Effect of renzapride on transit in constipation-predominant irritable bowel syndrome

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2004;2:895–904

Effect of Renzapride on Transit in Constipation-Predominant Irritable Bowel Syndrome MICHAEL CAMILLERI,* SANNA MCKINZIE,* JEAN FOX,* AMY FOXX– ORENSTEIN,* DUANE BURTON,* GEORGE THOMFORDE,* KARI BAXTER,* and ALAN R. ZINSMEISTER‡ *Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Program, Gastroenterology Research Unit, and ‡ Department of Health Sciences Research, Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, Minnesota

Background & Aims: The aim of this study was to evaluate the dose-ranging pharmacodynamic effects of renzapride, a 5-hydroxytryptamine 4 (5-HT4) receptor full agonist/5-HT3 receptor antagonist, on gastrointestinal transit and symptoms in patients with constipation-predominant irritable bowel syndrome (C-IBS). Methods: Forty-eight patients (46 women) with C-IBS underwent recording of baseline symptoms for 1 week. Twelve patients per group were randomized (double-blind, parallel design) to 11–14 days of renzapride (1, 2, or 4 mg) or placebo, once daily. Daily bowel habits and weekly satisfactory relief of IBS symptoms were recorded. At the end of treatment, gastric emptying (GE), small bowel transit (SBT), and colon transit (CT) were measured by scintigraphy. The relationship between CT and bowel function was evaluated. Results: A statistically significant linear dose response to renzapride was detected for CT (GC8 h, P ⴝ 0.004; GC24 h, P ⴝ 0.056), and ascending colon (AC) emptying t1/2 (P ⴝ 0.019), but not for GE (t1/2, P ⴝ 0.088; or SBT, P ⴝ 0.41). AC half-time transit (t1/2) for placebo and 4 mg of renzapride were (median) 17.5 vs. 5.0 hours, respectively. Improved bowel function scores (stool form and ease of passage, but not frequency) were significantly (P < 0.05) associated with accelerated CT. Pharmacokinetic analysis showed linear kinetics of renzapride with a mean t1/2 in plasma of 10 hours. Bowel function and satisfactory relief were not significantly altered by renzapride, although a type II error cannot be excluded. No significant adverse clinical, laboratory, or electrocardiogram (ECG) effects were observed. Conclusions: Renzapride causes clinically significant dose-related acceleration of CT, particularly ascending colonic emptying; this acceleration of transit is associated with improvement of bowel function in female C-IBS patients.

is not understood fully, but most likely is multifactorial. Alterations in gastrointestinal motility, visceral perception, and psychosocial factors contribute to overall symptom expression.3 It is one of the most frequently seen disorders by primary care physicians and gastroenterologists; a diagnosis of IBS has been reported by 4.5 million patients in the United States3,4 with other data suggesting its presence in up to 11%–14% of the adult population.3,4 Approximately 70% of IBS sufferers presenting to physicians in Western countries are women.11 Diagnostic criteria for IBS have been developed by Manning et al.12 and, more recently, at consensus meetings in Rome.13,14 Renzapride is a full agonist at 5-hydroxytryptamine 4 (5-HT4) receptors19 and is also an antagonist of 5-HT2b and 5-HT3 receptors.20,21 The 5-HT4 receptor is thought to mediate increased gut transit rate in humans and perhaps also to contribute to the alleviation of symptoms attributed to disordered gastrointestinal motility,15 such as constipation-predominant IBS (C-IBS). Activating 5-HT4 receptors is thought to result in an increase in adenylate cyclase activity that subsequently leads to the release of acetylcholine from postsynaptic neurons.22 Visceral afferent pathways are involved in mediation of the abdominal pain experienced by many of these patients with C-IBS. The mechanisms controlling visceral sensitivity are being investigated in animals and humans.23 Such pharmacodynamic studies may be useful to assess the clinical potential of experimental medications. For example, tegaserod was shown to accelerate small-bowel and colonic transit,15 and eventual clinical trials16 –18 confirmed the efficacy predicted by the pharmacody-

rritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by recurrent symptoms of abdominal pain and/or discomfort, accompanied by disturbed bowel function and a feeling of bloating.1– 4 This often results in an overall deterioration in quality of life in severe cases.5–10 The cause and physiology of IBS

