for 5-HT4. In cellular functional assays, YKP10811 showed antagonist activity at the 5-HT2B receptor with a median inhibitory concentration
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(IC50) of 2.1 mmol/L and no significant activity at the 5-HT2A receptor up to 10 mmol/L. YKP10811 showed no activity against serotonin-receptor subtypes 5-HT1B, 5-HT1D, or 5-HT2A at 1 nmol/L to 10 mmol/L, or for serotonin-receptor subtype 5-HT7 at 10 nmol/L to 30 mmol/L (data on file; SK Life Science, Inc, Fair Lawn, NJ). Thus, results from binding assays and functional assays fully support the conclusion that YKP10811 is a specific and selective 5-HT4–receptor agonist. Preclinical studies. In rats, YKP10811 accelerated colonic transit by 37% at a dose as low as 1 mg/kg. In dogs, 0.3 mg/kg YKP10811 accelerated colonic transit by 45.5% at 2 hours after dosing. The accelerated colonic transit in dogs was associated with significantly increased colon contractions and defecation. YKP10811 significantly reduced visceral hypersensitivity in multiple pain models in rats. Safety. The study of the specificity and selectivity of YKP10811 for the 5-HT4 receptor would predict a safe pharmacologic profile with potential for pharmacodynamic and clinical efficacy.15 In a phase I, double-blind, randomized, 9-day, placebo-controlled, multiple-ascending dose study in healthy volunteers at doses of 5, 15, 30, and 45 mg once daily, YKP10811 was well tolerated with minimal side effects (data on file; SK Life Science, Inc). Pharmacokinetics. After oral administration of either 10, 20, or 30 mg YKP10811 daily for 7 days, the variability for Cmax (maximum serum concentration) was 42.9% to 78.5% and for the area under the concentration-time curve (0-tau) was 29.7% to 58.8%. The geometric mean values of both Cmax and the area under the concentration-time curve (0-tau) increased with increasing dose of YKP10811. The median Tmax (time to reach Cmax) of YKP10811 ranged from 1.00 to 2.00 hours, with individual values ranging from 0.47 to 2.17 hours after dosing across the 3 YKP10811 dose levels.
Administration of Study Medication Patients received multiple oral doses of YKP10811 or placebo once daily for 8 days. The doses given were 10, 20, and 30 mg, or matching placebo. Drugs were administered with a total of 240 mL water. No food was allowed for at least 1.5 hours after dosing. The selected doses were based on phase I and preclinical studies (data on file; SK Life Science, Inc).
Gastrointestinal and Colonic Transit A validated scintigraphic method with known performance characteristics was used to measure gastric emptying, small-bowel transit, and colonic transit over 48 hours, using dual-isotope gamma camera scanning of abdominal images. This scintigraphic method is well validated and established,12,16 with published coefficients of variation [COVinter] and within subjects [COVintra] to plan phase IIA studies according to effect sizes desirable
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for pharmacodynamics and bowel function end points in patients with lower functional gastrointestinal disorders associated with constipation such as FC.17 Briefly, participants reported to the Clinical Research Unit, fasted, on the morning of testing as directed by study personnel. A urine pregnancy test was performed, when applicable, within 48 hours of the start of the test. 111In absorbed on activated charcoal particles was delivered to the colon by means of a methacrylate-coated, delayedrelease capsule. The capsule was ingested after an overnight fast, 1.5 hours before a breakfast test meal during baseline transit assessments. Then, 99mTc-sulfur colloid was used to label 2 scrambled eggs that were eaten with 1 slice of whole wheat bread and 1 glass of whole milk (296 kcal, 30% fat). This meal facilitated measurement of gastric and small-bowel transit. Patients ingested standardized meals for lunch and dinner immediately before the 4- and 8-hour scans. For measurement of gastric emptying, small-bowel, and colonic transit, scans were acquired before ingestion of the radiolabeled test meal, followed by scans taken immediately after (time 0) and at 30 minutes, and at 1, 1.5, 2, 4, 6, 8, 24, and 48 hours after the radiolabeled breakfast (egg meal).
Daily Symptom Assessments During the study, participants completed a daily diary to record their bowel functions for each bowel movement including consistency (Bristol Stool Form Scale scores were as follows: 1, hard lumps; 2, lumpy sausage; 3, cracked sausage; 4, smooth sausage; 5, soft lumps; 6, mushy; and 7, watery), ease of passage (1, manual disimpaction; 2, enema needed; 3, straining needed; 4, normal; 5, urgent without pain; 6, urgent with pain; 7, incontinent), and sense of completeness of evacuation (yes/no).18–20 The on-study bowel habit diary cards were dispensed at day 1 and the completed cards were collected at the end of the study visit on day 9. Stool consistency was appraised using the validated Bristol Stool Form Scale.18 For each of these symptom end points, the average number or score for the treatment period was calculated for each individual participant, as in prior studies.19,20
Safety Assessments Safety was determined by evaluating adverse events, vital signs (pulse rate, supine blood pressure, orthostatic blood pressure, oral temperature, and respiration rate), physical examinations, multiple 12-lead electrocardiograms at baseline and standard times after dosing, and clinical laboratory assessments (chemistry, hematology, coagulation, and urinalysis).
