Aliment Pharmacol Ther 2001; 15: 1745±1751.
Tegaserod, a 5-HT4 receptor partial agonist, accelerates gastric emptying and gastrointestinal transit in healthy male subjects L. D EGEN*, D. M ATZINGER *, M. MERZà, S. APPEL-DIN GEMAN SEà, S. OSBORNEà, S. LUÈ CH INGER*, R. BERTOLD *, H. MAECKE & C. BEGLINGER * *Division of Gastroenterology and Department of Nuclear Medicine, University Hospital, Basel, Switzerland; and àNovartis Pharma AG, Basel, Switzerland Accepted for publication 20 April 2001
SUMMARY
Background: Serotonin and its type-4 (5-hydroxytryptamine4) receptor play a major role in the physiology of the gastrointestinal tract. The effect of intravenous and/ or oral tegaserod, a 5-hydroxytryptamine4 receptor partial agonist, on gastric emptying, small bowel transit and colonic transit has not been studied in detail in humans. Aim: To assess the pharmacodynamic effects of repeated oral and intravenous administration of tegaserod on gastric emptying and small intestine and colonic transit. Methods: A randomized, placebo-controlled, doubleblind, three-way, crossover study of 6 mg oral and 0.6 mg intravenous tegaserod in 12 healthy male
INTRODUCTION
Recently, increasing evidence has indicated that serotonin type-4 (5-hydroxytryptamine4, 5-HT4) receptors play a signi®cant role in the maintenance of diverse gastrointestinal functions. The advent of innovative 5-HT4 receptor agonists, such as tegaserod (HTF919), has demonstrated that stimulation of 5-HT4 receptors can trigger the peristaltic re¯ex in animal and human gastrointestinal tract.1, 2 Preclinical studies have also demonstrated the stimulatory effect of 5-HT4 receptor activation on intestinal electrolyte/water secretion.3, 4 Correspondence to: Dr C. Beglinger, Division of Gastroenterology, University Hospital, CH-4031 Basel, Switzerland. E-mail:
[email protected] Ó 2001 Blackwell Science Ltd
subjects was performed. Each treatment arm of the study involved 3 days of twice-daily administration and 1 day of daily administration of the study drugs. Results: In comparison with placebo, oral and intravenous tegaserod signi®cantly increased the gastric emptying rate (P < 0.01), accelerated colonic ®lling (P < 0.01) and shortened colonic transit at 48 h (P < 0.05). Tegaserod shortened the small intestine transit time by 30% after oral and by 37% after intravenous administration. Conclusions: In healthy subjects, tegaserod markedly accelerated gastric emptying and small intestinal transit, and induced a small but signi®cant acceleration of colonic transit. Tegaserod can act as a promotile agent throughout the gastrointestinal tract.
Moreover, recent studies in cats and rats have shown that tegaserod at high doses can reduce afferent ®ring, suggesting that the compound can modulate 5-HT4 receptors.5, 6 Tegaserod (3-(5-methoxy-1H-indol-3-ylmethylene)N-pentyl-carbazimidamide) hydrogen maleate has been designed to selectively stimulate 5-HT4 receptors in the gastrointestinal tract.7, 8 It is a representative of a new chemical class of compound, aminoguanidine indoles, and is currently under clinical development for the treatment of irritable bowel syndrome with the symptoms of abdominal pain, bloating and constipation. Both preclinical and clinical investigations have shown that the 5-HT4 partial agonist, tegaserod, can stimulate motility throughout the gastrointestinal tract.9±13 Along the same lines, prucalopride (another 5-HT4 1745
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receptor agonist) has been shown to be ef®cacious in patients with constipation and in patients with constipation-predominant irritable bowel syndrome.14, 15 However, no detailed information is available on the effect of intravenous and/or oral tegaserod on gastric emptying, small bowel transit and colonic transit in healthy subjects. The present study was conducted to assess the pharmacodynamic effects of repeated intravenous administration vs. multiple oral doses of tegaserod on gastric emptying and gastrointestinal transit in healthy male subjects. In addition, the safety and pharmacokinetics of the compound were evaluated. MATERIALS AND METHODS
Patients Twelve healthy, non-smoking, male Caucasian subjects with a mean age s.d. of 39 7 years, a mean height s.d. of 180 8 cm and a mean body weight s.d. of 88 8 kg were included in the study. The weight of all subjects was within ±15 to + 15% of normal for their height and frame size, according to the Metropolitan Life Insurance table. The study protocol was approved by the Human Ethics Committee of the University Hospital in Basel and all subjects gave their written informed consent. Every subject was required to complete a medical interview, received a full physical examination and participated in an initial laboratory screening prior to inclusion in the study. None of the subjects included were receiving any medication or had any history of gastrointestinal disorders, food allergies or dietary restrictions. Study design This study employed a randomized, placebo-controlled, double-blind, double dummy, three-way, crossover design in which two subjects received treatment with three different treatment regimens in six different treatment sequences (Figure 1). The different treatment regimens consisted of: regimen 1, a twice-daily regimen for 3 days and a daily regimen on the fourth day of 0.6 mg tegaserod administered as an intravenous infusion given over 2 h and one placebo tablet; regimen 2, a twice-daily regimen for 3 days and a daily regimen on the fourth day of an oral administration of 6 mg tegaserod and an intravenous infusion of physiological saline given over 2 h; regimen 3, a twice-daily regimen
Figure 1. Schedule of drug administration to subjects enrolled in the study. Two subjects were enrolled into each of the six treatment arms. i.v., intravenous; p.o., per os (oral administration).
for 3 days and a daily regimen on the fourth day of an oral placebo tablet and an intravenous infusion of physiological saline given over 2 h. Drug administration was at a ®xed time and morning doses were given between 07.30 hours and 09.00 hours after fasting for at least 10 h. The study subjects stayed in the study centre for 24 h before and until 48 h after the last administration. During that period, they were not permitted to drink alcoholic drinks and ate only a standard diet. In the outpatient periods, subjects were offered standard meals to maintain consistency of diet as far as possible. Treatment periods were separated by a 7-day washout period. The oral dose was chosen to be the projected therapeutic dose of 6 mg b.d. for the treatment of irritable bowel syndrome, while the intravenous dose was selected on the basis of pharmacokinetic simulation results, which suggested that similar plasma concentration±time curves as compared to the 6 mg oral dose would be achieved. Gastric emptying, small bowel transit and colonic transit were measured starting on the second day of each treatment period. In addition to transit parameters, subjects were provided with a patient diary to record the time and consistency (based on a scale from 1 hard to 4 watery) of every bowel movement to permit the calculation of average stool frequency and average stool consistency for each period. Blood (5 mL) was drawn at regular intervals up to 24 h after the ®rst and after the last dose in each treatment period from a forearm vein into lithium-heparinized tubes for the determination of tegaserod concentrations in plasma. Samples were immediately centrifuged at 4 °C, procÓ 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1745±1751
PROKINETIC EFFECTS OF TEGASEROD
essed and stored at ±20 °C pending analysis. Safety assessments included physical examination, vital signs, head-up tilt, electrocardiogram, laboratory evaluations, local tolerability at the infusion site and adverse event monitoring. Plasma concentrations of tegaserod were analysed using a gas chromatography/mass spectrometry method with negative chemical ionization (limit of detection, 0.1 ng/mL) as described previously.16 Pharmacokinetic parameters were calculated using standard non-compartmental methods.17 Measurement of gastrointestinal transit Gastric, small bowel and colonic transit were measured by the non-invasive scintigraphic method developed at the Mayo Clinic.18 In short, polystyrene Amberlite 120IR-Plus resin pellets (average