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Am J Physiol Gastrointest Liver Physiol 294: G1114-G1119, 2008. First published March 27, 2008; doi:10.1152/ajpgi.00051.2008
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NEUROREGULATION AND MOTILITY

Dose-response effect of a β3-adrenergic receptor agonist, solabegron, on gastrointestinal transit, bowel function, and somatostatin levels in health

April B. M. Grudell,1 Michael Camilleri,1 Kim L. Jensen,1 Amy E. Foxx-Orenstein,1 Duane D. Burton,1 Michael D. Ryks,1 Kari L. Baxter,1 Donna S. Cox,3 George E. Dukes,3 Dennis L. Kelleher,3 and Alan R. Zinsmeister2

1Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) and 2Department of Health Sciences Research, Division of Biostatistics, College of Medicine, Mayo Clinic, Rochester, Minnesota; and 3GlaxoSmithKline, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania

Submitted 31 January 2008 ; accepted in final form 24 March 2008


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
β3-Adrenoceptors(β3-AR) are expressed by cholinergic myenteric neurons and β3-AR agonists are effective in experimental models of diarrhea. Our aim was to explore the effects of a β3-AR agonist, solabegron, on gastrointestinal transit, safety, bowel function, plasma somatostatin, and solabegron pharmacokinetics (PK) following single and multiple doses. In a single-center, double-blind, parallel-group trial, 36 healthy volunteers were randomized to oral solabegron (50 or 200 mg twice daily) or placebo. Transit was measured by a validated method (99mTc-labeled egg meal and 111In charcoal delivered to the colon via delayed-release capsule). Stool frequency, form, and ease of passage were measured on a validated daily diary; plasma somatostatin by radioimmunoassay and plasma solabegron and its active metabolite by validated liquid chromatography-tandem mass spectroscopy analysis followed by PK analysis using noncompartmental methods. There were no overall or dose-related effects of solabegron on gastric, small bowel, or colonic transit, plasma somatostatin levels, stool frequency, form, or ease of passage in healthy volunteers. Solabegron and active metabolite exposures (area under the curve and maximum serum concentration) at both dose levels were consistent with PK at similar doses in previous phase I studies. We concluded that 7 days of the β3-AR agonist, solabegron, 50 or 200 mg twice daily, did not significantly alter gastrointestinal or colonic transit or bowel function. In this study, medication was generally well tolerated with few adverse events reported and no clinically significant changes in vital signs observed. Further studies on clinical efficacy, visceral sensitivity, and gastrointestinal transit are required in irritable bowel syndrome patients.

colon; motility; pharmacokinetics

THERE IS A NEED FOR EFFECTIVE medications for the treatment of irritable bowel syndrome (IBS) (1, 2). Motor and sensory abnormalities are frequently observed in IBS; thus, in our study of 122 patients, 32% of patients with IBS had abnormal colonic transit (20.5% at 24 h and 11.5% at 48 h), 20.5% had increased sensation to distensions, and 16.5% of IBS patients had reduced rectal sensation (8). Forty-six percent of patients with diarrhea-predominant IBS (D-IBS) had accelerated transit at 24 or 48 h.

β3-Adrenoceptors (β3-ARs) are expressed in the human gastrointestinal tract (3, 19). β3-AR is a member of the family of G-protein-coupled receptors that have been cloned from human, mouse, and rat and are expressed in adipocytes, heart, skeletal muscle, and smooth muscle of the gastrointestinal and urogenital systems. β3-AR expression is colocalized with choline acetyl transferase in a majority of the neurons in human colonic myenteric and submucosal plexus (12). The human selective β3-AR agonist, solabegron, inhibits cholinergic contractions and enhances release of somatostatin with no effect on carbachol-induced contractions in human isolated colon. A rodent selective β3-AR agonist inhibits castor oil-induced diarrhea in rats (12).

β3-AR agonist reduces the elevated tone and inhibits spontaneous contractions in the human isolated colon, but the exact site of action is not clear. Activation of β3-AR results in inhibition of cholinergic contractions, and enhanced release of somatostatin agonists of these receptors have been shown to inhibit spontaneous contractions of the human colon and relax precontracted colonic longitudinal and circular muscle (4, 16, 22).

