Healthy Korean Male Volunteers Research Articles

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 baselinecorrected 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–∞. 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.

Pharmacodynamic (Hemodynamic) and pharmacokinetic comparisons of S-amlodipine gentisate and racemate amlodipine besylate in healthy Korean male volunteers: Two double-blind, randomized, two-period, two-treatment, two-sequence, double-dummy, single-dose crossover studies

Background: S-amlodipine gentisate, consisting entirely of the ( S)-enantiomer, was developed to increase the potency and improve the safety profile of amlodipine. Regulatory requirements for marketing of S-amlodipine gentisate in Korea require comparison of this agent versus amlodipine racemate. Objective: This study was conducted to compare the pharmacodynamic (PD) and pharmacokinetic (PK) characteristics of the S-amlodipine formulation ( S-amlodipine gentisate) and amlodipine racemate (amlodipine besylate). Methods: This study consisted of 2 separate substudies; PD and PK parameters were evaluated separately. Both studies were conducted using a doubleblind, randomized, 2-period, 2-treatment, 2-sequence, double-dummy, single-dose crossover design with S-amlodipine 5 mg and amlodipine racemate 10 mg, separated by a 2-week washout period. Blood pressure (BP) and heart rate were measured in the sitting position before dosing and at 1, 2, 4, 5, 6, 7, 8, 10, 12, 14, 24, 48, and 72 hours after oral administration of S-amlodipine or amlodipine racemate. Impedance cardiography parameters (stroke volume, cardiac index, and systemic vascular resistance) were measured before and at 1, 2, 4, 5, 6, 7, 8, 10, and 12 hours after dosing. For PK assessments, serial blood samples were collected before dosing and at 1, 2, 4, 6, 8, 10, 12, 14, 24, 48, 72, 96, 120, 144, and 168 hours after dosing, and drug concentrations were determined by HPLC-MS/MS. Adverse events (AEs) were collected using self-report or general health-related questions. Results: The PD study included 24 healthy men (mean [SD] age, 23.1 [3.1] years; weight, 69.2 [6.1] kg), and the PK study included 24 different healthy men (mean age, 25.1 [2.1] years; weight, 65.9 [5.9] kg). There were no statistically significant differences between the treatment groups in terms of systolic BP, diastolic BP, or heart rate by repeated-measures ANOVA. Likewise, in the analysis of impedance cardiography, the treatment groups did not display any significant differences in stroke volume, cardiac index, or systemic vascular resistance by repeatedmeasures ANOVA. The mean (SD) AUC 0–last was 129.7 (62.8) ng · h/mL after dosing with S-amlodipine and 129.0 (59.6) ng · h/mL after dosing with amlodipine racemate. The geometric mean ratio ( S-amlodipine: amlodipine racemate) of the S-amlodipine AUC 0−last was 1.01 (90% CI, 0.90–1.13). In the PD study, 4 AEs in 3 volunteers (3/24; 12.5%) and 8 AEs in 5 volunteers (5/24; 20.8%) were reported after dosing with S-amlodipine and amlodipine racemate, respectively. In the PK study, 18 AEs in 11 volunteers (11/24; 45.8%) and 20 AEs in 9 volunteers (9/24; 37.5%) were reported after dosing with S-amlodipine and amlodipine racemate, respectively. Five volunteers reported AEs after dosing with both S-amlodipine and amlodipine racemate. For the PD and PK studies combined, 30 AEs were judged to be possibly related to S-amlodipine (16 cases) or amlodipine racemate (14 cases). Twenty AEs were judged not to be related to S-amlodipine (6 cases) or amlodipine racemate (14 cases). The most common AEs considered at least possibly related to the study drug in both studies were headache (18 cases) and nausea (3 cases). Conclusions: In these single-dose studies, no significant differences were found in PD (hemodynamic) or PK parameters between S-amlodipine 5 mg and amlodipine racemate 10 mg. S-amlodipine had a safety profile comparable to that of amlodipine racemate in these healthy male volunteers.

Population Pharmacokinetic Analysis of Anastrozole in Healthy Korean male Volunteers

Population Pharmacokinetic Analysis of Anastrozole in Healthy Korean male Volunteers