Abbreviations used in this paper: AC, ascending colon; C-IBS, constipation-predominant irritable bowel syndrome; Cmax, maximum concentration; ECG, electrocardiogram; GC, geometric center; 5-HT, 5-hydroxytryptamine; IBS, irritable bowel syndrome; t1/2, pharmacokinetic half-life, transit half-time; Tmax, time at maximum concentration. © 2004 by the American Gastroenterological Association 1542-3565/04/$30.00 PII: 10.1053/S1542-3565(04)00391-X

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namic assessment.15 However, the previous study had not assessed whether the improvement in bowel function was associated with the acceleration in transit. Our hypothesis was that renzapride accelerated the emptying of the ascending colon and reduced the total colonic transit time in patients with C-IBS. Thus, our primary aim was to determine the dose-ranging pharmacodynamic effects of placebo, and 1, 2, and 4 mg once daily for 11–14 days, of renzapride on gastric emptying, small-bowel transit, and ascending and total colonic transit in patients with C-IBS. A secondary aim was to compare patient diary data of stool frequency, stool consistency, and ease of passage during baseline and treatment periods and to assess the relationship between transit responses and the change in bowel function. Additionally, the weekly response of patients for satisfactory relief of IBS symptoms and pharmacokinetics at the end of dosing, as well as safety, were described.

Materials and Methods Study Design and Methods This was a double blind, dose-ranging, randomized, placebo-controlled, parallel-group study of the pharmacodynamic effects of renzapride on gastrointestinal transit, and its pharmacokinetics, in 48 patients with C-IBS. The study consisted of an initial screening visit including evaluation to exclude evacuation disorder,24,25 baseline transit scintigraphy to qualify for randomization to study medication, and an 11to 14-day treatment period followed by repeat transit scintigraphy. After completing all screening tests and recording bowel habits in a daily diary for 7 days, patients returned for baseline transit scintigraphy to determine whether the randomization criteria (geometric center ⬍2.65 at 24 h, or ⬍3.0 at 24 h and ⬍3.90 at 48 h) were met. These randomization criteria are the mean values of geometric centers at 24 and 48 hours of normal healthy volunteers26,27 and were intended to exclude a possible ceiling effect caused by patients having a faster than normal baseline transit. Patients were randomized to placebo, or 1, 2, or 4 mg of renzapride (1 capsule/day to be taken with water each morning after food) for 11–14 days. Patients recorded both dosing times and bowel habits in a daily diary throughout the baseline and treatment period. Response to the question “Have you had satisfactory relief of your IBS symptoms this week?” also was recorded each week. Repeat transit was performed during the last 3 days of the treatment period. During the first 2 days of transit measurement, patients took the study medication at the Mayo Clinic General Clinical Research Center so that compliance would be assured and that timing of pharmacokinetic sampling would be accurate. Two ECGs were performed at least 30 minutes apart at the first visit, and 6 ECGs were performed at various times during the measurement of transit and pharmacokinetic sampling during the final 48 hours of the study.

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Participants Seventy-seven patients were recruited by public advertisement and by direct mailings to patients who had been seen previously in the Motility Clinic at Mayo Clinic. All subjects fulfilled modified Rome II criteria for IBS according to a bowel disease questionnaire,28 reported their predominant bowel dysfunction was constipation,24 and were screened for evidence of a rectal evacuation disorder by clinical examination, anorectal manometry, and balloon expulsion.29 To appraise the effect of an agent directed at the propulsive function of the colon accurately, we perceive it is essential to exclude an evacuation disorder and to ensure that, despite the report of constipation, the patients do not have accelerated colonic transit at baseline. Specific exclusion criteria were identification of an evacuation disorder, drug-induced constipation or alternative diagnosis, and concomitant medications that could interfere with the conduct or interpretation of the results. The 48 patients who met entry criteria were randomized. All patients gave informed consent and the study was approved by the Mayo Clinic Institutional Review Board.

Pharmacology of Renzapride Renzapride is a potent gastrointestinal prokinetic agent in studies of gastrointestinal motility and gastric emptying.21,22 In clinical studies conducted before this study involving nearly 700 patients with IBS, no clinically significant cardiovascular side effects, including QT prolongation, have been noted (N. Meyers, unpublished communication).30,31 Furthermore, in a comparative study of the ability to block electrical currents in the human cardiac ether-à-go-go– related gene potassium channel model, renzapride was 1000 times less potent than cisapride (N. Meyers, unpublished observation, March 2004). In 2 prior pharmacoscintigraphic studies, using very similar designs32 and after single oral doses of 2 mg in healthy human subjects in the fasted state, Cmax (maximum concentration) was approximately 4.0 ng/mL, Tmax (time at maximum concentration during fasting) was 1.4 hours, half emptying time (t1/2) was approximately 10.3 hours, and the area under the concentration-time curve0 – 48 was approximately 35.4 (ng/h) · mL (mean of both studies combined). Renzapride is not metabolized by cytochrome P450 enzymes and it does not interfere with cytochrome P450 –mediated metabolism of other drugs (N. Meyers, unpublished observation, March 2004).

Transit Measurements An adaptation of our established scintigraphic method was used to measure gastrointestinal and colonic transit.15,26,27,33 Briefly, 111-labeled indium absorbed on activated charcoal particles was delivered to the colon by means of a methacrylate-coated, delayed-release capsule.27 During baseline transit, only colonic transit was measured by means of images at 24 and 48 hours. The capsule was ingested after an overnight fast. At the end of the 2-week treatment period, the same colonic transit measurements were performed by means of the delayed

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release capsule administered at the same time as the dose of drug. After the capsule emptied from the stomach (documented by its position relative to radioisotopic markers placed on the anterior iliac crests), a radiolabeled meal was ingested. In this meal, 99m-labeled technetium 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.33 This meal facilitated measurement of gastric and small-bowel transit. Patients ingested standardized meals for lunch and dinner 4 and 8 hours after the radiolabeled meal. Relative to the time of breakfast meal ingestion, abdominal images were obtained every 15 minutes for the first 2 hours, then every 30 minutes for the next 4 hours, and at 8, 24, 32, and 48 hours. The performance characteristics of this test are summarized elsewhere.26

Transit Data Analysis A variable region of interest program was used to quantitate the counts in the stomach and each of 4 colonic regions: ascending, transverse, descending, and combined sigmoid and rectum. These counts were corrected for isotope decay, tissue attenuation, and downscatter of 111-labeled indium counts in the 99m-labeled technetium window.15,26,33 The primary summaries obtained for comparison of transit profiles were: gastric lag (time for 10% emptying) and t1/2, small-bowel transit time (by % colonic filling at 6 h, a valid surrogate for the small-bowel transit time33), and colonic geometric center at 4, 8, 24, 32, and 48 hours. The geometric center is the weighted average of counts in the different colonic regions: ascending (AC), transverse, descending, rectosigmoid, and stool. At any time, the portion of colonic counts in each colonic region is multiplied by its weighting factors as follows: (% AC ⫻ 1 ⫹ % transverse colon ⫻ 2 ⫹ % descending colon ⫻ 3 ⫹ % rectosigmoid ⫻ 4 ⫹ % stool ⫻ 5)/100 ⫽ geometric center. Thus, a high geometric center implies faster colonic transit. A geometric center of 1 implies that all of the isotope is in the ascending colon, and a geometric center of 5 implies that all of the isotope is in the stool. The t1/2 of ascending colon emptying also was estimated by plotting the activity-time curve for percent residing in the ascending colon; linear interpolation was used to connect points.

Assessment of Irritable Bowel Syndrome Symptoms, Stool Frequency, and Consistency During the week run-in and 2-week treatment periods, daily and weekly symptom data were collected by using a diary that incorporated questions or scales previously validated or used in the peer-reviewed literature.33–36 During the 2-week period of symptom monitoring during treatment, patients were asked once every 7 days if they had experienced satisfactory relief of their IBS symptoms during the previous 7 days. In prior studies, this end point has been validated for responsiveness and as an overall assessment that reflects multiple secondary end points of clinical relevance.34 –36

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Bowel function data were collected during the screening and treatment phases. We recorded patients’ stool frequency, consistency, ease of passage, and the sense of completeness of evacuation. Consistency was assessed by using the 7-point adjectival and pictorial validated Bristol stool scale,37 which ranges from unformed water (designated 7) to hard pellets (designated 1). Ease of stool passage was assessed by using a 7-point adjectival scale38 ranging from incontinence (designated 7) to requiring manual disimpaction (designated 1). We previously used the ease of passage instrument and showed responsiveness to therapeutic intervention in patients with functional constipation38 who were treated with an agent that increased frequency of bowel movements. The sense of incomplete evacuation38 was defined by a “yes” or “no” answer to the question: “Did you feel like you completely emptied your bowels?” During the entire study, patients completed a daily diary to record their bowel habits. Stool frequency, stool consistency, ease of passage, and sense of incomplete evacuation diary data were compared between the mean scores over 7 days during baseline and the 14-day treatment periods on the 4 treatment regimens.

Pharmacokinetic Analysis Blood samples were taken and plasma levels of renzapride were determined by using a validated liquid chromatography– mass spectrometry assay. Samples were taken at 13 separate time points over 24 hours from the time of the last dose of study drug. During this time, patients took their study medication at the General Clinical Research Center so that compliance was ensured and the timing of pharmacokinetic sampling, relative to the transit measurements, would be accurate. WinNonlin (Mountain View, CA)39 was used to calculate pharmacokinetic parameters.

Compliance During the treatment period, patients recorded their dosing with the study medication in their daily diary. Reasons for noncompliance also were recorded. Compliance was evaluated from the records in the patient’s diary and by the coordinator counting the number of unused capsules returned at the exit visit. Participants were considered compliant if they had not missed more than 3 doses of the study medication. However, immediately before the postmedication transit tests, all participants were documented to have received 3 consecutive days of dosing to ensure steady state.

Study Data Collected The following data were collected: transit times for gastric emptying, small-bowel transit, ascending colon, and total colonic transit; stool frequency, stool consistency, ease of passage, and sense of incomplete evacuation; satisfactory relief of IBS symptoms; plasma levels of renzapride under steadystate conditions for estimation of Cmax, Tmax, and terminal t1/2; routine safety testing by vital signs, laboratory analysis of hematology, and chemistry on blood samples taken at screen-

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ing and at end of the study; and cardiac safety monitored by electrocardiogram (ECG) recordings.

Statistical Analysis The primary response end points were GC8 h, GC24 h, and ascending colon emptying t1/2. The GC24 h as well as secondary end points gastric emptying t1/2, the percentage of marker in the colon at 6 hours, GC4 h and GC48 h, overall stool frequency, stool consistency, ease of passage, and sense of incomplete evacuation were analyzed using a 1-way analysis of variance. In addition, a 1-way analysis of covariance was used to assess the GC24 h and GC48 h by using the corresponding baseline value as the covariate. The specific contrast corresponding to a linear dose response also was tested. Pair wise comparisons of the active treatment groups vs. placebo were tested using Dunnett’s test. The other primary end point, ascending colon t1/2 emptying time (h), was assessed by using a proportional hazards regression model to account for one case for which the value was censored (i.e., ⬎50% of the marker remaining in the colon at 48 h). The comparison of active treatment groups vs. placebo for this end point used a Bonferroni adjustment for 3 pair wise comparisons. Data were collected as planned except in 1 of 48 patients. To enable an analysis using all patients randomized, an intent-totreat analysis imputed missing values for 1 patient for gastric emptying t1/2, GC 8 hours, and colonic filling at 6 hours by using the overall mean value of all nonmissing data. The residual error degrees of freedom was decreased by 1 to account for this imputation. An assessment of satisfactory relief (yes/no) at the end of the first and second weeks of treatment used the Fisher exact test to compare treatment groups for the proportion of patients with satisfactory relief of IBS symptoms. The individual bowel function responses (stool frequency, consistency, and ease of passage) and their composite (mean value) score were compared among treatment groups by using analysis of covariance with the corresponding baseline (run-in) value as the covariate. In each case, the analysis of covariance examined the overall (4 groups) treatment comparison and the linear dose response contrast. Pair wise comparisons of the covariate-adjusted treatment group mean values for active treatment vs. placebo were examined using Dunnett’s test. Pearson correlation coefficients were used to explore the associations between colonic transit posttreatment (GC24 h and GC48 h) and mean daily stool frequency, form, and ease of passage.

Results Patients Seventy-seven patients meeting modified Rome II criteria for C-IBS were screened. Twelve were excluded because of a rectal evacuation disorder or failed entry criteria, 5 were excluded because of abnormal laboratory

Figure 1. Trial flow.

values, and 2 were excluded because of abnormal ECG results before treatment. Seven patients were screened successfully but failed to meet randomization criteria for baseline transit and were discontinued from the study at that time. Three patients withdrew consent and were never randomized to the study medication (1 patient was randomized but did not take the drug owing to a migraine when attending to collect drug supply, 1 patient withdrew owing to time constraints, and 1 patient declined to undergo the flexible sigmoidoscopy and requisite examination). Thus, 48 patients (2 men, 46 women; mean age 39 ⫾ 1 y, body mass index 25.6 ⫾ 0.6 kg/m2; see Figure 1) were eligible and randomized. Patients were compliant with instructions to take study medication; 2 patients were excluded from the per protocol population because of intake of prohibited concomitant medications (selective serotonin reuptake inhibitors, SSRIs). The data reported are only for the intent-to-treat population. All remaining patients completed 11–14 days of treatment, and all but 1 patient had complete 48-hour transit data. All 48 randomized patients are included in the analyses with missing data from 1 patient imputed as described in the Statistical Analysis section. Figure 1 also summarizes patient demographics (age, sex, body mass index) by group. Gastric and Small-Bowel Transit The overall drug effect on enhancement of gastric emptying and small-bowel transit (estimated by the t1/2 and the percent colonic filling at 6 h, respectively, see Table 1) were not statistically significant among treatment groups (P ⫽ 0.24 and ⬎0.5, respectively). The tests for a linear dose response suggested (P ⫽ 0.088) shorter t1/2 gastric emptying times with increasing dose. An apparent stimulation of small-bowel transit is the result of the unusually prolonged gastric emptying t1/2

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Table 1. Baseline Colonic Transit (Geometric Centers at 24 and 48 Hours)

Placebo Renzapride, 1 mg Renzapride, 2 mg Renzapride, 4 mg

N

Baseline GC24 h

N

Baseline GC48 h

12 12 12 12

1.9 ⫾ 0.2 1.8 ⫾ 0.1 1.8 ⫾ 0.2 1.8 ⫾ 0.1

12 12 12 12

2.5 ⫾ 0.2 2.7 ⫾ 0.2 2.7 ⫾ 0.2 2.6 ⫾ 0.2

Posttreatment gastric, small-bowel, and colonic transit

Placebo Renzapride, 1 mg Renzapride, 2 mg Renzapride, 4 mg

N

GE t1/2 (min)

N

CF6 (%)

N

GC8a

N

GC24b

N

GC48

12 12 11 12

122 ⫾ 7 105 ⫾ 7 110 ⫾ 7 99 ⫾ 11

12 12 11 12

49 ⫾ 8 57 ⫾ 8 48 ⫾ 8 61 ⫾ 9

12 12 11 12

1.2 ⫾ 0.1 1.3 ⫾ 0.2 1.6 ⫾ 0.2 1.8 ⫾ 0.2c

12 12 12 12

1.9 ⫾ 0.3 1.9 ⫾ 0.1 2.1 ⫾ 0.2 2.4 ⫾ 0.2

12 12 12 12

2.8 ⫾ 0.4 3.1 ⫾ 0.3 3.2 ⫾ 0.3 3.3 ⫾ 0.3

NOTE. Data are expressed as mean ⫾ SEM. GE, gastric emptying t1/2; CF6, colonic filling at 6 h; GC, geometric center at 8 (GC8 h), 24 (GC24 h), and 48 (GC48 h) hours. aDenotes overall significance for renzapride vs. placebo for the transit parameters (P ⬍ 0.05). bTest for linear dose response, P ⫽ 0.056, analysis of covariance with baseline GC24 as covariate. cDenotes the difference (P ⬍ 0.05) for 4 mg renzapride vs. placebo (Dunnett’s test).

in the group randomly assigned to placebo, whose average t1/2 gastric emptying was about 20 minutes longer than reports from the same laboratory in healthy controls and in a separate cohort of patients with C-IBS,15 for any treatment or receiving placebo. Colon Transit and Ascending Colon Emptying A significant (linear) dose response to renzapride was detected for colonic transit (GC8 h, P ⫽ 0.004; GC24 h, P ⫽ 0.056; Figure 2A). Figure 2B is composed of scintigraphic images that pictorially show the effect of 4 mg of renzapride on colonic transit when compared with placebo. Inclusion of the baseline values of colonic transit as a covariate did not alter the results reported earlier. Similarly, a significant dose response was noted for AC emptying t1/2 (P ⫽ 0.019, Figure 3). The differences in AC t1/2 between placebo and 4 mg renzapride (median, 17.5 vs. 5.0 h, respectively) are clinically important. Colonic transit at 48 hours was not significantly different between the groups (Table 1). Satisfactory Relief of Irritable Bowel Syndrome Symptoms Satisfactory relief of IBS symptoms during the 2 weeks on treatment with renzapride or placebo is shown in Table 2. The effects of the drug were not statistically significant (Fisher exact test). Effects on Bowel Function Greater stool frequency and a looser stool consistency (Figure 4A) occurred in patients receiving

Figure 2. (A) The effect of renzapride on colonic transit summaries. Note that the dose-related effects of renzapride on colonic transit are shown most clearly in the GC8- and GC24-hour data. (B) These 2 sets of scintigraphic images were obtained from 2 different study patients—1 on placebo (top panel), and 1 on renzapride 4 mg (bottom panel). The left images are after 8 hours, and the right images are the 24-hour images for each individual. As these images show, renzapride accelerates movement of the radioisotope through the colon both at 8 and 24 hours, when compared with placebo.