They also slow gastrointestinal transit in wild-type mice but have no effect in β3-AR knockout mice (18). In a rat model of diarrhea, the β3-AR agonist CL316243 [GenBank] decreased castor oil-induced fecal weight (12). On the other hand, β3-AR agonist does not alter carbachol-induced contractions in human isolated colon (12).

Visceral sensitivity is also controlled in part by adrenergic modulation. The nonselective β-adrenergic agonist isoproterenol leads to release of somatostatin. Somatostatin is released from enteroendocrine and neural elements in the gastrointestinal tract and is thought to act as an endogenous analgesic substance (25). Levasseur and colleagues (20) showed that a β3-adrenergic receptor agonist led to release of somatostatin from rat gastric antral cells, which was blocked with an antagonist. β3-AR agonist inhibited mustard oil-induced visceral pain via somatostatin receptor-2 activation (12).

Given the colocalization on cholinergic neurons, it would appear that a β3-adrenergic agonist might be proposed for treatment of D-IBS. Currently, loperamide and alosetron are the main pharmacological therapies available for patients with D-IBS (2). Although loperamide is available over the counter, alosetron is not prescribed extensively given its potential to cause ischemic colitis.

Our aims were to assess dose-related effects of solabegron on gastrointestinal and colonic transit, bowel function, and plasma somatostatin levels in healthy human volunteers and to characterize the pharmacokinetic profile of solabegron and its active metabolite following single and multiple dosing.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Trial design. We performed a single-center, double-blind, randomized, placebo-controlled study to compare gastrointestinal transit between two different doses of solabegron (50 mg twice daily, 200 mg twice daily, n = 12 in each treatment group) and placebo (ClinicalTrials.gov Identifier: NCT00401479 [ClinicalTrials.gov] ; GSK study no. B3I106248). Allocation was concealed. Normal-weight participants were recruited, without restriction for gender, race, or ethnicity through public advertisement. All participants gave written, informed consent to participate in this study, which was approved by the Mayo Clinic Institutional Review Board.

Study procedure. Study participants were recruited by public advertisement and were enrolled in the study for 3 wk (including screen, 7 days of study medication, and follow-up). At the screening visit, subjects underwent a history and physical exam, laboratory work (chemistry, complete blood cell count, urinalysis), ECG, pregnancy test, were given a bowel habit diary to record their baseline bowel function using the Bristol Stool Scale for stool consistency rating (21) and completed the Bowel Disease Questionnaire (26). They returned in 7–14 days for repeat ECG, pregnancy test, return of their baseline bowel habit diary and receipt of the treatment bowel habit diary, receipt of study medication, and blood work (somatostatin levels). For the next 6 days, participants took the study medication twice daily. They returned for vital sign check on study day 2 and study day 5. On study days 6, 7, and 8 they completed the scintigraphic gastrointestinal transit test. Blood samples were also obtained for measurement of somatostatin and solabegron on study days 1 and 6 to determine both plasma concentrations and pharmacokinetic parameters, respectively. Seven to 14 days after the last dose of study medication, they returned for a final visit in which blood work, ECG, physical exam, and pregnancy test were repeated. The experimental design is summarized in Fig. 1.


Figure 1
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  		Fig. 1. Study procedures.

 
Solabegron. Solabegron hydrochloride is a potent and selective in vitro agonist of human β3-AR activity compared with human β1- and β2-adrenergic activity and is not an antagonist at either β1- or β2-ARs. Solabegron is a biaryl phenethanolamine compound [(1,1'-biphenyl)-3-carboxylic acid, 3'-((2-(((2R)-2-(3-chlorophenyl)-2-hydroxyethyl)amino)ethyl)amino)-,hydrochloride] of the class described by Uehling et al. (27). The primary metabolite of solabegron is the O-acyl glucuronide metabolite solabegron; it has similar activity to solabegron as a selective β3-adrenergic agonist.

Solabegron is a β3-adrenergic agonist that has been shown to reduce nerve-stimulated colonic smooth muscle contractions and stimulate release of somatostatin, which has analgesic properties, in human tissues. The pharmacokinetics of both solabegron (parent) and its active metabolite have been studied extensively in both single- and repeat-dose studies (unpublished data). Both parent and active metabolite are rapidly absorbed and depict a median time of maximum concentration (Tmax) of 1.5–3 h and 3–4 h, respectively, upon repeat dosing. Mean elimination half-life for parent compound ranges from 5 to 8 h and from 4.5 to 7.5 h for active metabolite. Both solabegron and active metabolite increase in a less than dose-proportional manner at doses ranging from 300 to 400 mg twice daily.

