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Absolute bioavailability of evacetrapib in healthy subjects determined by simultaneous administration of oral evacetrapib and intravenous [(13) C8 ]-evacetrapib as a tracer.

ABSTRACT: This open-label, single-period study in healthy subjects estimated evacetrapib absolute bioavailability following simultaneous administration of a 130-mg evacetrapib oral dose and 4-h intravenous (IV) infusion of 175?µg [(13) C8 ]-evacetrapib as a tracer. Plasma samples collected through 168?h were analyzed for evacetrapib and [(13) C8 ]-evacetrapib using high-performance liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameter estimates following oral and IV doses, including area under the concentration-time curve (AUC) from zero to infinity (AUC[0-?]) and to the last measureable concentration (AUC[0-tlast ]), were calculated. Bioavailability was calculated as the ratio of least-squares geometric mean of dose-normalized AUC (oral?:?IV) and corresponding 90% confidence interval (CI). Bioavailability of evacetrapib was 44.8% (90% CI: 42.2-47.6%) for AUC(0-?) and 44.3% (90% CI: 41.8-46.9%) for AUC(0-tlast ). Evacetrapib was well tolerated with no reports of clinically significant safety assessment findings. This is among the first studies to estimate absolute bioavailability using simultaneous administration of an unlabeled oral dose with a (13) C-labeled IV microdose tracer at about 1/1000(th) the oral dose, with measurement in the pg/mL range. This approach is beneficial for poorly soluble drugs, does not require additional toxicology studies, does not change oral dose pharmacokinetics, and ultimately gives researchers another tool to evaluate absolute bioavailability.

SUBMITTER: Cannady EA

PROVIDER: S-EPMC5064742 | biostudies-other | 2016 May

REPOSITORIES: biostudies-other

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Absolute bioavailability of evacetrapib in healthy subjects determined by simultaneous administration of oral evacetrapib and intravenous [(13) C8 ]-evacetrapib as a tracer.

Cannady Ellen A EA Aburub Aktham A Ward Chris C Hinds Chris C Czeskis Boris B Ruterbories Kenneth K Suico Jeffrey G JG Royalty Jane J Ortega Demetrio D Pack Brian W BW Begum Syeda L SL Annes William F WF Lin Qun Q Small David S DS

Journal of labelled compounds & radiopharmaceuticals 20151207 6

This open-label, single-period study in healthy subjects estimated evacetrapib absolute bioavailability following simultaneous administration of a 130-mg evacetrapib oral dose and 4-h intravenous (IV) infusion of 175 µg [(13) C8 ]-evacetrapib as a tracer. Plasma samples collected through 168 h were analyzed for evacetrapib and [(13) C8 ]-evacetrapib using high-performance liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameter estimates following oral and IV doses, including ar ...[more]

PMID: 26639670

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Project description:IntroductionThe 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 μg AG-221 containing approximately 300 nCi of [14C]-AG-221.MethodsThis 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 μg 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.ResultsThe 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.ConclusionsIn 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 registrationClinicalTrials.gov identifier, NCT02443168.FundingCelgene Corporation.

Project description:ObjectivesTedizolid phosphate is a novel antibacterial under investigation for the treatment of gram-positive infections. This study was conducted to assess the pharmacokinetics, safety, and tolerability of intravenous tedizolid phosphate as well as the oral bioavailability of tedizolid phosphate.DesignDouble-blind, single-ascending dose, multiple-dose pharmacokinetics study, as well as tolerability and open-label crossover studies.SettingSingle center in the United States (Covance Clinical Research Unit, Madison, WI) between September 2009 and January 2010.ParticipantsNinety healthy volunteers.InterventionSingle intravenous (IV) doses of tedizolid phosphate 50 mg (lead-in) and 100-400 mg. Single oral and IV dose of tedizolid phosphate 200 mg in crossover fashion. Multiple IV doses of tedizolid phosphate 200 and 300 mg for up to 7 days.Measurements and main resultsA dose-dependent increase was observed in the maximum plasma concentration (1.2-5.1 μg/ml) and the area under the concentration-time curve (17.4-58.7 μg × hr/ml) of tedizolid (the microbiologically active moiety of tedizolid phosphate) after single IV doses of tedizolid phosphate 100-400 mg. Administration of IV tedizolid phosphate 200 mg once/day for 7 days resulted in minimal (28%) tedizolid accumulation. The absolute oral bioavailability of tedizolid after a single 200-mg dose of tedizolid phosphate was 91%; pharmacokinetic parameters of tedizolid were similar with oral and IV administration. Treatment-related adverse events occurred in 41% of subjects. Most adverse events were related to infusion site and became more frequent with multiple dosing. In an additional 3-day tolerability study, IV tedizolid phosphate 200 mg and placebo were similarly tolerated, based on visual infusion phlebitis scores.ConclusionThese results from a population of healthy volunteers support once/day dosing of tedizolid phosphate 200 mg with both the oral and IV formulations, without the need for dose adjustment when switching administration routes.

Dataset Information

Absolute bioavailability of evacetrapib in healthy subjects determined by simultaneous administration of oral evacetrapib and intravenous [(13) C8 ]-evacetrapib as a tracer.

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Absolute bioavailability of evacetrapib in healthy subjects determined by simultaneous administration of oral evacetrapib and intravenous [(13) C8 ]-evacetrapib as a tracer.

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