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

Aims The purpose of the present study was to assess the pharmacokinetics of the novel selective 5-HT4 receptor agonist SDZ HTF 919 (HTF) including foo d effect, absolute bioavailability, interoccasion and intersubject variabil ities. Methods In the randomized, open-label, three treatment, four period crossov er 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 intra venous (i.v.) infusion over 40 min (fasted). Pharmacokinetic parameters wer e obtained by noncompartmental methods. A more comprehensive pharmacokineti c characterization was achieved by integrated modelling of oral (p.o.) and i.v. data. To describe the absorption phase a Weibull function and a classi cal first order input function were compared. Results Noncompartmental pharmacokinetic analysis revealed a rapid absorpti on (t(max) 1.3 h, fasted), an absolute bioavailability of 11 +/- 3%, a biph asic disposition phase with a terminal half-life of 11 +/- 5 h, a clearance of 77 +/- 15 1 h(-1), and a volume of distribution at steady state of 368 +/- 223 l. The coefficients of interoccasion and interindividual variabilit y 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 ex posure (approximate to 5% absolute bioavailability). Integrated p.o./i.v. p harmacokinetic modelling with a Weibull input function allowed accurate des cription of individual profiles. Modelling of the data h om the p.o. dosing improved the description of the terminal phase by inclusion of the i.v. da ta and additionally provided quantitative characterization of the absorptio n phase. Conclusions The pharmacokinetics of HTF could be well described by an integ rated modelling approach for both p.o. and i.v. data. The derived model wil l provide guidance in the design of future studies.