Study End Points, Statistical Methods, and Data Analysis Data in this article show median and interquartile ranges, unless otherwise stated. The primary efficacy
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analysis was based on an intent-to-treat (ITT) analysis of colonic GC at 24 hours and the t1/2 of gastric emptying for solids using analysis of covariance (ANCOVA) models with baseline GC24 and baseline GE t1/2, respectively, and treatment group in the statistical models. The Dunnett test was used for multiple comparisons of active drug with placebo. The secondary efficacy variables were colonic GC at 4 and 48 hours, colonic filling at 6 hours (CF6), and the t1/2 for ascending colon (AC) emptying. The ITT analyses imputed the missing values in 2 subjects using the overall mean (CT, CF6, AC t1/2, and bowel diary scores) and the overall median (GE t1/2 and time to first bowel movement after the initial dose). The degrees of freedom for error in the ANCOVA models were adjusted (subtracting one for each missing value imputed) to compensate for the imputations. In some instances, response end points first were transformed to rank scale to accommodate nongaussian distributions of the ANCOVA model residuals. In addition, a per-protocol analysis using proportional hazards models examined treatment effects on the GE t1/2 and time to first bowel movement in 55 of the 57 participants who completed all studies. The study (with at least 12 patients per treatment arm) was powered to detect an effect size of 43% in colonic transit GC24 and 26% in gastric emptying t1/2 (Table 1). All authors had access to the study data and reviewed and approved the final manuscript.
Results Participants, Demographics, and Baseline Parameters Supplementary Figure 1 shows the consolidated standards for reporting clinical trials (CONSORT) flow chart of participants in the study. Fifty-seven participants were randomized to the study, with 11, 15, 16, and 15 Table 1. Effect Size Shown Based on Performance Characteristics and Variance in Main End Points in the Proposed Study Assuming n¼12/ group Response type
Mean
SD
GE solids t1/2 min 130 29 (N ¼ 63) Colonic filling at 6 h, % 44 29 (N ¼ 63) GC at 24 h (N ¼ 62) 2.36 0.85 Ascending colon t1/2 h 15.0 8.0 (N ¼ 50)
Effect size,a % detectable with 80% CV% power (a ¼ .05) 22
26
66
79
36 53
43 63
NOTE. Table data are based on data from previous studies using similar methods. Note that the effect size demonstrable may be smaller for each dose contrast (n ¼ 18) vs placebo (n ¼ 12). CV%, coefficient of variation, %. a Effect size is the difference between means as a percentage of the listed mean.
participants, respectively, randomized to placebo, 10 mg, 20 mg, and 30 mg YKP10811. The demographic characteristics of the participants were as follows: 56 women and 1 man, mean age of 42.8 1.3 years, mean body mass index of 25.3 0.5 kg/m2, and a baseline GE t1/2 of 125.0 4.3 minutes and a GC24 of 1.83 0.05 (Table 2). A total of 55 patients completed the study, with early discontinuation in 2 participants (1 participant receiving placebo and 1 participant receiving 20 mg YKP10811).
Gastrointestinal and Colonic Transit Overall, the YKP10811 treatment effect on functional constipation was associated with accelerated small-bowel and colonic transit (Table 3). When assessing the overall effect of YKP10811, there was accelerated gastric emptying (t1/2) on per-protocol analysis (P ¼ .031; ITT analysis on ranks, P ¼ .16). Overall treatment effects also were observed for CF6h (P < .001). The Dunnett test based on ranks for CF6h was significant for YKP10811 at 20 mg and 30 mg (P < .001). The overall assessment of treatment effects of YKP10811 showed significant acceleration of AC emptying (t1/2) and colonic transit at 24 and 48 hours. Specifically, the ANCOVA models based on ranks indicated an accelerated AC emptying (t1/2, P ¼ .016) and colonic transit at GC 4, 24, and 48 hours (P ¼ .062, P < .01, and P ¼ .019, respectively). The Dunnett test based on ranks indicated AC t1/2 was associated significantly with accelerated transit for all 3 doses individually when compared with placebo (Dunnett test, P < .05 for all). In addition, 10 mg YKP10811 was associated with accelerated transit at all GC time points (eg, at 24 hours) (Figure 1) when compared with placebo (Dunnett test, P < .05), and with borderline accelerated colonic transit at 48 hours (Dunnett test, P ¼ .08) in the 30 mg group when compared with placebo (Table 3).
Daily Stool and Abdominal Symptoms Overall, YKP10811 treatment effect on functional constipation (relative to placebo) was associated with significantly accelerated time to pass a BM after first dosing (P < .01) and with borderline increased differences in stool consistency over the 8-day treatment period (P ¼ .064) (Table 4). The Dunnett test on ranks for time to pass BM after first dosing was associated significantly with all 3 doses of YKP10811 when compared with placebo (Dunnett test P < .05). Stool consistency (form) (Table 4) significantly improved (softer) with 20 and 30 mg doses of YKP10811 when compared with placebo (Dunnett test, P < .05). There was no significant difference in the number of BMs per day (Table 4).
