Pharmacokinetic Comparison Between a Fixed-Dose Combination of Atorvastatin/Omega-3-Acid Ethyl Esters and the Corresponding Loose Combination in Healthy Korean Male Subjects.

Purpose: Statins are widely used in combination with omega-3 fatty acids for the treatment of patients with dyslipidemia. The aim of this study was to compare the pharmacokinetic (PK) profiles of atorvastatin and omega-3-acid ethyl esters between fixed-dose combination (FDC) and loose combination in healthy subjects. Methods: A randomized, open-label, single-dose, 2-sequence, 2-treatment, 4-period replicated crossover study was performed. Subjects were randomly assigned to one of the 2 sequences and alternately received four FDC soft capsules of atorvastatin/omega-3-acid ethyl esters (10/1000 mg) or a loose combination of atorvastatin tablets (10 mg × 4) and omega-3-acid ethyl ester soft capsules (1000 mg× 4) for four periods, each period accompanied by a high-fat meal. Serial blood samples were collected for PK analysis of atorvastatin, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). PK parameters were calculated by a non-compartmental analysis. The geometric mean ratio (GMR) and its 90% confidence interval (CI) of the FDC to the loose combination were calculated to compare PK parameters. Results: A total of 43 subjects completed the study as planned. The GMR (90% CI) of FDC to loose combination for maximum concentration (Cmax) and area under the time-concentration curve from zero to the last measurable point (AUClast) were 1.0931 (1.0054-1.1883) and 0.9885 (0.9588-1.0192) for atorvastatin, 0.9607 (0.9068-1.0178) and 0.9770 (0.9239-1.0331) for EPA, and 0.9961 (0.9127-1.0871) and 0.9634 (0.8830-1.0512) for DHA, respectively. The intra-subject variability for Cmax and AUClast of DHA was 30.8% and 37.5%, respectively, showing high variability. Both the FDC and the loose combination were safe and well tolerated. Conclusion: The FDC of atorvastatin and omega-3-acid ethyl esters showed comparable PK characteristics to the corresponding loose combination, offering a convenient therapeutic option for the treatment of dyslipidemia.

Pharmacokinetics of Ginsenoside Compound K From a Compound K Fermentation Product, CK-30, and From Red Ginseng Extract in Healthy Korean Subjects.

Natural protopanaxadiol ginsenosides exhibit low absorption in the human intestine. However, ginsenoside compound K (CK) with 1 conjugated glucose molecule exhibits favorable absorption. The purpose of this study was to compare the pharmacokinetics of ginsenoside CK from a CK fermentation product, CK-30, and from a red ginseng extract. A randomized, open-label, 2-treatment, 2×2 crossover study was conducted. The volunteers were randomly divided into 2 groups. One group received CK-30, and the other group received 2.94 g of a red ginseng extract. After a 7-day washout period, the subjects received an alternative treatment for a single dose. The pharmacokinetic parameters, including the maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve from time 0 to time of last measurable concentration, were calculated. The median time to reach Cmax of ginsenoside CK after administration of CK-30 was 3.0 hours, whereas the corresponding value of the red ginseng extract was 10.0 hours. Compared with the red ginseng extract, CK-30 resulted in a higher systemic exposure to ginsenoside CK, with a 118.3-fold increase in Cmax and a 135.1-fold increase in area under the plasma concentration-time curve from time 0 to time of last measurable concentration. The systemic exposure to ginsenoside CK was significantly higher after administration of CK-30 than red ginseng extract.

Pharmacokinetic and pharmacodynamic properties of the calcimimetic agent cinacalcet (KRN1493) in healthy male Korean subjects: a randomized, open-label, single ascending-dose, parallel-group study.