diameter, 1 mm; range, 0.5±1.8 mm) were labelled with 100 lCi of 111InCl3.19 The ef®ciency of labelling was > 98%, as judged by thin layer chromatography.20 A capsule ®lled with approximately 0.5 g pellets (markers) and coated with one layer of methacrylate was given to the fasting subjects. The capsule dissolved in the ileocaecal region;20 accordingly, transport of the 111InCl3 marker was used to assess ileocaecal transfer and colonic transit. External radioactive markers were placed over both anterior superior iliac spines to estimate the location of the capsule. As soon as the radiolabelled capsule passed into the small bowel, a breakfast was ingested within 10 min, consisting of one scrambled egg, one piece of wholewheat bread and milk. The scrambled egg was mixed and cooked with 1 mCi of 99mTc-labelled Amberlite 410 resin pellets (average diameter, 1 mm) to a ®rm consistency to provide a solid medium. Gamma-camera imaging started immediately after completion of ingestion of the radiolabelled meal with a large ®eld-of-view gamma-camera with a medium energy, parallel hole collimator. Anterior and posterior images were obtained with the subject erect at the following time points: 0, 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 240, 300, 360, 480, 1440 and 2880 min. For the 99mTc counts and for the 111In counts, 140 keV and 245 keV energy windows (each with 10% window), respectively, were used. The estimated whole body dose equivalent was 130 mrem. Images were obtained at regular intervals up to 48 h after ingestion of the labelled meal and, for each image, 2 min of acquisition was selected. Using variable Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1745±1751
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regions of interest, the radioactivity was quanti®ed in the stomach. The geometric means of the counts obtained from the anterior and posterior images were calculated for each region and then corrected for radionuclide decay. The downscatter of 111In into the 99m Tc window was adjusted. Four hours after breakfast, a standardized non-radiolabelled lunch, and 8 h after breakfast, a dinner, were consumed. Gastric emptying curves were de®ned by the gastric lag time (lag phase) and post-lag emptying rate and the area under the percentage±time curve (AUC). The gastric lag time (min) analysed by the time±activity curve was the time taken for 10% of radiolabel to empty from the stomach.21 The gastric post-lag emptying rate (%/min) was characterized as the slope estimated by the linear regression analysis of the data points from the ®rst point beyond the lag time until the time when 90% of the radiolabel had emptied from the stomach.20 AUC was calculated by the linear trapezoidal rule from T 0 min to the time point when 90% of the radiolabel had emptied from the stomach. The small bowel transit time was calculated by subtracting the time for 10% of the isotope to empty from the stomach from the time taken to enter the colon. 22, 23 The overall colonic transit was analysed by the geometric centre method at 4, 6, 8, 24 and 48 h.20 This consisted of the weighted average of proportions of counts in four designed regions of interest of the colon. The regions were given the following weighting factors: ascending colon (1), transverse colon (2), descending colon (3) and rectosigmoid colon (4), respectively. The stool was designated ®ve. The proportion in each indicated region was multiplied by the weighting factor and the sum was calculated. A low geometric centre value suggested that the majority of the radiolabel was recovered closer to the caecum, whereas a high value indicated that the major part of the radiolabel was detected closer to the stool. Colonic ®lling was calculated as described previously.13, 18 Statistical analyses Data are presented as the mean S.E.M. unless speci®ed otherwise. The differences in pharmacodynamic measurements among treatments (gastric emptying, gastrointestinal transit, stool frequency, stool consistency) were analysed by an analysis of variance (ANOVA) model for a six-sequence, three-period, crossover design. P values of less than 0.05 were accepted as statistically