모빅캡슐(멜록시캄 7.5mg)에 대한 멜록시펜캡슐의 생물학적 동등성

The purpose of the present study was to evaluate the bioequivalence of meloxicam capsule, capsule( Boehringer Ingelheim Ltd., Korea) as a reference drug and capsule (Kukje Pharma Ind. Co., Ltd., Korea) as a test drug, according to the guidelines of Korea Food and Drug Administration(KFDA). Thirty two healthy male Korean volunteers received capsule containing meloxicam 7.5 mg in a crossover study. There was a one-week above washout period between the doses. Plasma concentrations of meloxicam were monitored for over a period of 72 hr after administration by using a high performance liquid chromatography-tandem mass spectrometer(LC-MS/MS). (the area under the plasma concentration-time curve from time zero to 72 hr), (maximum plasma drug concentration) and (time to reach ) were complied from the plasma concentration-time data. Analysis of variance(ANOVA) test was utilized for the statistical analysis of the parameters using logarithmically transformed and . The 90% confidence intervals of the ratio and the ratio for were log 0.8605-log 0.9847 and log 0.9765-log 1.1503, respectively. These values were within the acceptable bioequivalence intervals of log 0.80-log 1.25, recommended by KFDA. In all of these results, we concluded that capsule was bioequivalent to capsule, based on the rate and extent of absorption.

Pharmacokinetic interaction between oral lovastatin and verapamil in healthy subjects: role of P-glycoprotein inhibition by lovastatin

Lovastatin is an inhibitor of P-glycoprotein (P-gp) and is metabolized by the cytochrome P450 (CYP) 3A4 isoenzyme. Verapamil is a substrate of both P-gp and CYP3A4. It is therefore likely that lovastatin can alter the absorption and metabolism of verapamil. The pharmacokinetic parameters of verapamil and one of its metabolites, norverapamil, were compared in 14 healthy male Korean volunteers (age range 22-28 years) who had been administered verapamil (60 mg) orally in the presence or absence of oral lovastatin (20 mg). The design of the experiment was a standard 2 x 2 crossover model in random order. The pharmacokinetic parameters of verapamil were significantly altered by the co-administration of lovastatin compared to the control. The area under the plasma concentration-time curve (AUC (0-infinity)) and the peak plasma concentration of verapamil were significantly increased by 62.8 and 32.1%, respectively. Consequently, the relative bioavailability of verapamil was also significantly increased (by 76.5%). The (AUC (0-infinity)) of norverapamil and the terminal half-life of verapamil did not significantly changed with lovastatin coadministration. The metabolite-parent ratio was significantly reduced (29.2%) in the presence of lovastatin. Lovastatin increased the absorption of verapamil by inhibiting P-gp and inhibited the first-pass metabolism of verapamil by inhibiting CYP3A4 in the intestine and/or liver in humans.

The effects of ketoconazole and rifampicin on the pharmacokinetics of mirodenafil in healthy Korean male volunteers: An open-label, one-sequence, three-period, three-treatment crossover study

Background: Mirodenafil, a phosphodiesterase 5 inhibitor reported to be effective in the treatment of erectile dysfunction, is metabolized by cytochrome P450 (CYP) 3A4 to the active metabolite N-dehydroxyethyl mirodenafil. Mirodenafil may have drug-drug interactions with ketoconazole and/or rifampicin. Objective: The aim of this study was to investigate the effects of a potent inhibitor (ketoconazole) and inducer (rifampicin) of the CYP3A4 isozyme on the pharmacokinetics of mirodenafil to meet the regulatory requirements for the marketing of mirodenafil in Korea. Methods: An open-label, 1-sequence, 3-period, 3-treatment crossover study was conducted over 22 days in healthy Korean male volunteers. Each subject received 100 mg of mirodenafil in each of 3 study periods: mirodenafil alone (period 1); mirodenafil after pretreatment with ketoconazole 400 mg once daily for 3 days (period 2); and mirodenafil after pretreatment with rifampicin 600 mg once daily for 10 days (period 3). Serial blood samples were collected for pharmacokinetic analysis after the administration of mirodenafil in each study period. Plasma concentration-time data for mirodenafil and its major metabolite, N-dehydroxyethyl mirodenafil, were determined using LC-MS/MS and analyzed by a noncompartmental method. The results for mirodenafil coadministration with either ketoconazole or rifampicin were compared with those for mirodenafil alone. Adverse events (AEs) were identified by asking general health-related questions of the subjects, by physical examination, and by subject self-report throughout the study period. Results: Nineteen subjects were enrolled (mean [SD] age, 23.2 [2.76] years [range, 19–29 years]; weight, 69.3 [6.50] kg [range, 61.0–84.0 kg]; body mass index, 22.4 [1.77] kg/m 2 [range, 20.0–26.0 kg/m 2]) and 18 subjects completed the study. One subject discontinued the study due to protocol violation and was replaced. The AUC 0−∞) of mirodenafil increased 5.04-fold (90% CI, 3.78–6.72) and the metabolic ratio decreased 0.21-fold after pretreatment with ketoconazole compared with mirodenafil alone. After pretreatment with rifampicin, the AUC0-X) of mirodenafil decreased 0.03-fold (90% CI, 0.02–0.05) and the metabolic ratio increased 2.9-fold. Twelve cases of headache, 6 of nasal congestion, 2 of feeling hot, 2 of epistaxis, and 1 each of dizziness, nausea, and somnolence were considered to be related to administration of mirodenafil. Twenty-eight AEs were reported in period 2 (in 68.4% of subjects), during which systemic exposure to mirodenafil was highest, whereas 7 AEs were reported in period 1 (in 31.6% of subjects) and 5 AEs in period 3 (in 16.7% of subjects). Conclusion: In these healthy Korean male volunteers, the coadministration of ketoconazole and rifampicin resulted in significant changes in systemic exposure to mirodenafil.

