The gefitinib 250 mg tablet is orally bioavailable in both healthy volunteers and cancer patients; bioavailability is independent of dose and unaffected by food to any clinically significant extent. Gefitinib undergoes rapid plasma clearance and has an extensive volume of distribution, resulting in a pharmacokinetic profile supportive of a once-daily dosage regimen.
Needle length and intramuscular injection are not absolute requirements for autoinjector efficacy, but the monitoring of injection location, biphasic adrenaline levels, and cardiovascular responses is important for the assessment of their therapeutic relevance in anaphylaxis.
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.
Objective: The aim of this study was to investigate the effects of a potent CYP3A4 inducer, rifampicin (Study A), and a potent CYP3A4 inhibitor, itraconazole (Study B), on the pharmacokinetics of a single 300mg dose of vandetanib in healthy subjects.Study Design and Setting: Two phase I, randomized, open-label, two-way crossover, single-center studies. Participants and Intervention: Study A: 18 healthy male subjects aged 21–44 years were randomized to receive each of the following two regimens, separated by a ≥6-week washout period: (i) oral rifampicin 600mg/day on days 1–31 with a single oral dose of vandetanib 300mg on day 10; and (ii) a single oral dose of vandetanib 300mg on day 1. Study B: 16 healthy male subjects aged 20–44 years were randomized to receive each of the following two regimens, separated by a 3-month washout period: (i) oral itraconazole 200mg/day on days 1–24 with a single oral dose of vandetanib 300mg on day 4; and (ii) a single oral dose of vandetanib 300mg on day 1.Main Outcome Measure: Blood samples for measurement of vandetanib (both studies) concentrations and its metabolites, N-desmethylvandetanib and vandetanib N-oxide (Study A only), were collected before and at various timepoints after vandetanib administration for up to 28 days (Study A) and 37 days (Study B). Pharmacokinetic parameters were determined using noncompartmental methods. The area under the plasma concentration-time curve from time 0 to 504 hours (AUC504) and maximum plasma concentration (Cmax) of vandetanib were compared in the presence and absence of rifampicin, and in the presence and absence of itraconazole.Results: Study A: coadministration of vandetanib with rifampicin resulted in a statistically significant reduction in AUC504 (geometric least square [GLS]mean ratio [vandetanib + rifampicin/vandetanib alone] 0.60; 90% CI 0.58, 0.63). There was no significant difference in Cmax of vandetanib (GLSmean ratio 1.03; 90% CI 0.95, 1.11). AUC504 and Cmax of N-desmethylvandetanib increased by 266.0% and 414.3%, respectively, in the presence of rifampicin compared with vandetanib alone. Exposure to vandetanib N-oxide was very low compared with that of vandetanib, but was increased in the presence of rifampicin. Study B: coadministration of vandetanib with itraconazole resulted in a significant increase in AUC504 (GLSmean ratio [vandetanib + itraconazole/vandetanib alone] 1.09; 90% CI 1.01, 1.18) and no significant change in Cmax (GLSmean ratio 0.96; 90% CI 0.83, 1.11). Vandetanib was well tolerated in both studies.Conclusions: Exposure to vandetanib, as assessed byAUC504 in healthy subjects, was reduced by around 40% when a single dose was given in combination with the potent CYP3A4 inducer rifampicin. Because of this, it may be appropriate to avoid coadministration of potent CYP3A4 inducers with vandetanib. Vandetanib exposure was increased by about 9% when it was taken in combination with the CYP3A4 inhibitor itraconazole. It is unlikely that coadministration of vandetanib and potent CYP3A4 inhibitors will need to be con...
Moxifloxacin can be integrated effectively in a SAD study to establish assay sensitivity, and a TQT study may be replaced by a SAD study which has the required assay sensitivity. Further experience is warranted to verify this conclusion.
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