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signi®cant. Daily stool frequency and average stool consistency measurements were analysed using an ANOVA for the effect sequence, subject within sequence, period and treatment. RESULTS
The analysis of covariance (ANCOVA) revealed that the sequence in which the subjects underwent the three treatments had no signi®cant in¯uence on the variables measured. Pharmacokinetics The pertinent summary single-dose pharmacokinetic parameters of tegaserod after intravenous infusion of 0.6 mg over 2 h or oral administration of 6 mg as a tablet are given in Table 1. Tegaserod was rapidly absorbed with measurable plasma concentrations about half an hour after oral drug intake (data not shown). Maximum plasma concentrations were reached about 2 h after oral administration. Maximum plasma tegaserod concentrations and AUC after intravenous administration were approximately double those observed following oral administration. Multiple-dose tegaserod pharmacokinetic parameters were similar to those observed after a single dose and indicated the absence of drug accumulation. This is in agreement with previously published data on tegaserod.16
(P < 0.01 vs. placebo), respectively. Figure 2 further illustrates the gastric emptying data. There was a signi®cant acceleration of the rates of gastric emptying (P < 0.001 vs. placebo), which was con®rmed by a decrease in the area under the curve (gAUC) after both oral and intravenous tegaserod (Table 2). Gastric emptying parameters were statistically not signi®cantly different following administration of tegaserod by the oral or intravenous route. Small bowel transit Both oral and intravenous tegaserod had a marked, statistically signi®cant effect on the small bowel transit time compared with placebo. Times were shortened by 30% after oral tegaserod and by 37% after intravenous tegaserod (P < 0.05 vs. placebo; Table 2). Colonic transit Oral and intravenous tegaserod produced a statistically signi®cant acceleration of proximal colonic ®lling compared with placebo (P < 0.01 and P < 0.001, respectively; Table 2). Transit through the colon was slightly faster with tegaserod, as both oral and intravenous administration induced a geometric centre shift to higher values after 24 h, which was statistically signi®cant after 48 h in comparison to placebo (P < 0.01 and P < 0.05, respectively; Table 2).
Gastric emptying For placebo, the mean gastric lag time for solid emptying was 38.1 min. After the lag phase, the emptying curve approximated a linear pattern (Figure 2, Table 2). With oral or intravenous tegaserod, the mean gastric lag time was statistically signi®cantly shortened by 27% (P < 0.05 vs. placebo) and by 38%
Table 1. Pharmacokinetic parameters after a single oral (6 mg) or intravenous (0.6 mg given as a 2 h infusion) administration of tegaserod in 12 healthy male subjects (data are means S.E.M.)
Cmax (ng/mL) AUC0±tz (h.ng/mL)
Intravenous tegaserod (0.6 mg)
Oral tegaserod (6 mg)
1.96 0.16 3.65 0.33
0.90 0.16 1.73 0.33
Figure 2. Effect of oral and intravenous tegaserod on gastric emptying of a solid meal in comparison with placebo in 12 healthy male subjects (data are means s.e.). Area under the curve (AUC) for oral and intravenous tegaserod signi®cantly different from placebo, P < 0.05. Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1745±1751
PROKINETIC EFFECTS OF TEGASEROD Table 2. Effect of oral and intravenous tegaserod on gastric emptying, small bowel transit and colonic transit parameters in comparison to placebo in 12 healthy male subjects (data are means S.E.M.)
Gastric emptying parameters Gastric lag time (min) Gastric emptying rate (%/min) gAUC0±6 h
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Placebo
Intravenous tegaserod (0.6 mg)
38.1 5.2 0.3 0.03 14169 1066
23.6 3.0 27.8 3.4* 0.5 0.04 0.5 0.04 10256 615 10808 586
Small bowel/colonic transit parameters SBTT (min) 155 25 GC at 24 h 2.8 0.2 GC at 48 h 4.4 0.1 Colonic ®lling (AUC0±6 h) 4770 749
98 16* 3.2 0.3 4.7 0.1* 8618 1129à
Oral tegaserod (6 mg)
108 20* 3.1 0.2 4.7 0.1 7049 886
GC, geometric centre; SBTT, small bowel transit time. *P < 0.05 vs. placebo. P < 0.01 vs. placebo. àP < 0.001 vs. placebo.