BACKGROUND: Cinacalcet (KRN1493) was developed to manage secondary hyperparathyroidism in patients with chronic kidney disease. The characteristics of cinacalcet have not been studied in the Korean population. OBJECTIVE: The aim of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties and tolerability of single-dose cinacalcet 50 to 100 mg in healthy male Korean subjects for the purposes of a New Drug Application package for the Korean Food and Drug Administration. METHODS: A randomized, open-label, single ascending-dose, parallel-group study was conducted in healthy male Korean subjects. Subjects were randomly assigned to receive a single oral dose of cinacalcet 50, 75, or 100 mg. Serial blood samples for PK/PD analysis were taken for up to 96 hours after administration. Plasma cinacalcet concentrations were analyzed by HPLC-MS/MS. PK parameters were determined using noncompartmental methods. Plasma intact parathyroid hormone (iPTH) concentrations, albumin-corrected serum calcium concentrations, and serum phosphorus concentrations were measured for PD evaluation. For the evaluation of tolerability, adverse events (AEs) were collected using investigators' questionnaires, subjects' spontaneous reports, clinical laboratory tests, ECG, and physical examinations including vital sign measurements. RESULTS: Sixteen subjects in the 50-mg group, 16 in the 75-mg group, and 6 in the 100-mg group completed the study and were included in the PK/PD analysis. The mean (SD) age, height, and weight of the study population were 4.3 (3.0) years, 174.8 (4.9) cm, and 68.2 (7.5) kg, respectively. The median T(max) value in each of the 3 dose groups was 6.0 hours. Mean C(max) values in the 50-, 75-, and 100-mg dose groups were 12.0 (5.5), 17.2 (14.9), and 43.1 (15.5) µg/L; mean AUC(0-∞) values were 126.6 (56.4), 184.3 (87.9), and 417.4 (169.9) µg · h/L. Characteristics were not linear, based on the data over the dose range of 50 to 100 mg. Mean plasma iPTH concentrations in the 50-, 75-, and 100-mg dose groups were decreased from baseline by 64.0% (11.7%), 63.1% (14.6%), and 70.6% (6.3%). Albumin-corrected serum calcium concentrations displayed patterns similar to those of the plasma iPTH concentrations. Sixteen AEs were reported in 11 subjects. No clinically significant abnormalities were observed in the tolerability assessments. CONCLUSIONS: A single oral dose of cinacalcet was well-tolerated up to 100 mg in this small, selected population of healthy male Korean subjects. In addition, the PK characteristics of cinacalcet and its accompanying PD changes-the decreases in the concentrations of plasma iPTH and albumin corrected serum calcium-were demonstrated in the same population. ClinicalTrials.gov identifier: NCT00942773.

The effect of the newly developed angiotensin receptor II antagonist fimasartan on the pharmacokinetics of atorvastatin in relation to OATP1B1 in healthy male volunteers.

OBJECTIVE: Interactions between coadministered drugs may unfavorably affect pharmacokinetics. This study evaluated whether fimasartan, an angiotensin receptor II antagonist, affected the pharmacokinetics of atorvastatin. METHODS: A randomized, open-label, 2-period, 2-sequence, crossover, multiple-dosing study was conducted with 24 healthy male volunteers. Twelve subjects received 80-mg atorvastatin once daily for 7 days; later, they received 80-mg atorvastatin with 240-mg fimasartan for 7 days. Twelve other subjects received the same drugs in the opposite sequence. Blood samples were collected scheduled intervals for 24 hours after the last dosing to determine plasma concentrations of atorvastatin acid, atorvastatin lactone, 2-hydroxy atorvastatin acid, and 2-hydroxy atorvastatin lactone. RESULTS: Compared with atorvastatin alone, coadministration of fimasartan and atorvastatin increased the atorvastatin acid mean (95% confidence interval) maximum concentration (Cmax,ss) by 1.89-fold (1.49-2.39) and the area under the concentration curve (AUCτ,ss) by 1.19-fold (0.96-1.48). Fimasartan also increased the mean 2-hydroxy atorvastatin acid Cmax,ss and AUCτ,ss by 2.45-fold (1.80-3.35) and 1.42-fold (1.09-1.85), respectively. The Cmax,ss and AUCτ,ss of the lactone forms of atorvastatin showed smaller changes than those observed for the acidic forms. CONCLUSION: We showed that fimasartan raised plasma atorvastatin concentrations. In vitro tests suggested that this effect may have been mediated by fimasartan inhibition of organic anion-transporting polypeptide 1B1.

Influence of Ginkgo biloba extract on the pharmacodynamic effects and pharmacokinetic properties of ticlopidine: an open-label, randomized, two-period, two-treatment, two-sequence, single-dose crossover study in healthy Korean male volunteers.