Prior to our trial, solabegron had been tested in 442 human subjects at doses ranging from 25 mg daily to 400 mg twice a day (unpublished data). At doses less than 200 mg per day, no clinically significant adverse events occurred; with a dose of 400 mg administered orally twice a day for 12 days, the most common adverse event was headache.

Assessment of stool frequency and consistency. During the study, patients completed a daily diary to record their bowel habits and to allow stool frequency, stool consistency, ease of passage, and sense of incomplete evacuation diary data to be compared between the baseline and treatment periods.

Stool frequency was defined as the number of episodes of defecation recorded per day in the bowel habit diary; stool consistency was defined by the seven-point pictorial Bristol stool scale (21), which ranges from unformed/watery to hard pellets; ease of passage was defined by the seven-point adjectival scale, which ranges from incontinence to requiring manual disimpaction (13); and sense of incomplete evacuation was defined by a yes-or-no answer to the question "Did you feel like you completely emptied your bowels?"

Clinical laboratory tests. Hematology, clinical chemistry, and urinalysis testing were performed at screen and follow-up visit or the early termination visit; other tests only at screening were serum thyroid stimulating hormone and amylase. For female subjects of childbearing potential, a urine pregnancy test was conducted prior to administration of study medication on day 1 and within 48 h prior to exposure to any radiation.

Gastrointestinal transit measurement with scintigraphy. We have previously used the method (14) extensively and have demonstrated the reproducibility and performance to be expected of transit measurements obtained with scintigraphy. In this technique, a methacrylate-coated, delayed-release capsule containing 0.1 mCi of 111InCl3 absorbed on activated charcoal particles is ingested. Two hours after ingestion of this capsule, two scrambled eggs labeled with 99mTc-sulfur colloid are ingested with one slice of whole wheat bread and one glass of skim milk. Anterior and posterior gamma camera (Siemens, Diacam, Malvern, PA) images are then obtained at 0, 1, 2, 4, 6, 24, and 48 h after radioactive meal ingestion. The primary outcome variables include the percentage of radioisotope emptied from the stomach at 1, 2, and 4 h, the gastric half-emptying time from linear interpolation of the gastric residuals, the percentage of colonic filling at 6 h, and the colonic geometric center (GC) at 4, 8, 24, and 48 h.

Plasma somatostatin. Serial blood samples for somatostatin were collected prior to dosing (–5 min) and at 30, 60, 120, and 240 min after administration of study drug on both day 1 and day 6. Each sample (10 ml) was collected in a chilled Vacutainer (BD, Franklin Lakes, NJ) and centrifuged at –4°C, and plasma was separated and stored at –20°C for future analysis using radioimmunoassay at a commercial laboratory (Inter Science Institute, Inglewood, CA) using an in-house antibody. The limit of detection of the assay is <1 pg/ml, and interassay reproducibility expressed as percent CV ranges from 9.3 to 15.7% for plasma somatostatin concentrations of 35 and 5.4 pg/ml, respectively.

Pharmacokinetics. Serial blood samples for solabegron and its active metabolite were collected prior to dosing and at 0.5, 1, 1.5, 2, 4, 6, and 8 h after administration of study drug on both day 1 and day 6. Blood samples (~4.0 ml each) for pharmacokinetic analysis of solabegron and its primary metabolite were collected in tubes containing lithium heparin additive. Samples were centrifuged in a refrigerated centrifuge (~4°C) at ~1,500 g for 10–15 min, and the resulting plasma was pipetted and placed in appropriately labeled polypropylene storage tubes [3.6 ml Nunc tube (Roskilde, DK-4000)]. Plasma was stored immediately at –20°C or below until transported for analysis. All plasma samples were analyzed for solabegron and its primary active metabolite by the Department of Worldwide BioAnalysis in Drug Metabolism and Pharmacokinetics of GlaxoSmithKline. Plasma concentrations of solabegron and active metabolite were measured by liquid chromatography-tandem mass spectroscopy (methodology on file at Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Pharmaceuticals). The calibration curve range for parent compound and active metabolite was 1–1,000 ng/ml.

Statistical analysis. An intent-to-treat analysis using all randomized subjects was performed. Any missing data was imputed, using the overall mean across all subjects for each end point, with adjustment in the degrees of freedom as needed.

Primary and secondary end points (colonic GC at 8, 24, and 48 h, gastric emptying at 2 and 4 h, colonic filling at 6 h, ascending colonic transit time, overall stool frequency, consistency, ease of passage) were analyzed by one-way analysis of covariance for the three treatment groups. Gender was used as a covariate in analyzing effects of solabegron on gastrointestinal transit. Specific pairwise comparisons (each dose vs. placebo) were also conducted. Descriptive statistics (mean, standard deviation, minimum, median, and maximum) were calculated for somatostatin plasma concentrations and pharmacokinetic parameters for solabegron and its active metabolite using noncompartmental methods.

Study power. The study was powered to detect a clinically meaningful difference in transit parameters, specifically colonic transit at 24 h and gastric emptying at 2 h; data describing stool frequency, stool consistency, and ease of passage were assessed in a descriptive fashion. The study had 80% power (using a two-sample z-test at a two-sided {alpha} level of 0.05) to detect effect sizes for colonic transit GC 24 and ascending colonic half time of elimination of the drug (t1/2) of 39 and 35%, respectively. The proposed study would detect changes in transit of a magnitude that would be of clinical significance in patients with constipation (that is, a change in GC of 1 unit) treated with colonic prokinetics (5, 9, 23) or of similar magnitude in patients with diarrhea given a 5-HT3 antagonist such as alosetron (28).


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Participant demographics and main results. Table 1 shows patient age and gender distributions as well as summary data. One participant (placebo group) had missing data for only the GC at 8 h, one subject in the 50 mg group had missing data on all end points, and one subject in the 200 mg group had missing data for only GC at 48 h. Thus we did an imputation for, at most, two subjects, depending on the specific end point.


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  		Table 1. Demographics and posttreatment responses of the 3 treatment groups

 
Effect of solabegron on colonic transit. There was no effect of treatment on overall colonic transit (Fig. 2) or on ascending colon emptying time (Fig. 3).


Figure 2
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  		Fig. 2. Overall colonic transit by geometric center (GC) at different times; no significant effect of treatment is observed.

 

Figure 3
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  		Fig. 3. Ascending colon (AC) emptying half time (t1/2) is not significantly altered by solabegron treatment.

 
Effect of solabegron on bowel function. There was no effect of treatment on bowel function (Table 1).

Effect on plasma somatostatin. Figure 4 summarizes the plasma somatostatin concentrations observed at different times on day 1 and day 6. Note that there are no differences in the plasma levels in response to the 50 or 200 mg dose of solabegron.


Figure 4
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  		Fig. 4. Plasma somatostatin concentrations on day 1 and day 6. Study medication was administered at time 0 on each study day. Note that there are no significant differences in the plasma somatostatin concentrations with solabegron treatment.

 
Pharmacokinetics. As depicted in Table 2, following single and repeat oral dosing of solabegron at dose levels of 50 and 200 mg, solabegron was rapidly absorbed with median Tmax values ranging from 1 to 3 h. Solabegron was also rapidly eliminated with mean t1/2 values ranging from 1.63 to 2.33 h. Mean area under the curve over time [AUC(0-t)] and maximum concentration (Cmax) values increased with the increase in dose from 50 to 200 mg in a less than dose-proportional manner. Small to moderate between-subject variability [24–40% coefficient of variation (CV)] was associated with the solabegron pharmacokinetic parameters. In addition, when subjects were administered solabegron at both dose levels, the results showed, as indicated in Table 3, that the active metabolite had a median Tmax ranging from 2.96 to 4 h. Like the parent compound, the active metabolite was also rapidly eliminated with mean t1/2 values ranging from 2.34 to 3.28 h. Finally, mean AUC(0-t) and Cmax values increased with the increase in solabegron dose from 50 to 200 mg in a less than dose-proportional manner.