Bowel movements Baseline stool frequency and consistency were comparable for all treatments. Average bowel movements per treatment period increased slightly during both oral and intravenous tegaserod, but the results were statistically not signi®cantly different from placebo (data not shown). When analysed per study day, oral tegaserod increased mean stool frequency in comparison with placebo and intravenous tegaserod on study day 1 (2.3 vs. 1.4 and 1.4, respectively) and the difference approached statistical signi®cance (P 0.0502 for both comparisons). DISCUSSION
The major new ®ndings in this study were that, in healthy male subjects, tegaserod, a 5-HT4 receptor partial agonist, markedly accelerated gastric emptying and shortened intestinal and colonic transit times following oral as well as intravenous administration. The data suggest that tegaserod could have potent promotile effects in both the upper and lower gastrointestinal tract. Data in patients with gastroparesis are not yet available, but the results of the current study warrant the testing of tegaserod in this population. No comparative studies with cisapride, a gastroprokinetic agent, are available. However, cisapride, a mixed 5-HT4 receptor agonist/5-HT3 receptor antagonist, has not been shown to have a consistently signi®cant effect on gastric emptying in healthy subjects.24, 25 This comparison may not be possible because cisapride Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1745±1751
may no longer be available in many countries due to effects on cardiac repolarization.26 Our results show that tegaserod accelerates small bowel transit. This potent promotile effect has recently been con®rmed in irritable bowel syndrome patients by Prather et al., who reported that oral tegaserod, 2 mg b.d. for 1 week, accelerated small intestinal transit (in a randomized, double-blind, placebo-controlled trial in patients with constipation-predominant irritable bowel syndrome).13 Prather et al.13 also observed that tegaserod, 2 mg b.d., decreased colonic transit time compared with placebo treatment, an effect which might have been due to increases in proximal colonic emptying (as quanti®ed by scintigraphy). The differences between the results obtained in the current study and those reported by Prather et al. may be explained by the fact that irritable bowel syndrome patients (mostly women) were investigated by Prather et al., whereas the current study investigated healthy male subjects. Experiments with dogs showed a signi®cant acceleration of proximal colonic transit.9 In an exploratory study in healthy subjects, in whom colonic transit was prolonged by a speci®c diet (liquid formula diet with ®bre supplementation), oral tegaserod, 5 mg capsules b.d., signi®cantly shortened colonic transit time assessed by radio-opaque markers.11 The present study with tegaserod, 0.6 mg intravenously over 2 h b.d. or 6 mg tablets b.d., has documented a small, albeit signi®cant, effect on colonic ®lling and on colonic transit time. The ®ndings are compatible with the idea that the effect of tegaserod is rather more on the proximal part of the colon, which is in agreement
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with preclinical observations.9, 27 At this stage, we cannot exclude the possibility that the effect of tegaserod on colonic transit is primarily due to an accelerated entry of contents into the ascending colon, an effect which has been known for many years to accelerate colonic transit. Although no direct comparisons with other promotile agents have been made, the magnitude of the effects of tegaserod on gastric emptying and transit in the current study, compared with those exerted by promotile agents available so far, suggests that there may be a signi®cant pharmacodynamic advantage for tegaserod. None of the current agents is particularly effective in stimulating small bowel motility. The present study was designed so that the exposure to tegaserod after oral or intravenous administration would be similar. Using a computer simulation, a dose of 0.6 mg tegaserod given by intravenous infusion over 2 h was chosen to have a similar pharmacokinetic pro®le to the 6 mg tablet. However, in this study, the plasma concentration±time pro®les were not superimposable for the oral and intravenous administration of tegaserod, with lower systemic exposure to the drug occurring after oral administration. These ®ndings may suggest that the higher plasma concentrations observed after intravenous administration are not necessary to induce the pharmacodynamic effects on gastrointestinal motility. Detailed dose±response studies will be necessary to answer this question. The stimulatory effect of tegaserod on gastrointestinal motor function is thought to be mediated by the activation of 5-HT4 receptors. Thorough preclinical investigation has revealed that tegaserod stimulates the release of speci®c neurotransmitters, such as calcitonin gene-related peptide, substance P and vasoactive intestinal peptide, from human jejunal segments and stimulates peristaltic re¯exes in vitro.1 Tegaserod enhances propulsive activity in guinea pig colonic segments, mirrored by the increase in transit rate of arti®cial faecal pellets.2 In conclusion, tegaserod, a 5-HT4 receptor partial agonist, markedly accelerated gastric emptying, as well as small intestinal transit, and induced a small, but statistically signi®cant, acceleration of colonic transit in healthy male subjects. The data suggest that tegaserod may potentially offer signi®cant advantages over currently available promotile drugs in the treatment of functional motility disorders.