Adverse Events There were no deaths and no serious adverse events. Two subjects discontinued prematurely (1 on placebo, 1
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Table 2. Patient Demographics and Baseline Values
N Age, y Females BMI, kg/m2 Baseline GE t1/2 min Baseline colonic transit GC24
Placebo
10 mg YKP10811
20 mg YKP10811
30 mg YKP10811
11 39.1 2.0 100% 24.0 1.3 136.7 (117.7–149) 1.79 (1.46–1.99)
15 44.0 3.2 100% 26.0 0.8 113.2 (105–152.9) 2.16 (1.57–2.31)
16 47.0 2.2 94% 26.4 0.9 115.3 (89.6–127.5) 1.84 (1.57–2.1)
15 41.0 2.6 100% 24.9 0.9 118 (109–136.5) 1.73 (1.49–1.97)
NOTE. Means SEM are shown except baseline GE and GC24: median (interquartile range). BMI, body mass index.
on 20 mg YKP10811) secondary to prolongation of QTc on one electrocardiography each; the prolongation was less than 5 ms greater than the prespecified limit of 470 ms. Table 5 shows the adverse events associated with YKP10811. There were no significant differences between the treatment groups. There was an overall borderline treatment effect on diarrhea (Cochran–Armitage test for trend [dose effect] was P ¼ .15). One subject on 10 mg YKP10811 had “watery stools,” 1 subject on 20 mg had “explosive watery stools,” and 4 subjects on 30 mg had “diarrhea.” One subject on placebo had “diarrhea.”
Discussion In this single-center, randomized, parallel-group, double-blinded, placebo-controlled study in patients with functional constipation, YKP10811, a selective 5HT4–receptor agonist, enhanced gastrointestinal and colonic transit and improved bowel function during an 8day treatment trial. The effect of YKP10811 on colonic transit was mirrored by improvements in softer stool consistency and faster time to first bowel movement, suggesting that YKP10811 has encouraging effects on these clinical end points. In addition to pharmacodynamic
effects in patients with functional constipation, the improvements in bowel functions are validated and measurable end points recommended for treatment of functional constipation.20 These findings suggest that YKP10811 may be a potential new medication for the treatment of functional constipation. YKP10811 had a robust effect on accelerating, by 30% to 40%, the AC emptying when compared with placebo. Ascending colon emptying has been reported to have the greatest contribution to overall colonic transit21 because the ascending and transverse colon constitute the “reservoir” or storage regions of the human colon.22 In addition, YKP10811 accelerated colonic transit at 24 and 48 hours, and this was associated with faster time to first bowel movement after the first dose and looser stool consistency during 8 days of treatment. Among the other 5-HT4–receptor agonists previously studied with the same method, 4 mg prucalopride23 and 30 and 50 mg velusetrag24 also accelerated AC emptying. The overall effect of naronapride (ATI-7505) on AC t1/2 suggested borderline treatment differences (P ¼ .075), with only one pairwise comparison between 10 mg and placebo 3 times daily being borderline significant (unadjusted P ¼ .042), whereas 3 mg and 20 mg doses 3 times daily did not accelerate AC t1/2.25
Table 3. Gastrointestinal and Colonic Transit Placebo N GE T1/2 mina GE 4 h CF6, %b AC T1/2, hd Colonic transit GC4e Colonic transit GC24b Colonic transit GC48f
123.4 0.97 28.5 20.5 0 1.67 2.70
11 (104–172) (0.81–1) (19–47) (19.59–20.9) (0–0.94) (1.62–1.81) (2.25–2.99)
NOTE. Data are presented as medians and interquartile ranges. a P ¼ .031 by per-protocol analysis (ITT, P ¼ .16 on rank scale). b Analysis of variance on rank P < .01. c P < .05 by the Dunnett test (corrected for multiple comparisons). d Analysis of variance on ranks P ¼ .016. e Analysis of variance on ranks P ¼ .062. f Analysis of variance on ranks P¼ .019. g Analysis of variance on ranks P ¼ .08.
10 mg YKP10811 112 1 58 15.17 1 3.18 4.1
15 (100–136.6) (0.96–1.0) (20–78) (3.50–16.99)c (0–1.57)c (2.26–3.52)c (3.47–4.96)c
20 mg YKP10811 98 1 82 14.72 1 2.60 4.15
16 (85.38–117) (1.0–1.0) (62–95)c (7.19–17.2)c (0–1.0) (1.79–3.74)c (3.64–5)c
30 mg YKP10811 106 1 80 14.86 1 2.06 3.28
15 (91.6–122.4) (1.0–1.0) (55–89)c (9.78–17.88)c (0.85–1.0)c (1.81–2.91) (2.85–4.88)g
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Figure 1. Colonic transit GC24h, presented as medians (interquartile range).