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  		Table 2. Pharmacokinetic parameters of plasma solabegron

 

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  		Table 3. Pharmacokinetic parameters of plasma levels of active metabolite of solabegron

 
Safety. Solabegron was generally well tolerated. Twenty-two of the 36 subjects experienced at least one adverse event. The most common adverse events (>10%) reported were headache and various gastrointestinal complaints. There was one adverse event of headache reported as severe; all others were mild or moderate. Mean blood pressure and heart rate changes and outlier analyses were similar across both solabegron doses and placebo. There were no clinically significant changes in clinical chemistries or hematology.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
This pharmacodynamic study in healthy volunteers did not detect a difference in the gastrointestinal or colonic transit in response to two specific doses of solabegron. Similarly, no significant changes were observed for bowel function by using descriptive analyses. The study was powered to detect a 35–39% change in colonic transit summaries, and clearly this was not achieved (see Figs. 2 and 3) in healthy human volunteers. This study did not detect stimulated release somatostatin in response to two doses of solabegron. The pharmacokinetic results of both solabegron (parent) and active metabolite are consistent with similar doses in previous phase I studies. Given the pharmacokinetic results of both solabegron and active metabolite, it is also apparent not only that subjects received study drug, but that solabegron exposures after both single and twice-daily dosing achieved expected levels. These results are informative in relation to the potential application of this pharmacological approach in patients with IBS.

The study had a number of strengths including the design and the validated measures of colonic transit by scintigraphy, which have been previously demonstrated to have defined performance characteristics that were accounted for in the sample size calculations. Significant alterations in these transit measurements in response to candidate drugs also have been predictive of efficacy (e.g., alosetron, renzapride, tegaserod, prucalopride, neurotrophins, lubiprostone, linaclotide) or lack of efficacy (e.g., piboserod) in phase IIB or phase III clinical trials of agents that have well-defined motor effects. Therefore, using this approach to determine whether solabegron would appreciably alter colonic transit has construct validity.

A possible explanation for the failure to show a pharmacological effect on colonic transit or bowel function is that β3-AR agonists did not inhibit carbachol-induced colonic contractions in experimental animals. In IBS patients, the postprandial aggravation of symptoms may be driven by cholinergic input that may not be impeded, according to the experimental studies with carbachol. On the other hand, β3-AR agonists alter colonic tone in experimental animals, suggesting that this motor effect may alter colonic compliance, and this may also contribute to its effects on visceral sensation. The effects of solabegron on visceral sensitivity, compliance, tone, and phasic and tonic responses to meal ingestion in IBS patients, as well as efficacy in phase II and phase III trials are therefore eagerly awaited. This is particularly relevant given the observations regarding the expression of β3-AR (12) in myenteric and submucosal neurons (including cholinergic neurons) in mammalian and rodent intestine, and the evidence that β3-AR modulation alters human colonic muscle contractility (16, 17, 22), colonic tone, and compliance in dogs (15).

The failure to detect increases in circulating plasma somatostatin in response to solabegron is not directly supportive of the hypothesis of a somatostatin-linked visceral analgesic effect of solabegron. However, this result on circulating plasma somatostatin concentrations does not discount the possibility of a local release of somatostatin by neurons in the submucosal and myenteric plexus or other nonneuronal cells such as immune cells and endocrine cells in the mucosa in response to solabegron and a consequent local effect on visceral hypersensitivity.

The safety of solabegron, as evidenced by adverse events, laboratory analyses, and vital signs, is similar to previous healthy volunteer studies at similar doses.

The limitations of this study are the relatively small sample size and the conduct of the study in healthy subjects rather than in patients. The former is a limitation, but it was guided by a power statement that suggests the lack of effect of solabegron on colonic transit does not represent a type II statistical error. The latter limitation has to be addressed by further studies in patients.

In conclusion, at the doses tested in healthy volunteers, the β3-AR agonist, solabegron, does not significantly alter gastrointestinal or colonic transit, bowel function, or plasma somatostatin concentrations. Solabegron and active metabolite exposures (AUC and Cmax) at both 50 and 200 mg twice daily were consistent with pharmacokinetics at similar doses in previous phase I studies. Solabegron was generally well tolerated with few adverse events, and, specifically, there was no associated bowel dysfunction. Thus, although the first evaluation of the potential of modulating β3-AR mechanisms in healthy human volunteers suggests there is no significant effect on transit, further studies are required to evaluate the role of β3-AR modulation on colonic compliance, tone, and sensation in humans and on symptoms in patients with irritable bowel syndrome.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by GlaxoSmithKline. The study was enabled by the Mayo Clinic Clinical Research Unit, Gastrointestinal Imaging and Physiology Core (National Institutes of Health Grant RR-024150).


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. Camilleri, Mayo Clinic, Charlton 8-110, 200 First St. S.W., Rochester, MN 55905 (e-mail: camilleri.michael{at}mayo.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 DISCUSSION
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