Dataset Information

Concomitant oral and intravenous pharmacokinetics of trametinib, a MEK inhibitor, in subjects with solid tumours.

ABSTRACT: The aim of this phase 1, single centre, open label study in four patients with solid tumours was to determine the absolute bioavailability of a 2?mg oral dose of trametinib. Trametinib is an orally bioavailable, reversible and selective allosteric inhibitor of MEK1 and MEK2 activation and kinase activity.A microtracer study approach, in which a 5??g radiolabelled i.v. microdose of trametinib was given concomitantly with an unlabelled 2?mg oral tablet formulation, was used to recover i.v. and oral pharmacokinetic parameters, simultaneously.The least-squares mean (90% confidence interval) absolute bioavailability of trametinib (2?mg tablet) was 72.3% (50.0%, 104.6%). Median tmax after oral administration was 1.5?h and the geometric mean terminal half-life was 11?days. The geometric mean clearance and volume of distribution after i.v. administration were 3.21?l?h(-1) and 976?l, respectively, resulting in a terminal elimination half-life of 11?days.Trametinib absolute bioavailability was moderate to high, whereas first pass metabolism was low.

SUBMITTER: Leonowens C

PROVIDER: S-EPMC4243903 | BioStudies | 2014-01-01

REPOSITORIES: biostudies

ACCESS DATA

Similar Datasets

Project description:INTRODUCTION:The purpose of this study was to evaluate the absolute bioavailability (BA) of AG-221 following a single oral dose of 100 mg AG-221 and an intravenous (IV) dose of?~?100 ?g AG-221 containing approximately 300 nCi of [14C]-AG-221. METHODS:This was a phase 1, open-label study. Six subjects who met all of the inclusion criteria and none of the exclusion criteria were enrolled in the study. After an overnight fast of at least 10 h, the subjects received an oral dose (coated tablet) of 100 mg of AG-221 at 0 h on dosing day. Four hours after the oral dose, the subjects received 100 ?g AG-221 containing?~?300 nCi of [14C]-AG-221 administered as an IV bolus. Blood samples were collected and analyzed for plasma concentrations of AG-221 and [14C]-AG-221 using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) system and high-performance liquid chromatography (HPLC) fractionation followed by accelerator mass spectrometry analysis (AMS), respectively. Safety was evaluated throughout the study. RESULTS:The absolute BA after a 100-mg oral dose of AG-221 was measured as 57.2%. While the total clearance was 1.37 L/h,?~?1/60 of the liver blood flow in a typical 70-kg human subject, the first-pass extraction was estimated to be less than 2%, assuming that the total clearance was entirely due to liver metabolism. Thus, the fraction of the AG-221 dose absorbed was at least 50%. AG-221 was safe and well tolerated when given under fasted conditions in a single 100-mg dose as a coated tablet with a microtracer [14C]-AG-221 solution, as few drug-related treatment-emergent adverse events (TEAEs) were reported. No clinically significant changes or findings were noted in the clinical laboratory evaluations, vital sign measurements, and electrocardiograms (ECGs) performed during this study. CONCLUSIONS:In healthy subjects under fasting conditions, the absolute BA following oral administration of a 100-mg AG-221 tablet was 57.2%. AG-221 was safe and well tolerated in healthy male subjects when administered as a single 100-mg film-coated tablet plus 100 µg [14C]-AG-221 given intravenously. TRIAL REGISTRATION:ClinicalTrials.gov identifier, NCT02443168. FUNDING:Celgene Corporation.

Project description:BACKGROUND AND OBJECTIVES:In-vitro data suggest that clearance of vilaprisan is mediated by cytochrome P450 3A4 (oxidation) and aldoketoreductases (reduction). To fully understand the elimination and biotransformation pathways of vilaprisan, a selective progesterone receptor modulator, and to quantify the impact of cytochrome P450 3A4 inhibition on the pharmacokinetics of vilaprisan, two clinical studies in healthy postmenopausal women were conducted. METHODS:In study 1, pharmacokinetics, mass balance, and metabolite patterns were determined after single oral administration of 5 mg of [14C]-labeled vilaprisan in six subjects. In study 2, pharmacokinetics were determined after single oral administration of 4 mg of vilaprisan without and with concomitant administration of the strong cytochrome P450 3A4 inhibitor itraconazole (200 mg/day) in 14 subjects. In addition, a microtracer dose of vilaprisan was given intravenously to determine absolute bioavailability, clearance, and volume of distribution. RESULTS:The dominant single compound in plasma was vilaprisan. No plasma metabolites exceeding 10% of total drug-related area under the concentration-time curve were detected. The absolute oral bioavailability of vilaprisan was ~ 60%. The mean clearance was ~ 7 L/h and the volume of distribution at steady state was ~ 360 L. Excretion occurred primarily via feces (73.5 ± 3.70% of dose; urine: 13.1 ± 1.71%; total recovery: 86.6 ± 2.81%), mostly in a metabolized form. Only small amounts of the parent drug were found in excreta. When vilaprisan was administered together with itraconazole, exposure to vilaprisan was increased 6.2-fold (90% confidence interval 5.4-7.2). CONCLUSIONS:Vilaprisan is predominantly metabolized in the liver to a complex variety of metabolites, which are mainly excreted with feces. The pivotal role of cytochrome P450 3A4 in the metabolism of vilaprisan was confirmed. CLINICAL TRIAL REGISTRATION:EudraCT numbers 2013-000707-16 (mass balance study) and 2014-004929-41 (drug-drug interaction/microtracer study); NCT02456129 (drug-drug interaction/microtracer study).

Dataset Information

Concomitant oral and intravenous pharmacokinetics of trametinib, a MEK inhibitor, in subjects with solid tumours.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure