Comparison of Pharmacokinetic Profiles of Beraprost Sustained Release in Japanese, Chinese, and Korean Healthy Adult Males.

BACKGROUND AND OBJECTIVES: Beraprost sodium (BPS), an orally administrable prostaglandin I2 derivative, is used for the treatment of chronic arterial occlusion and pulmonary arterial hypertension and has potential efficacy in nephropathy. Beraprost sustained release (beraprost SR) is an oral sustained-release formulation of BPS. To confirm the dose rationale reported in a multi-regional study of nephropathy patients in Asia, this open-label study evaluated ethnic differences in the pharmacokinetic profiles of BPS and its active diastereomer (BPS-314d) after beraprost SR administration among healthy Japanese, Chinese, and Korean adult males. METHODS: Twelve healthy subjects in each ethnic group were enrolled. Subjects received a single oral dose of 120 µg beraprost SR under fasting conditions. RESULTS: The geometric mean ratio (90% confidence interval) of the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration (AUClast) of BPS was 1.12 (0.85-1.48) and 1.40 (1.05-1.86) in Chinese, and 1.18 (0.90-1.55) and 1.18 (0.89-1.58) in Korean compared to Japanese subjects. These differences were not clinically relevant. Similarly, differences in the Cmax and AUClast of BPS-314d were also small among the ethnic groups. Urinary excretion of BPS and BPS-314d was limited in all ethnic groups. Together, these findings indicate that the pharmacokinetics of beraprost SR are not affected by ethnic background. CONCLUSIONS: There were no clinically meaningful ethnic differences in the pharmacokinetics of BPS and BPS-314d following beraprost SR administration among Japanese, Chinese and Korean populations.

The Pharmacokinetics of Beraprost Sodium Following Single Oral Administration to Subjects With Impaired Kidney Function.

The purpose of the present study was to evaluate the pharmacokinetics of beraprost sodium (BPS) and its active enantiomer, BPS-314d, in Japanese subjects with impaired kidney function. The plasma and urine concentrations of BPS and BPS-314d were measured following the single oral administration of 120 µg of BPS as the sustained-release tablet, TRK-100STP, under fasting conditions to 18 subjects with impaired kidney function (stage 2, 3, and 4 chronic kidney disease [CKD] as categorized by the estimated glomerular filtration rate) and to 6 age-, body weight-, and gender-matched subjects with normal kidney function (stage 1 CKD). The Cmax values (mean ± SD) of BPS in stage 1, 2, 3, and 4 CKD, respectively, were 84.9 ± 22.9, 119.8 ± 36.4, 190.6 ± 137.3, and 240.2 ± 110.5 pg/mL; its AUC0-48h were 978 ± 226, 1252 ± 427, 1862 ± 964, and 1766 ± 806 pg·h/mL, respectively, and its cumulative urinary excretion rates were 0.704 ± 0.351%, 0.638 ± 0.292%, 0.485 ± 0.294%, and 0.159 ± 0.136%. The Cmax values of BPS-314d were 22.4 ± 6.4, 30.8 ± 8.5, 46.7 ± 30.6, and 54.4 ± 25.2 pg/mL, its AUC0-48h were 155 ± 56, 226 ± 67, 341 ± 176, and 329 ± 143 pg·h/mL, and its cumulative urinary excretion rates were 0.428 ± 0.242%, 0.349 ± 0.179%, 0.356 ± 0.270%, and 0.096 ± 0.099%, respectively. Adverse events were reported in 2 subjects with stage 2 CKD and 1 subject with stage 4 CKD. The Cmax and AUC0-48h of BPS and BPS-314d were higher based on the severity of impaired kidney function. No relationship was observed between the incidence of adverse events and the severity, and tolerability was confirmed. We consider that dose adjustment is not necessary, but BPS is more carefully treated in patients with impaired kidney function.

Clinical Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Darexaban, an Oral Direct Factor Xa Inhibitor, in Healthy Elderly Japanese Subjects.

The clinical pharmacokinetics, pharmacodynamics, safety and tolerability of darexaban after single and multiple once-daily doses of 60, 120, and 240 mg in healthy elderly Japanese subjects were assessed. Following oral administration, darexaban was rapidly and extensively metabolized to darexaban glucuronide, which is an active glucuronide metabolite. Plasma concentrations of darexaban glucuronide increased with dose, and Cmax and AUC increased dose-dependently after both single and repeated doses. Cumulative urinary excretion of darexaban glucuronide up to 24 hours after repeated doses ranged from 28.59% to 36.50%. PT-INR, aPTT, and FXa activity were prolonged or decreased dose-dependently after both single and repeated doses of darexaban. The time-profile of pharamcodynamic parameters closely followed the time-concentration profile of darexaban glucuronide. Five adverse events occurred in the present study (4: darexaban [16.7%]; 1: placebo [8.3%]), all of which were mild in severity and required no treatment.

Liquid chromatography-electrospray tandem mass spectrometric assay suitable for quantitation of YM155, a novel small-molecule survivin suppressant, in dog plasma.

This paper describes a sensitive and selective liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for determination of the novel survivin suppressant YM155, 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium, which is developed for the treatment of solid tumors. This method uses a liquid-liquid extraction from 0.25 mL of dog plasma. LC separation was carried out on a Genesis Silica column (50 mm x 3.0 mm i.d.) at a flow-rate of 0.5 mL/min. Compounds were eluted using a mobile phase of 5 mm ammonium acetate and 0.1% formic acid in water-0.1% formic acid in acetonitrile, 17:83 (v/v). MS/MS detection was carried out with an MDS-Sciex API3000 triple quadrupole mass spectrometer in positive electrospray ionization mode. The standard curve was linear from 0.05 to 50 ng/mL (r > or = 0.9968). The lower limit of quantitation was 0.05 ng/mL. Good intra- and inter-day assay precision (within 7.4% RSD) and accuracy (within +/-12.3%) were obtained. The extraction recovery was 66.2%. The method was successfully applied to preclinical pharmacokinetic studies in dogs.