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Figure 3. AC emptying t1/2 shown as the probability to empty 50% of the isotope in the defined time. Note that the 4-mg dose significantly accelerated AC emptying relative to placebo (P ⬍ 0.05), and the median t1/2 was shortened substantially by renzapride, particularly the 4-mg dose.

renzapride, but the tests for linear dose response were not statistically significant (P ⫽ 0.19 and 0.16 for stool frequency and consistency, respectively). Effect on ease of stool passage also was not significant (P ⫽ 0.20; Figure 4B). An overall assessment of bowel function in the composite stool score (incorporating stool frequency, consistency, and ease of passage) showed a similar pattern, with trends to improved symptoms of bowel function relative to placebo (P ⫽ 0.11 for linear dose effect). Improved bowel function scores (stool form and ease of passage, but not stool frequency) were significantly (P ⬍ 0.05) associated with accelerated colonic transit at 24 and 48 hours (Figure 5). Pharmacokinetics of Renzapride Pharmacokinetic data from 5 patients receiving renzapride were not available owing to technical reasons (sampling or assay problems). Renzapride was absorbed rapidly at all doses with an average Tmax of 1.5 ⫾ 0.42, 1.4 ⫾ 0.65, and 1.4 ⫾ 0.43 hours, and showed linear absorption kinetics with an average Cmax of 3.3 ⫾ 0.98, 7.7 ⫾ 2.65, and 15.3 ⫾ 2.98 ng/mL for the 1-, 2-, and 4-mg doses, respectively. Similar linearity was observed with the area under the concentration-time curve0 –24 (27.7 ⫾ 5.47, 61.1 ⫾ 15.76, and 118.6 ⫾ 29.97 (ng/

Figure 4. Stool frequency, (A) stool form, and (B) ease of passage in response to renzapride or placebo. Note the greater consistency (implying looser stools on average) and greater ease of passage with renzapride treatment.

mL) h, respectively). The average t1/2 was approximately 9.3 ⫾ 1.86, 9.6 ⫾ 4.14, and 10.1 ⫾ 2.33 hours, respectively, consistent with either once- or twice-daily dosing. Figure 6 shows a plot of the change in colonic transit (GC24 h) and peak systemic drug levels in response to renzapride. The filled symbols in Figure 6 identify patients who reported satisfactory relief of IBS symptoms at week 2 for all active dose groups. Note that the administered dose of renzapride influenced the plasma concentration at Tmax and that participants who reported satisfactory relief of IBS symptoms tended to have larger changes in colonic transit (higher positive values reflecting faster colonic transit). Thus, only 2 of 12

Table 2. Subjects Reporting Adequate Relief

Week 1 Week 2 Either week 1 or week 2

Placebo (n ⫽ 12)

1 mg (n ⫽ 12)

2 mg (n ⫽ 12)

4 mg (n ⫽ 12)

1/11 2/11 2/11

2/12 4/12 4/12

6/12 5/11 6/12

5/12 4/10 5/12

NOTE. Four patients failed to provide an indication of adequate relief (‘No’ or ‘Yes’) at week 1 or week 2, or both weeks; 1 subject receiving placebo failed to provide information. The results in the text of the statistical analysis are based only on patients with nonmissing data.

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Figure 5. Relationship between stool form or ease of stool passage and colonic transit estimated by the colonic GC24 hours (upper panels) and GC48 hours (lower panels).

patients with satisfactory relief had a negative change in the colonic geometric center at 24 hours with treatment, whereas 7 of 19 patients without satisfactory relief had a negative change in colonic transit with treatment. However, the overall correlation is relatively weak (r ⫽ 0.13) and marked interindividual variations in the pharmacokinetic and the pharmacodynamic responses are noted. Adverse Events Table 3 summarizes the adverse events. Note that there were no differences in total number and the nature of adverse events reported for each dose group and placebo. There were no significant ECG changes or changes in any other safety parameters. All adverse events were mild or moderate, and there were no severe adverse events. No patients discontinued the study after starting the study medication.