YKP10811 had no significant effect on the number of spontaneous bowel movements or bowel movements per week. However, the short duration of the study and the sample size of the study were based on the plan to show an effect size of 43% in the primary end point, colonic GC at 24 hours. The study showed the effect of YKP10811 on colonic transit and gastric emptying. Emptying of the proximal colon correlates linearly with fecal weight,26 which reflects largely stool water content, and, as expected based on prior studies,16 the overall colonic transit was correlated linearly with stool consistency, with less significant association with the number of bowel movements per day. Our prior studies also estimated that the sample size required in a phase IIA study to show a 30% effect on stool consistency would be 24 patients per treatment arm, and similar effects on stool number would require 34 patients per treatment arm.17 In fact, the effect size of YKP10811 on stool consistency was approximately 50% and, hence, showed a statistically significant effect with approximately 15 patients per treatment arm. The findings of shorter gastric emptying t1/2 and increased CF6 (small-bowel transit) suggest prokinetic effects in the stomach, even in patients with functional constipation whose baseline gastric emptying was 125.0 4.3 minutes (SEM), which is comparable with the data
from 319 healthy participants studied in the same laboratory with the same meal (121.7 1.7 min).27 The acceleration of stomach and small-bowel transit is consistent with preclinical studies that showed that 1 hour after dosing, YKP10811 radiolabeled with 14C was found mainly in the small intestine (55%) and cecum (38%) (unpublished data; SK Life Science, Inc). This significant effect (approximately 20% acceleration of gastric emptying t1/2 with the 20 and 30 mg doses of YKP10811) suggests that there is a prokinetic effect of potential relevance on gastric motility disorders, such as gastroparesis and functional dyspepsia.28,29 Interestingly, the results showed a lack of dose response in the treatment groups receiving YKP10811. Furthermore, YKP10811, 30 mg, had no significant effect on colonic transit GC24h and GC48h. These results may be the result of the dual action (agonist/antagonist) of YKP10811 seen in in vitro studies. YKP10811 facilitated the electrical field stimulation–induced neurogenic twitch of guinea pig ileum at lower concentrations (10 mmol/L: IC50, 30.42 mmol/L). This type of dual action (agonist/antagonist) of YKP10811 under the same assay conditions also was shown in the peristaltic reflex test with an EC50 of 0.5 mmol/L and an IC50 of 21 mmol/L. There is a significant gap in concentration ranges (>40-fold difference) for stimulatory vs inhibitory effects of YKP10811 in vitro (unpublished data; SK Life Science, Inc). Overall, YKP10811 was well tolerated and without any major side effects in our study. Two participants, 1 receiving placebo and 1 receiving 20 mg YKP10811 had prolonged QTc (>470 ms). Both participants discontinued the study on the advice of the investigators, even though the QTc prolongation was minimal (
A Randomized Trial of 5-Hydroxytryptamine4–Receptor Agonist, YKP10811, on Colonic Transit and Bowel Function in Functional Constipation Andrea Shin,*,a Andres Acosta,*,a Michael Camilleri,* Amy Boldingh,* Duane Burton,* Michael Ryks,* Deborah Rhoten,* and Alan R. Zinsmeister‡ *Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Department of Medicine, ‡Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, Minnesota BACKGROUND & AIMS:
YKP10811, a selective agonist of the serotonin 5-hydroxytryptamine-4 receptor, increases gastrointestinal (GI) motility. We investigated the safety and effects of YKP10811 on GI and colonic transit and bowel movements (BMs) in patients with functional constipation in a randomized, double-blind, placebo-controlled study.
METHODS:
Patients with functional constipation, based on the Rome III criteria, were assigned randomly to groups given YKP10811 10 mg (n [ 15), 20 mg (n [ 16), 30 mg (n [ 15), or placebo (n [ 11) daily for 8 days. Transit of solids was measured by validated scintigraphy at baseline and on days 7 to 9. Patients kept diaries on days 1 to 9, recording time to first BM, number of BMs/day, and stool consistency (based on the Bristol Stool Form Scale). To evaluate safety, we collected data on adverse events and clinical laboratory test and electrocardiograms results. The primary efficacy end points were determined from an intent-to-treat analysis assessing colonic transit at 24 hours and the half-time (t1/2) of gastric emptying, using analysis of covariance models. Secondary efficacy end points included measures of colonic transit (geometric center at 4 and 24 hours), small-bowel transit (based on colon filling at 6 hours), t1/2 of ascending colon emptying, and bowel functions. We used the Dunnett test to compare the effects of each dose with placebo. A per-protocol analysis (PPA) assessed the t1/2 of gastric emptying and time to first BM using proportional hazards models.
RESULTS:
Fifty-five participants completed the study. YKP10811 was associated with a significant acceleration in colon filling at 6 hours (P < .05), t1/2 of ascending colon emptying, and colonic transit at 24 and 48 hours, as well as increased stool consistency over 8 days (based on intent-to-treat analysis). In general, the 10-mg and 20-mg doses were the most effective in accelerating colonic transit. No serious adverse events were observed.
CONCLUSIONS:
YKP10811, a selective agonist of the serotonin receptor 5-hydroxytryptamine-4, accelerates GI and colonic transit and improves bowel functions in patients with functional constipation, compared with placebo. ClinicalTrial.Gov: NCT01523184.
Keywords: Prokinetic; Clinical Trial; Drug; Benzamide.
he prevalence of functional constipation (FC) is 16% in adults and almost double that number (33.5%) in people older than age 60 years.1,2 Functional constipation can be subclassified as normal colonic transit, slow colonic transit, and/or defecatory disorder.1,3 Better understanding of the mechanisms of FC has led to insights on receptors, neurotransmitters, fluid and electrolyte secretion and reabsorption, and novel targets. Recently approved medications for the treatment of FC include the secretagogues lubiprostone and linaclotide.4 These medications do not appear to activate gastrointestinal muscle contraction directly.5,6 The
T
5-hydroxytryptamine (5-HT)4 receptor is an established target for increasing smooth muscle contractility. Thus, when stimulated by 5-HT4–receptor ligands, there are a
Authors share co-first authorship.
Abbreviations used in this paper: AC, ascending colon; ANCOVA, analysis of covariance; EC50, median effective concentration; FC, functional constipation; GC, geometric center; GE, gastric emptying; GI, gastrointestinal; 5-HT, 5-hydroxytryptamine; IC50, median inhibitory concentration; ITT, intent-to-treat. © 2015 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2014.08.012
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increased levels of intracellular cyclic adenosine monophosphate facilitating cholinergic neurotransmission in the myenteric plexus, thereby inducing contractions in the gastrointestinal tract.7 There is a subgroup of patients who do not achieve satisfactory relief of FC. Such patients appear to receive benefit from treatment with 5HT4–receptor agonists such as prucalopride,8 which is approved for prescription and marketing in several countries; however, it is not yet approved in the United States. YKP10811 (C24H30ClFN4O4 HCl) is a novel benzamide derivative with high binding affinity to the 5-HT4 receptor. The aim of this phase II, single-center, randomized, parallel-group, multiple-dose, double-blind, placebo-controlled study was to evaluate the effects of 8 days of treatment with 10, 20, and 30 mg YKP10811, once daily, on gastrointestinal and colonic transit, and on bowel functions in patients with FC. In addition, we aimed to assess the safety and tolerability of multiple doses of YKP10811.