BACKGROUND: Ginkgo biloba extract is an herbal medicine used in the treatment of vascular disorders that may be coadministered with antiplatelet agents such as ticlopidine. Regulatory authorities requested evaluation of the pharmacodynamic and pharmacokinetic interactions between these entities, according to the drug-development guidance for fixed-dose combination formulations in Korea. OBJECTIVE: This study was performed to evaluate the potential pharmacodynamic and pharmacokinetic interactions between ticlopidine and Ginkgo biloba extract. METHODS: An open-label, randomized, 2-period, 2-treatment, 2-sequence, single-dose crossover study was conducted in healthy Korean male volunteers. All volunteers were randomly assigned to a sequence group for the 2 treatments, which consisted of ticlopidine 250 mg alone and ticlopidine 250 mg with Ginkgo biloba extract 80 mg, separated by a 1-week washout period between the treatments. Bleeding time was determined just before dosing and at 5, 12, and 48 hours after dosing. Platelet aggregation was evaluated before dosing and at 4, 8, 26, and 48 hours after dosing. Blood samples (8 mL) from each of the volunteers were collected from an indwelling intravenous cannula inserted into a forearm vein before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours after dosing. Ticlopidine concentrations were determined by a validated method using HPLC and ultraviolet detection. Adverse events were identified using general health-related questions, vital signs, physical examinations, ECGs, and laboratory tests. RESULTS: A total of 24 healthy men participated in the study (mean [SD] age, 24.1 [4.3] years; weight, 66.6 [7.4] kg; height, 174.7 [5.0] cm). The baseline corrected bleeding times were not significantly different between the ticlopidine-alone and ticlopidine/ Ginkgo biloba groups, and changes in platelet aggregation were not significantly different between the groups. Likewise, the pharmacokinetic parameters of ticlopidine were not significantly different between the groups; the geometric mean ratios of the ticlopidine/ Ginkgo biloba group to the ticlopidine-alone group were 1.03 (90% CI, 0.92-1.16) for C(max), 1.08 (90% CI, 0.98-1.19) for AUC(0-last), and 1.10 (90% CI, 1.00-1.20) for AUC(0-infinity). A total of 28 adverse events were reported: 11 in the ticlopidine-alone group and 17 in the ticlopidine/Ginkgo biloba group. The adverse events judged to be possibly related to ticlopidine in the ticlopidine-alone group were epigastric discomfort (2 cases), diarrhea (1), skin eruption (1), and a feeling of being cold (1) or hot (1). The adverse events judged to be related to ticlopidine or Ginkgo biloba in the ticlopidine/Ginkgo biloba group were epigastric discomfort (2), diarrhea (2), nausea (2), and headache (1). CONCLUSIONS: In this small group of healthy Korean men, the addition of a single dose of Ginkgo biloba extract did not prolong the bleeding time and was not associated with additional antiplatelet effects compared with the administration of ticlopidine alone. The coadministration of Ginkgo biloba extract with ticlopidine was not associated with any significant changes in the pharmacokinetic profile of ticlopidine compared with ticlopidine administered alone.

Comparison of the pharmacokinetics of ticlopidine between administration of a combined fixed-dose tablet formulation of ticlopidine 250 mg/ginkgo extract 80 mg, and concomitant administration of ticlopidine 250-mg and ginkgo extract 80-mg tablets: an open-label, two-treatment, single-dose, randomized-sequence crossover study in healthy Korean male volunteers.

BACKGROUND: Ticlopidine is an antiplatelet agent used for the prevention of vascular accidents. In clinical practice in Korea, ginkgo extract may be administered along with ticlopidine to enhance the inhibition of platelet aggregation. OBJECTIVE: To meet the requirements for marketing a combined fixed-dose formulation in Korea, the investigators compared the pharmacokinetic characteristics of ticlopidine in a combined fixed-dose tablet of ticlopidine/ginkgo extract with the concomitant administration of ticlopidine and ginkgo extract tablets. METHODS: An open-label, 2-period, 2-treatment, single-dose, randomized-sequence crossover study was conducted in healthy Korean male volunteers. Subjects were randomly allocated to 2 sequence groups. In one period, a combined ticlopidine 250 mg/ ginkgo extract 80-mg fixed-dose tablet was administered and, in the other period, ticlopidine 250-mg and ginkgo extract 80-mg tablets were concomitantly administered. A 7-day washout separated the 2 periods. For analysis of pharmacokinetic properties, including C(max), T(max), t((1/2)), AUC(0-infinity), and AUC(0-last), serial blood sampling was performed up to 48 hours after study drug administration during each period. Ticlopidine concentrations in plasma were determined by a validated method using LC-MS/MS. In order for the 2 treatments to be considered bioequivalent, the 90% CI of the geometric means ratios for C(max) and AUC needed to be between 80% and 125%. Bleeding time was determined before dosing (0 hour) and at 5 and 24 hours after dosing. Adverse events (AEs) were identified through patient interview, recording of blood pressure, heart rate, and body temperature, physical examination, 12-lead ECG, and laboratory assessments. RESULTS: Twenty-four healthy Korean male subjects (mean [range] age, 23.9 [22-38] years; height, 174.0 [162-184] cm; weight, 67.4 [56-80] kg) completed the study. Median (range) T(max) of ticlopidine was 1.5 (0.5-2.0) hours in both groups. The mean (SD) t((1/2)) of ticlopidine in the combined fixed-dose formulation and the concomitant administration groups was 19.5 (3.4) and 19.0 (3.3) hours after study drug administration, respectively. The geometric means ratios of ticlopidine AUC(0-last), AUC(0-infinity), and C(max) between the combined fixed-dose formulation and concomitant administration were 1.04 (90% CI, 0.96-1.13), 1.04 (90% CI, 0.96-1.13), and 1.09 (90% CI, 0.96-1.23), respectively. The mean (SD) bleeding time at predose (0), and 5 and 24 hours after dose administration was 4.5 (1.6) to 5.4 (1.7) minutes in the combined fixed-dose formulation group and 4.4 (1.6) to 5.1 (1.1) minutes in the concomitant administration group. Five subjects (3 in the combined fixed-dose formulation group and 2 in the concomitant administration group) had bleeding times >8 minutes, but this was not considered to be clinically significant. A total of 24 AEs were reported in 13 of 24 subjects: nausea (3 cases), diarrhea (3), dizziness (3), epigastric discomfort (2), headache (2), rhinorrhea (2), purulent sputum (2), dyspepsia (1), upper abdominal pain (1), cough (1), pharyngolaryngeal pain (1), oropharyngeal swelling (1), dysphonia (1), and dysphagia (1). All were considered mild or moderate in nature. There was no statistically significant difference between the 2 treatments in the number of AEs or in the number of subjects who reported an AE. CONCLUSION: Administration of a single dose of a combined fixed-dose formulation of ticlopidine 250 mg/ ginkgo extract 80-mg tablets and concomitant administration of ticlopidine and ginkgo extract tablets did not result in statistically significant differences in the pharmacokinetics of ticlopidine in these healthy Korean male volunteers.

