Concomitant use of imatinib and rifampicin or other potent inducers of CYP4503A may result in subtherapeutic plasma concentrations of imatinib. In patients in whom rifampicin or other CYP3A inducers are prescribed, alternative therapeutic agents with less potential for enzyme induction should be selected.

Purpose To evaluate the safety and maximum-tolerated dose (MTD) of weekly patupilone, a natural epothilone B, in patients with advanced solid tumors. Patients and Methods Patients were treated with patupilone (0.3 to 3.6 mg/m2) for 6 weeks on/3 weeks off or 3 weeks on/1 week off. Dose-limiting toxicities (DLTs), MTD, and pharmacokinetics were determined for each schedule of administration. Results Ninety-one patients were enrolled. The most common tumor types included ovarian, breast, and colon cancers. Doses of patupilone less than 2.5 mg/m2 using either the 6 weeks on/3 weeks off or the 3 weeks on/1 week off schedule were tolerated well. At higher doses, DLTs were observed using both dosing schedules, with diarrhea the most common DLT. The MTD for both treatment schedules was 2.5 mg/m2. After a short infusion, patupilone blood concentrations declined in a multiphasic manner with a terminal half-life of 4 days. Drug clearance was nonrenal and was not related to body-surface area. Over the dose range evaluated, systemic drug exposure was approximately dose proportional. Three patients achieved a partial response, and 31 patients had stable disease. Two patients experiencing a partial response had received prior taxane therapy. Conclusion Patupilone is well tolerated when administered at a dose of 2.5 mg/m2, using either a 6 weeks on/3 weeks off or a 3 weeks on/1 week off schedule. In contrast with murine studies, patupilone has a relatively prolonged terminal half-life in humans. The partial responses in patients previously treated with taxanes is consistent with promising preclinical results.

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.

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.