Materials and Methods Participants Participants with functional constipation were recruited by public advertisement. Eligible participants provided their written consent before initiation of the study. Each subject completed a validated bowel disease questionnaire9 and was evaluated for functional constipation by Rome III criteria10; in addition, there was no evidence of a rectal evacuation disorder as assessed by physical examination11 conducted by the study investigators. All participants met eligibility criteria, including the following: age 18 through 65 years, body mass index of 18 through 40 kg/m2, reported fewer than 3 bowel movements per week by daily bowel questionnaire, baseline colonic transit by scintigraphy geometric center (GC) of 2.7 or less at 24 hours, failed available constipation medications including laxatives and fiber, and had a negative qualitative urine drug or alcohol test at screening. The study was approved by the Mayo Clinic Institutional Review Board.
Study Design We conducted a single-center, randomized, parallelgroup, multiple-dose administration over 8 days, double-blind, placebo-controlled study. Allocation of study drug was concealed from the clinical research team. We evaluated the effects of YKP10811 (10, 20, and 30 mg once daily, approximately n ¼ 15 each) on gastrointestinal (GI) and colonic transit, and bowel function, safety, and tolerability in patients with FC. The study was conducted in accordance with the Declaration of Helsinki and with Good Clinical Practice guidelines. Written informed consent was obtained from all patients
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before participation. The study was registered at ClinicalTrial.Gov (NCT01523184). Treatment allocation and concealment were conducted by an independent Mayo statistician who otherwise was not involved in the study. The randomization was communicated to and retained by the study research pharmacist, and was concealed from all study investigators until completion of the study and locking up of the data. Randomization was performed within blocks of consecutive patients. Only the independent Mayo statistician and pharmacist knew the block size being used. All randomized patients and study center and contract research organization personnel were blinded to study treatment allocation until data analyses. In addition, participant eligibility was based on the baseline measurement of colonic transit (GC measured over 24 hours [GC24] 2.7) using scintigraphy (which also assessed baseline gastric emptying [GE]). The baseline colonic transit at 24 hours of 2.7 or less (indicating that the average location of the isotope was in the lower part of the descending colon) was selected for eligibility to ensure that the patients had a similar spectrum of colonic transit, and it corresponded to the average colonic transit in healthy volunteers.12,13 Patient randomization was stratified on sex and the baseline GC24 value ( 1.6 vs >1.6) to ensure that there was balance in the number of patients with slow colonic transit (GC24 < 1.6), which was the average colonic transit measurement in 61 patients with slow-transit constipation in our laboratory.14 Patients underwent scintigraphic assessment of gastric, small-bowel, and colonic transit of solids over the 48-hour period from days 7 to 9. A bowel function diary was kept from days 1 to 9; participants recorded the time to first bowel movement after dosing, number of stools per day, average stool consistency (Bristol Stool Scale), ease of passage, and completeness of evacuation.
Study Medication Pharmacology. YKP10811 (C24H30ClFN4O4 HCl) is a novel substituted benzamide derivative, small molecule with high binding affinity to the 5-HT4 receptor (Ki ¼ 4.96 nmol/L). In cellular functional assays conducted with the 5-HT4 receptor, YKP10811 showed weak agonist activity that was dose dependent and reproducible (median effective concentration [EC50] ¼ 0.78 nmol/L). These results indicated that YKP10811 acts as a partial agonist of the 5-HT4 receptor. YKP10811 did not show any significant off-target binding to any other receptors, enzymes, or serotonin-receptor subtypes at 1 mmol/L, except for binding to the 5-HT2A receptor (Ki ¼ 600 nmol/L) and the 5-HT2B receptor (Ki ¼ 31 nmol/L). Thus, YKP10811 has 120-fold and 6-fold lower affinity, respectively, for 5-HT2A and 5-HT2B receptors than for 5-HT4. In cellular functional assays, YKP10811 showed antagonist activity at the 5-HT2B receptor with a median inhibitory concentration
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(IC50) of 2.1 mmol/L and no significant activity at the 5-HT2A receptor up to 10 mmol/L. YKP10811 showed no activity against serotonin-receptor subtypes 5-HT1B, 5-HT1D, or 5-HT2A at 1 nmol/L to 10 mmol/L, or for serotonin-receptor subtype 5-HT7 at 10 nmol/L to 30 mmol/L (data on file; SK Life Science, Inc, Fair Lawn, NJ). Thus, results from binding assays and functional assays fully support the conclusion that YKP10811 is a specific and selective 5-HT4–receptor agonist. Preclinical studies. In rats, YKP10811 accelerated colonic transit by 37% at a dose as low as 1 mg/kg. In dogs, 0.3 mg/kg YKP10811 accelerated colonic transit by 45.5% at 2 hours after dosing. The accelerated colonic transit in dogs was associated with significantly increased colon contractions and defecation. YKP10811 significantly reduced visceral hypersensitivity in multiple pain models in rats. Safety. The study of the specificity and selectivity of YKP10811 for the 5-HT4 receptor would predict a safe pharmacologic profile with potential for pharmacodynamic and clinical efficacy.15 In a phase I, double-blind, randomized, 9-day, placebo-controlled, multiple-ascending dose study in healthy volunteers at doses of 5, 15, 30, and 45 mg once daily, YKP10811 was well tolerated with minimal side effects (data on file; SK Life Science, Inc). Pharmacokinetics. After oral administration of either 10, 20, or 30 mg YKP10811 daily for 7 days, the variability for Cmax (maximum serum concentration) was 42.9% to 78.5% and for the area under the concentration-time curve (0-tau) was 29.7% to 58.8%. The geometric mean values of both Cmax and the area under the concentration-time curve (0-tau) increased with increasing dose of YKP10811. The median Tmax (time to reach Cmax) of YKP10811 ranged from 1.00 to 2.00 hours, with individual values ranging from 0.47 to 2.17 hours after dosing across the 3 YKP10811 dose levels.