Effects of Angelicae tenuissima radix, Angelicae dahuricae radix and Scutellariae radix extracts on cytochrome P450 activities in healthy volunteers.

Three kinds of herbal medicines, commonly used in Korea, Angelicae tenuissima radix, Angelicae dahuricae radix and Scutellariae radix were studied to evaluate their effect on cytochrome P450 (CYP) activities in healthy volunteers. A total of 24 healthy male volunteers were assigned to one of three parallel herbal treatment groups, each consisting of eight volunteers. A cocktail of probe drugs for CYP enzymes was orally administered before and after multiple administrations of herbal medicines, three times a day for 13 days. Probe drugs used to measure CYP activities were caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4). The probe drugs and their metabolites were quantified in plasma or urine using HPLC or LC-MS/MS. Changes in each CYP activity was evaluated by metabolic ratio of the probe drug (concentration ratio of metabolite to parent form at reference time point) following the herbal medication period, compared to the baseline values. A. dahuricae radix significantly decreased CYP1A2 activity to 10% of baseline activity (95% CI: 0.05-0.21). S. radix also showed significant changes in CYP2C9 and CYP2E1 activities. Compared to baseline values, the metabolic activities of losartan were decreased to 71% (0.54-0.94). In addition, S. radix showed a 1.42-fold (1.03-1.97) increase in chlorzoxazone metabolic activity. However, CYP activities were not meaningfully influenced by A. tenuissima radix. Changes in certain CYP activities were observed after the administration of S. radix and A. dahuricae radix in healthy volunteers. Therefore, herbal medicines containing S. radix or A. dahuricae radix are candidates for further evaluation of clinically significant CYP-mediated herb-drug interactions in human beings.

Gastroprotective action of Cochinchina momordica seed extract is mediated by activation of CGRP and inhibition of cPLA(2)/5-LOX pathway.

Cochinchina momordica seed extract (SKMS10), which is composed of the major compounds momordica saponins, has been evaluated for its gastroprotective effects in rat models of acute gastric mucosal damage. Ethanol and water immersion restraint stress (WRS) induced gastric damage, including hemorrhages and edema, was significantly attenuated by pretreatment with SK-MS10. In addition, SK-MS10 reduced increases of mucosal myeloperoxidase (MPO), IL-1ß, and TNFα levels and the expression of cPLA(2), and 5-LOX induced by ethanol or WRS. SK-MS10 also increased hexosamine, adherent mucus, and the expression of MUC5AC. Furthermore, SK-MS10 enhanced the mucosal expression of the CGRP gene and its serum levels.N(G)-methyl L-arginine (L-NMMA) or capsaicin desensitization reversed the SK-MS10-induced gastroprotection effect. These results suggest that SK-MS10 is a gastroprotective agent against acute gastric mucosal damage by suppressing proinflammatory cytokines, downregulating cPLA(2), 5-LOX, and increasing the synthesis of mucus. Furthermore, CGRP-NO pathway was found to play an important role in these gastroprotective effects of SK-MS10.