First Pharmacokinetic—Pharmacodynamic Study in Humans with a Selective 5‐Hydroxytryptamine₄ Receptor Agonist

Abstract

This report describes the first study in humans with SDZ HTF 919 (HTF), a novel, selective 5-hydroxytryptamine4 (5-HT4) receptor partial agonist and investigates its tolerability, pharmacokinetics, and pharmacodynamics. Three cohorts of 12 men, of whom 8 were treated with active drug and 4 with placebo, participated in the double-blind, randomized, parallel-group, ascending-dose study. A single dose and subsequently twice-daily multiple doses of 25, 50, and 100 mg were given for 14 days. Adverse events, clinical laboratory variables, electrocardiogram, vital signs, and psychometric effects were recorded. Basic pharmacokinetic characteristics of HTF were derived. Loose stool and total colonic transit time were assessed. Mild to moderate adverse gastrointestinal events, predominantly loose stools, occurred at all dose levels and reflect the pharmacologic properties of HTF. The incidence of headache increased with dose. Dose-normalized (to 25 mg) systemic exposures were 25 +/- 12, 19 +/- 11, and 26 +/- 10 hr.ng/mL in single doses and 26 +/- 12, 23 +/- 12, and 33 +/- 12 hr.ng/mL in multiple doses for the three doses. Steady-state concentrations of HTF were reached after 8 days of daily administration and moderate accumulation was observed. Loose stool occurred on average between 2 and 4 hours after drug administration. The overall HTF-mediated median decrease from baseline (26 and 38 hours) in total colonic transit time was 4.8 hours, versus 1.8 hours with placebo. In conclusion, the novel 5-HT4 receptor agonist HTF was tolerated at oral doses of 25 mg to 100 mg administered twice daily. Pharmacokinetics in both single and multiple doses indicate no deviation from dose proportionality. The applicability of the total colonic transit time as a measurement of surrogate prokinetic effect warrants further investigation in patient populations.

Drugs Acting on the Gut: Prokinetics, Antispasmodics, Laxatives

“…Bioavailability is 11% and decreased by up to 65% when taken with food [ 79,80 ] . It is metabolized in the liver and 66% is excreted unchanged in stool and 33% as metabolites in urine.…”

Tegaserod: Long-Term Treatment for Irritable Bowel Syndrome Patients with Constipation in Primary Care

“…Therefore, it might be hypothesized that patients who previously responded to the withdrawn drug cisapride, a 5-HT 4 receptor agonist with other modes of action differing from tegaserod, e.g. 5-HT 3 receptor antagonist, M 2 muscarinic agonist activities [31], might be particularly likely to respond to tegaserod. Subgroup analyses demonstrated that tegaserod significantly improved IBS-C symptoms, whether or not patients had previously received and responded to cisapride.…”

Hiperalgesia visceral e dor abdominal crônica: abordagem diagnóstica e terapêutica

“…Drogas como antiespasmódicos, supressores ácido-pépticos e procinéticos não são freqüentemente úteis. Recentemente, entretanto, novas drogas com efeitos antiespasmódicos e antinociceptivos têm sido instituídas no arsenal terapêutico da dor abdominal inespecífica, tais como a mebeverina e o tegaserode, utilizadas na síndrome do intestino irritável 20,21,24,25 . Contudo, faz-se necessária uma abordagem multidisciplinar do paciente:…”

“…Drugs such as antispasmodics, peptic and prokinetic acid suppressors are not frequently useful. Recently, however, new drugs with antispasmodic and antinociceptive effects have been included in the therapeutic armamentarium for nonspecific abdominal pain, such as mebeverine and tegaserode, used in irritable bowel syndrome 20,21,24,25 . Amultidisciplinary approach of the patient is however needed: 1) Antidepressants -to decrease visceral hypersensitivity; 2) Direct sodium channel blocker antispasmodic and partial selective 5-HT4 agonist; 3) Anxiolytics -with limited use duration; 4) Central action analgesics -opioid -for severe and disabling pain; 5) Psychotherapy; · Especially indicated for patients with physical or sexual abuse history or any other environmental trauma;…”

“…· Tegaserode maleate (Zelmac) 24,25 : partial and selective 5-HT4 receptors agonist located in nervous terminations of neurons with calcitonin gene related peptide (CGRP), which send sensory stimulations to interneurons coupled to motor neurons. Tegaserode agonist effect stimulates bowel movements, gastric emptying and small intestine motility and increases colon motility.…”