Dataset Information

Absolute Bioavailability of Esaxerenone and Food Effects on its Pharmacokinetics After a Single Oral Dose in Healthy Japanese Subjects: An Open-Label Crossover Study.

ABSTRACT: INTRODUCTION:To investigate the absolute bioavailability of esaxerenone and the effects of food on its pharmacokinetics (PK) after a single oral dose in healthy Japanese subjects. METHODS:Twenty-four Japanese males aged 20-45 years were randomised to six groups (each n?=?4) in this single-centre, open-label, three-way, three-period crossover study. Esaxerenone (5 mg) was administered in the fasting state as a single oral dose, single intravenous infusion over 1 h, or in the postprandial state as a single oral dose. Plasma samples were taken before and during the 96 h after drug administration. Drug concentrations were measured using liquid chromatography-tandem mass spectrometry. PK parameters were calculated using noncompartmental analysis, and safety was assessed. RESULTS:After fasting intravenous administration, total body clearance was 3.69 L h-1 and volume of distribution was 92.7 L. The plasma concentration-time profile of esaxerenone was similar after fasting and postprandial administration. Absolute bioavailability of a single oral 5-mg dose of esaxerenone was 89.0% in the fasting state and 90.8% postprandially. Point estimates (1.010 and 1.019, respectively) and 90% confidence intervals for geometric least squares mean peak plasma concentrations and area under the plasma concentration-time curve ratios after postprandial versus fasting oral esaxerenone were within the prespecified range (0.80, 1.25). No severe adverse events occurred throughout the study. CONCLUSIONS:Esaxerenone has a high absolute bioavailability of approximately 90% and food has no effect on esaxerenone PK after a single oral dose of 5 mg in healthy Japanese subjects. Additionally, no safety concerns were identified. CLINICAL TRIAL REGISTRATION:JapicCTI No. 163452. FUNDING:Daiichi Sankyo Co., Ltd.

SUBMITTER: Kurata A

PROVIDER: S-EPMC6824388 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Absolute Bioavailability of Esaxerenone and Food Effects on its Pharmacokinetics After a Single Oral Dose in Healthy Japanese Subjects: An Open-Label Crossover Study.

Kurata Akifumi A Furuie Hidetoshi H Ishizuka Tomoko T Nakatsu Takafumi T Shimizu Takako T Kato Manabu M Nishikawa Yasuhiro Y Ishizuka Hitoshi H

Advances in therapy 20190522 7

<h4>Introduction</h4>To investigate the absolute bioavailability of esaxerenone and the effects of food on its pharmacokinetics (PK) after a single oral dose in healthy Japanese subjects.<h4>Methods</h4>Twenty-four Japanese males aged 20-45 years were randomised to six groups (each n = 4) in this single-centre, open-label, three-way, three-period crossover study. Esaxerenone (5 mg) was administered in the fasting state as a single oral dose, single intravenous infusion over 1 h, or in the postpr ...[more]

PMID: 31119692

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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:AIMS:To characterize the pharmacokinetics, pharmacodynamics and safety of esaxerenone, a mineralocorticoid receptor antagonist, in healthy adult Japanese men. METHODS:Double-blind, placebo-controlled, sequential, dose-escalation studies were conducted in subjects randomized to receive oral once-daily esaxerenone (ranges: 5-200 mg [single-dose]; 10-100 mg over 10 days [multiple-dose]) or placebo under fasting conditions. Plasma concentrations were analysed by liquid chromatograph-tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartment analysis. Plasma/urine levels of pharmacodynamic biomarkers for mineralocorticoid receptor activity were evaluated. RESULTS:In total, 48/48 and 39/40 subjects completed the single- and multiple-dose studies, respectively. Exposures were generally dose-proportional. The tmax , t1/2 and CL/F remained unchanged, independent of dose; the respective ranges were 1.5-4.0 h, 22.3-25.1 h, and 4.0-5.2 l h-1 (multiple-dose study). Vz /F ranged from 136.5 to 283.7 l in the multiple-dose study, and exposure reached steady state by day 4. The mean observed accumulation ratio, by dose, ranged from 1.36-1.98. The urinary Na+ /K+ ratio increased after single-dose administration; however, its relationship to the doses tested remains unclear. Plasma renin activity, active renin concentration and aldosterone concentration increased dose-dependently. Although blood potassium levels increased dose-dependently in the multiple-dose study (reaching a maximum mean ± standard deviation of 4.63 ± 0.354 mmol l-1 in the 100-mg group), no safety/tolerability-related problems were detected in either study. CONCLUSIONS:Exposure levels in healthy adults receiving esaxerenone were generally dose-proportional. Dose-dependent changes in plasma pharmacodynamic biomarkers for the mineralocorticoid receptor were identified during multiple-dose treatment and support the pharmacological activity of esaxerenone. No important safety concerns were identified.