ACKNOWLEDGEMENTS
We thank Luisa Baselgia, Rebekka Surbeck and Gerdien Gamboni for expert technical assistance and Carita Frei for excellent editorial assistance. This study was supported by Novartis Pharma AG, Basel, Switzerland. REFERENCES 1 Grider JR, Foxx-Orenstein AE, Jin JG. 5-Hydroxytryptamine4 receptor agonists initiate the peristaltic re¯ex in human, rat, and guinea pig intestine. Gastroenterology 1998; 115(2): 370±80. 2 Jin JG, Foxx-Orenstein AE, Grider JR. Propulsion in guinea pig colon induced by 5-hydroxytryptamine (HT) via 5-HT4 and 5-HT3 receptors. J Pharmacol Exp Ther 1999; 288(1): 93±7. 3 Burleigh DE, Borman RA. Short-circuit current responses to 5-hydroxytryptamine in human ileal mucosa are mediated by a 5-HT4 receptor. Eur J Pharmacol 1993; 241: 125±8. 4 Kellum JM, Albuquerque FC, Stoner MC, Harris RP. Stroking human jejunal mucosa induces 5-HT release and Cl± secretion via afferent neurons and 5-HT4 receptors. Am J Physiol 1999; 277(3 Part 1): G515±20. 5 Schikowski A, Mathis C, Thewissen M. Dose-dependent modulation of rectal afferent sensitivity by a 5-HT4 receptor agonist. Gastroenterology 1999; 116: A643(Abstract). 6 Coelho AM, Rovira P, Fioramonti J, Bueno L. Antinociceptive properties of HTF 919 (tegaserod), a 5-HT4 receptor partial agonist, in a rat model of colorectal distension. Gastroenterology 2000; 118(4 Suppl. 2): A4393(Abstract). 7 Buchheit KH, Gamse R, Giger R, et al. The serotonin 5-HT4 receptor. 1. Design of a new class of agonists and receptor map of the agonist recognition site. J Med Chem 1995; 38: 2326±30. 8 Pfannkuche HJ, Buhl T, Gamse R, et al. The properties of a new prokinetically active drug, SDZ HTF 919. Neurogastroenterol Motil 1995; 7: 280. 9 Nguyen A, Camilleri M, Kost LJ, et al. SDZ HTF 919 stimulates canine colonic motility and transit in vivo. J Pharmacol Exp Ther 1997; 280(3): 1270±6. 10 Fioramonti J, Million M, Bueno L. Investigations on a 5-HT4 agonist (SDZ HTF 919) and its main metabolite in conscious dogs: effects on gastrointestinal motility and impaired gastric emptying. Gastroenterology 1998; 114: A752: G3103. 11 Appel S, Kumle A, Hubert M, Meier R. Clinical pharmacodynamics of SDZ HTF 919, a new 5-HT4 receptor agonist, in a model of slow colonic transit. Clin Pharmacol Ther 1997; 62: 546±55. 12 Degen LP, Matzinger D, Merz M, et al. Tegaserod (HTF 919) a 5-HT4 receptor partial agonist accelerates gastrointestinal (GI) tract. Neurogastroenterol Motil 2000; 12(4): 382. 13 Prather CM, Camilleri M, Zinsmeister AR, McKinzie S, Thomforde G. Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome. Gastroenterology 2000; 118: 463±8. Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1745±1751
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