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once- or twice-daily dosing. We observed only a weak relationship between pharmacokinetic and pharmacodynamic parameters, and a fairly wide interindividual response to intake of the same dose for the primary pharmacodynamic end point. This suggests that pharmacokinetics cannot necessarily be used to predict pharmacodynamic responses when assessing the efficacy of an experimental therapy in gastrointestinal motility disorders. Thus, pharmacokinetic parameters may not adequately reflect the pharmacodynamic effects of locally active medications. We observed a statistically significant acceleration of overall colonic transit and particularly ascending colonic emptying. These findings generally confirm the prokinetic effects of renzapride21,22,40 and show that the effects of the drug on colonic transit are dose related. This pharmacodynamic study measured gastrointestinal and colonic transit after 2 weeks of treatment. Three phase II placebo-controlled trials of 8 –12 weeks duration have investigated the effects of renzapride on symptoms of IBS and bowel movement frequency in ⬎500 patients with C-IBS30,31 and in ⬎160 patients with alternating or mixed IBS symptoms (N. Meyers, unpublished communication). Thus, our pharmacodynamic observations are consistent with the overall effects of renzapride on the response to treatment of IBS noted in the first trials. The present study shows there is also a significant relationship between improved stool consistency and ease of passage and acceleration of colonic transit (Figure 5). This provides further information about the clinical ef-

Discussion This study documents the direct effects of renzapride on measured colon transit in patients with C-IBS. The study shows that there is a significant linear dose response in the acceleration of colonic transit by renzapride in patients with C-IBS. Our study also shows that the acceleration of transit is significantly associated with an improvement in stool consistency and ease of stool passage. However, clinical efficacy was not shown in this pharmacodynamic study with relatively small sample size. The pharmacokinetics of renzapride are linear in C-IBS patients, as previously noted in healthy subjects. The mean t1/2 of 10 hours also is consistent with either

Figure 6. Plot of change in colonic transit (GC24h) and peak systemic drug levels in response to renzapride. The filled symbols identify patients who reported satisfactory relief of IBS symptoms at week 2 (all dose groups). Data are not plotted for 5 patients. (In the 1-mg group, 1 patient had no pharmacokinetic data; in the 2-mg group, 1 patient did not answer the weekly relief question, and 1 nonresponder had no PK data; in the 4-mg group, 2 patients did not answer the relief question in week 2.)〫;, 1 mg; □, 2 mg; , 4 mg. , , , denoted responders for relief of IBS symptoms at week 2.




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Table 3. Adverse Events in Patients Taking Renzapride or Placebo Symptoms

Placebo (n ⫽ 12)

Renzapride, 1 mg (n ⫽ 12)

Renzapride, 2 mg (n ⫽ 12)

Renzapride, 4 mg (n ⫽ 12)

⬍3 AEs ⱖ3 AEs Headache Borborygmi Diarrhea Gas Abdominal cramps Nausea Vomiting Number of adverse events per participant

9 3 3 2 0 1 2 1 0 1.33 ⫾ 1.56

11 1 1 3 1 1 2 0 0 1.17 ⫾ 1.40

7 5 5 0 1 2 2 0 2 2.58 ⫾ 2.23

9 3 3 3 0 0 2 0 0 1.33 ⫾ 1.56

fects on bowel function associated with acceleration of colonic transit shown with the scintigraphic technique. The improvement in stool parameters and colonic transit shown in a pharmacodynamic study parallels the preliminary evidence of efficacy in normalizing bowel function observed in clinical trials in greater numbers of patients with C-IBS.30,31 The proportion of patients reporting satisfactory relief of IBS symptoms in our study was greater with 2- and 4-mg doses than with placebo and 1 mg of renzapride. Collapsing data across the 3 renzapride groups showed that treatment is potentially promising (P ⫽ 0.15 by Fisher exact test). However, our study was not powered to detect a significant difference in this clinical end point. Our study aimed to show a doserelated effect of renzapride on the primary pharmacodynamic end points, and this was achieved with the sample sizes deemed necessary before the study. Taken together, the data suggest that renzapride should be studied formally to assess its potential in the management of symptoms in patients with C-IBS. Accelerated colonic transit was not observed compared with the placebo group at the 48-hour mark, but this likely reflects the greater variation in the responses at 48 hours compared with 24 hours. This is shown by the larger SDs at 48 hours when the stool had a relatively greater distribution throughout the colon compared with earlier times when it was confined to the proximal colon (e.g., at 8 and 24 h). The effects of renzapride on transit profiles at 48 hours in patients with more significant constipation or in those associated with more severely delayed colonic transit need to be evaluated. The mechanism of the physiologic action of renzapride was not investigated in the present study. However, it is clear that renzapride is capable of markedly accelerating transit in the ascending colon. An effect of renzapride on high amplitude propagated contractions or clusters of contractions in the proximal colon might be suggested given the marked acceleration of transit (median ascending colon t1/2 with 4 mg of renzapride was 5 h compared