Project description:UnlabelledInhaled umeclidinium (UMEC) and the combination of inhaled UMEC with vilanterol (UMEC/VI) are approved maintenance treatments for chronic obstructive pulmonary disease in the US and EU. This was a randomized, open-label, three-period crossover, single- and repeat-dose study to assess the pharmacokinetics (PK), safety, and tolerability of inhaled UMEC/VI 62.5/25 μg (delivering 55/22 μg) and UMEC/VI 125/25 μg (delivering 113/22 μg) compared with their monotherapy components (UMEC 62.5 μg, UMEC 125 μg and, VI 25 μg [delivering 55, 113, and 22 μg, respectively]) in healthy Chinese subjects (n=20). UMEC and VI were rapidly absorbed following single and repeat dosing (time to maximum plasma concentration [tmax]: UMEC = 5 min; VI = 5 min). The median tlast was 2–4 h for UMEC and 1–2 h for VI following single doses of UMEC/VI and UMEC monotherapy (both doses). UMEC reached steady-state prior to Day 10; steady-state for VI could not be assessed. UMEC accumulation following repeat dosing was 11–34% based on Cmax and 19–59% based on area under the concentration-time curve from time zero to 2 h (AUC(0-2)). VI accumulation following repeat dosing was 25–66% based on Cmax and 17–43% based on AUC(0-2). The evidence was not sufficient to suggest that systemic exposure was substantially different between UMEC/VI combination therapy and the constituent monotherapies following single or repeat dosing. Following both single- and repeat-dose administration, the inter-subject coefficient of variation for all UMEC PK parameter estimates ranged from 12% to 165% for all treatments, indicating a wide range of variability in inhaled PK parameters. Twelve subjects experienced ≥1 adverse event (AE). Six subjects experienced ≥1 treatment-related AE; the most commonly reported treatment-related AE was chest discomfort (n=3 [15%]). No clinically important changes in vital signs or electrocardiogram parameters were reported. These data suggest that single- and repeat-dose administration of UMEC/VI combination therapy in healthy Chinese subjects did not result in substantial differences in systemic exposure compared with UMEC and VI as monotherapies.Trial registrationClinicaltrials.gov NCT01899638 NCT01899638.

Project description:BACKGROUND: Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) is usually administered by injection, and its oral administration in a clinical setting has been not yet reported. Here we demonstrate the bioavailability of orally administered rhGM-CSF in healthy volunteers. The rhGM-CSF was expressed in Bombyx mori expression system (BmrhGM-CSF). METHODS AND FINDINGS: Using a single-dose, randomized, open-label, two-period crossover clinical trial design, 19 healthy volunteers were orally administered with BmrhGM-CSF (8 microg/kg) and subcutaneously injected with rhGM-CSF (3.75 microg/kg) respectively. Serum samples were drawn at 0.0h, 0.5h ,0.75h,1.0h,1.5h,2.0h ,3.0h,4.0h,5.0h,6.0h,8.0h,10.0h and 12.0h after administrations. The hGM-CSF serum concentrations were determined by ELISA. The AUC was calculated using the trapezoid method. The relative bioavailability of BmrhGM-CSF was determined according to the AUC ratio of both orally administered and subcutaneously injected rhGM-CSF. Three volunteers were randomly selected from 15 orally administrated subjects with ELISA detectable values. Their serum samples at the 0.0h, 1.0h, 2.0h, 3.0h and 4.0h after the administrations were analyzed by Q-Trap MS/MS TOF. The different peaks were revealed by the spectrogram profile comparison of the 1.0h, 2.0h, 3.0h and 4.0h samples with that of the 0.0h sample, and further analyzed using both Enhanced Product Ion (EPI) scanning and Peptide Mass Fingerprinting Analysis. The rhGM-CSF was detected in the serum samples from 15 of 19 volunteers administrated with BmrhGM-CSF. Its bioavailability was observed at an average of 1.0%, with the highest of 3.1%. The rhGM-CSF peptide sequences in the serum samples were detected by MS analysis, and their sizes ranging from 2,039 to 7,336 Da. CONCLUSIONS: The results demonstrated that the oral administered BmrhGM-CSF was absorbed into the blood. This study provides an approach for an oral administration of rhGM-CSF protein in clinical settings. TRIAL REGISTRATION: www.chictr.orgChiCTR-TRC-00000107.

Project description:OBJECTIVES:Tedizolid 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. DESIGN:Double-blind, single-ascending dose, multiple-dose pharmacokinetics study, as well as tolerability and open-label crossover studies. SETTING:Single center in the United States (Covance Clinical Research Unit, Madison, WI) between September 2009 and January 2010. PARTICIPANTS:Ninety healthy volunteers. INTERVENTION:Single 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 RESULTS:A dose-dependent increase was observed in the maximum plasma concentration (1.2-5.1 ?g/ml) and the area under the concentration-time curve (17.4-58.7 ?g × 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. CONCLUSION:These 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 Esaxerenone and Food Effects on its Pharmacokinetics After a Single Oral Dose in Healthy Japanese Subjects: An Open-Label Crossover Study.

Publications

Absolute Bioavailability of Esaxerenone and Food Effects on its Pharmacokinetics After a Single Oral Dose in Healthy Japanese Subjects: An Open-Label Crossover Study.

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