Administration of Study Medication Patients received multiple oral doses of YKP10811 or placebo once daily for 8 days. The doses given were 10, 20, and 30 mg, or matching placebo. Drugs were administered with a total of 240 mL water. No food was allowed for at least 1.5 hours after dosing. The selected doses were based on phase I and preclinical studies (data on file; SK Life Science, Inc).
Gastrointestinal and Colonic Transit A validated scintigraphic method with known performance characteristics was used to measure gastric emptying, small-bowel transit, and colonic transit over 48 hours, using dual-isotope gamma camera scanning of abdominal images. This scintigraphic method is well validated and established,12,16 with published coefficients of variation [COVinter] and within subjects [COVintra] to plan phase IIA studies according to effect sizes desirable
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for pharmacodynamics and bowel function end points in patients with lower functional gastrointestinal disorders associated with constipation such as FC.17 Briefly, participants reported to the Clinical Research Unit, fasted, on the morning of testing as directed by study personnel. A urine pregnancy test was performed, when applicable, within 48 hours of the start of the test. 111In absorbed on activated charcoal particles was delivered to the colon by means of a methacrylate-coated, delayedrelease capsule. The capsule was ingested after an overnight fast, 1.5 hours before a breakfast test meal during baseline transit assessments. Then, 99mTc-sulfur colloid was used to label 2 scrambled eggs that were eaten with 1 slice of whole wheat bread and 1 glass of whole milk (296 kcal, 30% fat). This meal facilitated measurement of gastric and small-bowel transit. Patients ingested standardized meals for lunch and dinner immediately before the 4- and 8-hour scans. For measurement of gastric emptying, small-bowel, and colonic transit, scans were acquired before ingestion of the radiolabeled test meal, followed by scans taken immediately after (time 0) and at 30 minutes, and at 1, 1.5, 2, 4, 6, 8, 24, and 48 hours after the radiolabeled breakfast (egg meal).
Daily Symptom Assessments During the study, participants completed a daily diary to record their bowel functions for each bowel movement including consistency (Bristol Stool Form Scale scores were as follows: 1, hard lumps; 2, lumpy sausage; 3, cracked sausage; 4, smooth sausage; 5, soft lumps; 6, mushy; and 7, watery), ease of passage (1, manual disimpaction; 2, enema needed; 3, straining needed; 4, normal; 5, urgent without pain; 6, urgent with pain; 7, incontinent), and sense of completeness of evacuation (yes/no).18–20 The on-study bowel habit diary cards were dispensed at day 1 and the completed cards were collected at the end of the study visit on day 9. Stool consistency was appraised using the validated Bristol Stool Form Scale.18 For each of these symptom end points, the average number or score for the treatment period was calculated for each individual participant, as in prior studies.19,20
Safety Assessments Safety was determined by evaluating adverse events, vital signs (pulse rate, supine blood pressure, orthostatic blood pressure, oral temperature, and respiration rate), physical examinations, multiple 12-lead electrocardiograms at baseline and standard times after dosing, and clinical laboratory assessments (chemistry, hematology, coagulation, and urinalysis).
Study End Points, Statistical Methods, and Data Analysis Data in this article show median and interquartile ranges, unless otherwise stated. The primary efficacy
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analysis was based on an intent-to-treat (ITT) analysis of colonic GC at 24 hours and the t1/2 of gastric emptying for solids using analysis of covariance (ANCOVA) models with baseline GC24 and baseline GE t1/2, respectively, and treatment group in the statistical models. The Dunnett test was used for multiple comparisons of active drug with placebo. The secondary efficacy variables were colonic GC at 4 and 48 hours, colonic filling at 6 hours (CF6), and the t1/2 for ascending colon (AC) emptying. The ITT analyses imputed the missing values in 2 subjects using the overall mean (CT, CF6, AC t1/2, and bowel diary scores) and the overall median (GE t1/2 and time to first bowel movement after the initial dose). The degrees of freedom for error in the ANCOVA models were adjusted (subtracting one for each missing value imputed) to compensate for the imputations. In some instances, response end points first were transformed to rank scale to accommodate nongaussian distributions of the ANCOVA model residuals. In addition, a per-protocol analysis using proportional hazards models examined treatment effects on the GE t1/2 and time to first bowel movement in 55 of the 57 participants who completed all studies. The study (with at least 12 patients per treatment arm) was powered to detect an effect size of 43% in colonic transit GC24 and 26% in gastric emptying t1/2 (Table 1). All authors had access to the study data and reviewed and approved the final manuscript.
Results Participants, Demographics, and Baseline Parameters Supplementary Figure 1 shows the consolidated standards for reporting clinical trials (CONSORT) flow chart of participants in the study. Fifty-seven participants were randomized to the study, with 11, 15, 16, and 15 Table 1. Effect Size Shown Based on Performance Characteristics and Variance in Main End Points in the Proposed Study Assuming n¼12/ group Response type
Mean
SD
GE solids t1/2 min 130 29 (N ¼ 63) Colonic filling at 6 h, % 44 29 (N ¼ 63) GC at 24 h (N ¼ 62) 2.36 0.85 Ascending colon t1/2 h 15.0 8.0 (N ¼ 50)
Effect size,a % detectable with 80% CV% power (a ¼ .05) 22
26
66
79
36 53
43 63
NOTE. Table data are based on data from previous studies using similar methods. Note that the effect size demonstrable may be smaller for each dose contrast (n ¼ 18) vs placebo (n ¼ 12). CV%, coefficient of variation, %. a Effect size is the difference between means as a percentage of the listed mean.
participants, respectively, randomized to placebo, 10 mg, 20 mg, and 30 mg YKP10811. The demographic characteristics of the participants were as follows: 56 women and 1 man, mean age of 42.8 1.3 years, mean body mass index of 25.3 0.5 kg/m2, and a baseline GE t1/2 of 125.0 4.3 minutes and a GC24 of 1.83 0.05 (Table 2). A total of 55 patients completed the study, with early discontinuation in 2 participants (1 participant receiving placebo and 1 participant receiving 20 mg YKP10811).
Gastrointestinal and Colonic Transit Overall, the YKP10811 treatment effect on functional constipation was associated with accelerated small-bowel and colonic transit (Table 3). When assessing the overall effect of YKP10811, there was accelerated gastric emptying (t1/2) on per-protocol analysis (P ¼ .031; ITT analysis on ranks, P ¼ .16). Overall treatment effects also were observed for CF6h (P < .001). The Dunnett test based on ranks for CF6h was significant for YKP10811 at 20 mg and 30 mg (P < .001). The overall assessment of treatment effects of YKP10811 showed significant acceleration of AC emptying (t1/2) and colonic transit at 24 and 48 hours. Specifically, the ANCOVA models based on ranks indicated an accelerated AC emptying (t1/2, P ¼ .016) and colonic transit at GC 4, 24, and 48 hours (P ¼ .062, P < .01, and P ¼ .019, respectively). The Dunnett test based on ranks indicated AC t1/2 was associated significantly with accelerated transit for all 3 doses individually when compared with placebo (Dunnett test, P < .05 for all). In addition, 10 mg YKP10811 was associated with accelerated transit at all GC time points (eg, at 24 hours) (Figure 1) when compared with placebo (Dunnett test, P < .05), and with borderline accelerated colonic transit at 48 hours (Dunnett test, P ¼ .08) in the 30 mg group when compared with placebo (Table 3).
Daily Stool and Abdominal Symptoms Overall, YKP10811 treatment effect on functional constipation (relative to placebo) was associated with significantly accelerated time to pass a BM after first dosing (P < .01) and with borderline increased differences in stool consistency over the 8-day treatment period (P ¼ .064) (Table 4). The Dunnett test on ranks for time to pass BM after first dosing was associated significantly with all 3 doses of YKP10811 when compared with placebo (Dunnett test P < .05). Stool consistency (form) (Table 4) significantly improved (softer) with 20 and 30 mg doses of YKP10811 when compared with placebo (Dunnett test, P < .05). There was no significant difference in the number of BMs per day (Table 4).
Adverse Events There were no deaths and no serious adverse events. Two subjects discontinued prematurely (1 on placebo, 1
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Table 2. Patient Demographics and Baseline Values
N Age, y Females BMI, kg/m2 Baseline GE t1/2 min Baseline colonic transit GC24
Placebo
10 mg YKP10811
20 mg YKP10811
30 mg YKP10811
11 39.1 2.0 100% 24.0 1.3 136.7 (117.7–149) 1.79 (1.46–1.99)
15 44.0 3.2 100% 26.0 0.8 113.2 (105–152.9) 2.16 (1.57–2.31)
16 47.0 2.2 94% 26.4 0.9 115.3 (89.6–127.5) 1.84 (1.57–2.1)
15 41.0 2.6 100% 24.9 0.9 118 (109–136.5) 1.73 (1.49–1.97)
NOTE. Means SEM are shown except baseline GE and GC24: median (interquartile range). BMI, body mass index.
on 20 mg YKP10811) secondary to prolongation of QTc on one electrocardiography each; the prolongation was less than 5 ms greater than the prespecified limit of 470 ms. Table 5 shows the adverse events associated with YKP10811. There were no significant differences between the treatment groups. There was an overall borderline treatment effect on diarrhea (Cochran–Armitage test for trend [dose effect] was P ¼ .15). One subject on 10 mg YKP10811 had “watery stools,” 1 subject on 20 mg had “explosive watery stools,” and 4 subjects on 30 mg had “diarrhea.” One subject on placebo had “diarrhea.”
