Integrated modelling of the clinical pharmacokinetics of SDZ HTF 919, a novel selective 5‐HT₄ receptor agonist, following oral and intravenous administration

Abstract

AimsThe purpose of the present study was to assess the pharmacokinetics of the novel selective 5-HT 4 receptor agonist SDZ HTF 919 (HTF) including food effect, absolute bioavailability, interoccasion and intersubject variabilities. Methods In the randomized, open-label, three treatment, four period crossover study, HTF was administered to 12 young healthy male subjects as a 12 mg tablet (twice under fasted and once under fed conditions) and a 3 mg intravenous (i.v.) infusion over 40 min (fasted). Pharmacokinetic parameters were obtained by noncompartmental methods. A more comprehensive pharmacokinetic characterization was achieved by integrated modelling of oral ( p.o.) and i.v. data. To describe the absorption phase a Weibull function and a classical first order input function were compared. Results Noncompartmental pharmacokinetic analysis revealed a rapid absorption (t max 1.3 h, fasted), an absolute bioavailability of 11±3%, a biphasic disposition phase with a terminal half-life of 11±5 h, a clearance of 77±15 l h −1 , and a volume of distribution at steady state of 368±223 l. The coefficients of interoccasion and interindividual variability in C max and AUC ranged between 17 and 28%. Food intake caused a delay (t max 2.0 h) and decrease in absorption with consequently lower systemic exposure (#5% absolute bioavailability). Integrated p.o./i.v. pharmacokinetic modelling with a Weibull input function allowed accurate description of individual profiles. Modelling of the data from the p.o. dosing improved the description of the terminal phase by inclusion of the i.v. data and additionally provided quantitative characterization of the absorption phase. Conclusions The pharmacokinetics of HTF could be well described by an integrated modelling approach for both p.o. and i.v. data. The derived model will provide guidance in the design of future studies.

Desensitization of the peristaltic reflex induced by mucosal stimulation with the selective 5-HT4agonist tegaserod

“…The desensitizing effect of tegaserod was detectable at concentrations as low as 5 nM, increasing with higher concentrations up to 5 M. A previous study (18) had shown that the addition of tegaserod to the mucosa elicited ascending contraction and descending relaxation with an EC 50 of 2-5 nM; maximal response was obtained with 0.1-1 M. Similarly, intraluminal perfusion of isolated colonic segments with tegaserod increased the velocity of propulsion of fecal pellets with an EC 50 of 7 nM (22). Maximal increase in propulsive activity was observed at concentrations of 0.1-1 M. Considering that in human studies (2,7), about two-thirds of the oral dose of tegaserod is excreted unchanged in the feces, it is likely that the colonic mucosa is exposed to concentrations similar to that used in the present study. This also suggests that addition of tegaserod to the mucosa as in the present study is likely to reflect a major route by which the colon lumen is exposed to tegaserod after oral administration.…”

“…Because tegaserod is poorly absorbed, two-thirds of the orally administered dose is eliminated unchanged in the feces (2,7). It is likely that high concentrations may be expected to prevail in the lower intestine and colon that could blunt the response to tegaserod by inducing rapid and long-lasting desensitization of the peristaltic reflex similar to that seen in the present study.…”

The rationale, efficacy and safety evidence for tegaserod in the treatment of irritable bowel syndrome

“…The most detailed published data derive from a randomised crossover study [78], in which the drug was taken by 12 young healthy male subjects as a 12 mg tablet, both under fasted and fed conditions, or a 3 mg intravenous infusion showed that the oral agent was rapidly absorbed, and plasma concentrations peaked after about 1.3 h, with a half-life of 11 h for the intravenous route. The data demonstrated absolute bioavailability of 11+/-3%.…”

Determination of tegaserod by LC–ESI-MS/MS and its application to a pharmacokinetic study in healthy Chinese volunteers

“…The precision was calculated by using one-way ANOVA. The evaluation of precision was based on the criteria [4] that the relative standard deviation for each concentration level should not be more than ±15% except for the LLOQ, for which it should not be more than ±20%. Similarly, for accuracy, the mean value should not deviate by ±15% of the actual concentration except for the LLOQ where it should not deviate by more than ±20% of the actual concentration.…”

“…Plasma concentrations of tegaserod were analyzed using a gas chromatography/mass spectrometry method with negative chemical ionization (limit of detection, 0.1 ng/ml) [4].…”