with 17.5 h with placebo). This hypothesis needs to be tested by means of intraluminal manometry. Moreover, the transit profile suggests that renzapride exerts its main propulsive effects via an action in the proximal colon in C-IBS patients. In previous reports, it also was shown that renzapride accelerated small-bowel transit.21,32,33,40 Acceleration of AC emptying may result from the delivery of large fluid volumes to the AC as might occur with osmotic loads to the small bowel41 or accelerated delivery of normal volumes from the small bowel. Thus, acceleration of small intestinal transit or small intestinal fluid and electrolyte secretion may have been postulated as the drivers of accelerated colonic transit. However, this seems unlikely given the fact that gastric and small-bowel transits were no different in our study of patients with C-IBS treated with renzapride compared with placebo. Previous studies have shown delayed proximal colon emptying in patients with disorders of lower gut function associated with constipation, such as idiopathic constipation.42 These data suggest that renzapride would be a useful agent for patients with delayed proximal colon emptying. Renzapride is a full agonist at 5-HT4 receptors, which are located on cholinergic neurons throughout the gastrointestinal tract. In vitro studies suggest that renzapride is not selective for 5-HT4 receptors because it also has affinity for and antagonizes 5-HT3 and 5-HT2b receptors. These pharmacodynamic studies show unequivocally that the predominant motor effect of this agent is to accelerate colonic transit. This is likely to result from stimulation of excitatory neurons, rather than an antagonistic effect on 5-HT3 receptors, which would be expected to retard colonic transit as previously observed with the agent alosetron in diarrhea-predominant IBS and carcinoid diarrhea43,44 using the same method. There is also a potential theoretical advantage of renzapride given its actions as a 5-HT3 receptor antagonist.

October 2004

Such receptors are considered important in mediating visceral afferent function.45– 48 Pharmacodynamic and clinical studies with renzapride to date have documented safety, its proposed mode of action has been characterized, and once-daily administration appears effective. As with all the colonic prokinetic agents, we perceive that appropriate patient selection is essential; specifically, the exclusion of pelvic floor disorders is important. Of the 77 patients screened in this trial, 8 had evidence for evacuation disorder and were excluded from drug randomization. In this subset of patients with obstructed defecation, rehabilitation and re-education of the pelvic floor is the favored therapy. It is not clear whether renzapride would be an effective treatment or whether it would accelerate transit in such patients. We chose to exclude such patients to avoid a potential error in the assessment of the drug’s effects in patients with C-IBS. In summary, renzapride causes dose-dependent acceleration of overall colonic transit and, particularly, AC emptying. Although accelerated emptying is associated significantly with improved bowel function in female patients with C-IBS, it is necessary to conduct further randomized controlled trials in these patients to assess clinical efficacy. The lack of significant changes in bowel function or satisfactory relief may be owing to a type II error in this study, which focused on pharmacodynamics and had a sample size aimed at showing pharmacodynamic, not clinical, efficacy. Given its effects on the colon, renzapride is likely to be of benefit to patients without rectal evacuation disorders. The possible use of this novel agent in patients with disordered transit through the upper gut, those with generalized gastrointestinal motility disorders causing delayed transit, and patients with colonic neuromuscular disorders causing constipation, needs to be addressed more fully.

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Address requests for reprints to: Michael Camilleri, M.D., Mayo Clinic, Charlton 8-110, 200 First Street SW, Rochester, Minnesota 55905. e-mail: [email protected]; fax: (507) 255-5720. Supported by Alizyme Therapeutics Ltd. (Cambridge, United Kingdom), in part by Mayo General Clinical Research Center grant #M01RR00585, and by grants R01 DK54681 and K24 DK02638 from the National Institutes of Health (to M.C.). The authors thank Richard Palmer and Nick Meyers (Alizyme Therapeutics Ltd.) for helpful discussion.