Discussion In this single-center, randomized, parallel-group, double-blinded, placebo-controlled study in patients with functional constipation, YKP10811, a selective 5HT4–receptor agonist, enhanced gastrointestinal and colonic transit and improved bowel function during an 8day treatment trial. The effect of YKP10811 on colonic transit was mirrored by improvements in softer stool consistency and faster time to first bowel movement, suggesting that YKP10811 has encouraging effects on these clinical end points. In addition to pharmacodynamic
effects in patients with functional constipation, the improvements in bowel functions are validated and measurable end points recommended for treatment of functional constipation.20 These findings suggest that YKP10811 may be a potential new medication for the treatment of functional constipation. YKP10811 had a robust effect on accelerating, by 30% to 40%, the AC emptying when compared with placebo. Ascending colon emptying has been reported to have the greatest contribution to overall colonic transit21 because the ascending and transverse colon constitute the “reservoir” or storage regions of the human colon.22 In addition, YKP10811 accelerated colonic transit at 24 and 48 hours, and this was associated with faster time to first bowel movement after the first dose and looser stool consistency during 8 days of treatment. Among the other 5-HT4–receptor agonists previously studied with the same method, 4 mg prucalopride23 and 30 and 50 mg velusetrag24 also accelerated AC emptying. The overall effect of naronapride (ATI-7505) on AC t1/2 suggested borderline treatment differences (P ¼ .075), with only one pairwise comparison between 10 mg and placebo 3 times daily being borderline significant (unadjusted P ¼ .042), whereas 3 mg and 20 mg doses 3 times daily did not accelerate AC t1/2.25
Table 3. Gastrointestinal and Colonic Transit Placebo N GE T1/2 mina GE 4 h CF6, %b AC T1/2, hd Colonic transit GC4e Colonic transit GC24b Colonic transit GC48f
123.4 0.97 28.5 20.5 0 1.67 2.70
11 (104–172) (0.81–1) (19–47) (19.59–20.9) (0–0.94) (1.62–1.81) (2.25–2.99)
NOTE. Data are presented as medians and interquartile ranges. a P ¼ .031 by per-protocol analysis (ITT, P ¼ .16 on rank scale). b Analysis of variance on rank P < .01. c P < .05 by the Dunnett test (corrected for multiple comparisons). d Analysis of variance on ranks P ¼ .016. e Analysis of variance on ranks P ¼ .062. f Analysis of variance on ranks P¼ .019. g Analysis of variance on ranks P ¼ .08.
10 mg YKP10811 112 1 58 15.17 1 3.18 4.1
15 (100–136.6) (0.96–1.0) (20–78) (3.50–16.99)c (0–1.57)c (2.26–3.52)c (3.47–4.96)c
20 mg YKP10811 98 1 82 14.72 1 2.60 4.15
16 (85.38–117) (1.0–1.0) (62–95)c (7.19–17.2)c (0–1.0) (1.79–3.74)c (3.64–5)c
30 mg YKP10811 106 1 80 14.86 1 2.06 3.28
15 (91.6–122.4) (1.0–1.0) (55–89)c (9.78–17.88)c (0.85–1.0)c (1.81–2.91) (2.85–4.88)g
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Figure 1. Colonic transit GC24h, presented as medians (interquartile range).
YKP10811 had no significant effect on the number of spontaneous bowel movements or bowel movements per week. However, the short duration of the study and the sample size of the study were based on the plan to show an effect size of 43% in the primary end point, colonic GC at 24 hours. The study showed the effect of YKP10811 on colonic transit and gastric emptying. Emptying of the proximal colon correlates linearly with fecal weight,26 which reflects largely stool water content, and, as expected based on prior studies,16 the overall colonic transit was correlated linearly with stool consistency, with less significant association with the number of bowel movements per day. Our prior studies also estimated that the sample size required in a phase IIA study to show a 30% effect on stool consistency would be 24 patients per treatment arm, and similar effects on stool number would require 34 patients per treatment arm.17 In fact, the effect size of YKP10811 on stool consistency was approximately 50% and, hence, showed a statistically significant effect with approximately 15 patients per treatment arm. The findings of shorter gastric emptying t1/2 and increased CF6 (small-bowel transit) suggest prokinetic effects in the stomach, even in patients with functional constipation whose baseline gastric emptying was 125.0 4.3 minutes (SEM), which is comparable with the data
from 319 healthy participants studied in the same laboratory with the same meal (121.7 1.7 min).27 The acceleration of stomach and small-bowel transit is consistent with preclinical studies that showed that 1 hour after dosing, YKP10811 radiolabeled with 14C was found mainly in the small intestine (55%) and cecum (38%) (unpublished data; SK Life Science, Inc). This significant effect (approximately 20% acceleration of gastric emptying t1/2 with the 20 and 30 mg doses of YKP10811) suggests that there is a prokinetic effect of potential relevance on gastric motility disorders, such as gastroparesis and functional dyspepsia.28,29 Interestingly, the results showed a lack of dose response in the treatment groups receiving YKP10811. Furthermore, YKP10811, 30 mg, had no significant effect on colonic transit GC24h and GC48h. These results may be the result of the dual action (agonist/antagonist) of YKP10811 seen in in vitro studies. YKP10811 facilitated the electrical field stimulation–induced neurogenic twitch of guinea pig ileum at lower concentrations (10 mmol/L: IC50, 30.42 mmol/L). This type of dual action (agonist/antagonist) of YKP10811 under the same assay conditions also was shown in the peristaltic reflex test with an EC50 of 0.5 mmol/L and an IC50 of 21 mmol/L. There is a significant gap in concentration ranges (>40-fold difference) for stimulatory vs inhibitory effects of YKP10811 in vitro (unpublished data; SK Life Science, Inc). Overall, YKP10811 was well tolerated and without any major side effects in our study. Two participants, 1 receiving placebo and 1 receiving 20 mg YKP10811 had prolonged QTc (>470 ms). Both participants discontinued the study on the advice of the investigators, even though the QTc prolongation was minimal (