Comparative pharmacokinetic evaluation of two formulations of bicalutamide 50-mg tablets: An open-label, randomized-sequence, single-dose, two-period crossover study in healthy Korean male volunteers

Background: Bicalutamide is an oral nonsteroidal antiandrogen drug used during hormone ablation therapy for prostate cancer. A new generic formulation of bicalutamide has been developed. Objectives: This study was conducted to meet Korean and US regulatory requirements for the marketing of the generic 50-mg tablet formulation of bicalutamide. To this end, the pharmacokinetic properties of the new (test) formulation were compared with those of the currently marketed (reference) formulation. Tolerability was also evaluated. Methods: An open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in healthy Korean male volunteers. Subjects received either the test or reference formulation of bicalutamide 50-mg tablets in the first period and crossed over to the alternative formulation in the second period. Serial blood samples for pharmacokinetic analysis were taken over 672 hours after dosing. Plasma concentrations of bicalutamide were measured by HPLC-MS/MS. Pharmacokinetic parameters, including AUC 0–672h, were determined by noncompartmental analysis. Log-transformed C max and AUC 0–672h for the 2 formulations were compared. Tolerability was monitored based on laboratory tests, ECGs, vital signs, and physical examinations. Results: Of the 34 subjects initially enrolled, 33 completed the study. The mean (SD) age, height, and weight of participants were 25.8 (4.1) years, 173.6 (5.7) cm, and 68.9 (7.8) kg, respectively. The median T max was 36.0 hours for both formulations. The mean (SD) t ½, C max, and AUC 0–672h for the reference formulation were 135.4 (28.6) hours, 933.2 (169.2) μg/L, and 215,680.1 (48,753.4) μg · h/L, respectively. Corresponding values for the test formulation were 134.3 (30.7) hours, 946.7 (179.9) μg/L, and 221,708.8 (54,935.1) μg · h/L. The 90% CIs for the mean ratios (test/reference) of log-transformed C max and AUC 0–672h were 0.97 to 1.06 and 0.98 to 1.07, respectively. Twelve adverse events were reported for each formulation, none of which were considered drug related in the test-formulation group and 4 of which were considered drug related in the reference-formulation group (3 cases of headache, 1 case of erythematous rash). Conclusions: In this single-dose study in healthy Korean male subjects, the new formulation of bicalutamide 50-mg tablets met Korean and US regulatory criteria for assumption of bioequivalence with the currently marketed formulation. Both formulations were generally well tolerated, with no clinically relevant safety concerns.

Pharmacokinetics and bioequivalence evaluation of gliclazide/metformin combination tablet and equivalent doses of gliclazide and metformin in healthy Korean subjects

To evaluate the bioequivalence of a gliclazide/metformin combination tablet (at dose of 80/500 mg) with co-administration of metformin (500 mg) and gliclazide (80 mg) as individual tablets in healthy male Korean volunteers. The study was conducted as an open-label, randomized, 2-period crossover design in 32 healthy male Korean volunteers who received a combination tablet of gliclazide/metformin at a dose of 80/500 mg or co-administration of gliclazide and metformin as individual tablets in each study period. There was a 7-day washout period between doses. Serum concentrations of gliclazide and metformin up to 32 hours after administration were determined using a validated HPLC method with UV detection. The pharmacokinetic parameters such as AUC0-t (the area under the curve from zero to the time), AUC0- yen (the area under the curve from zero to infinity), Cmax (maximum serum concentration), tmax (time to reach Cmax) and t1/2 (terminal half-life), were analyzed by non-compartmental analysis. Analysis of variance (ANOVA) was carried out using logarithmically transformed AUC0-t, AUC0- yen and Cmax, and untransformed tmax. In addition, blood glucose concentration was also logarithmically transformed and analyzed. Tolerability and safety profiles were also investigated. There were no significant differences between the single combination tablet and the individual tablets in AUC0-t, AUC0- yen, Cmax and blood glucose concentration. The point estimates (90% confidence intervals) for AUC0-t, AUC0- yen and Cmax were 1.0293 (0.9476 - 1.1178), 1.0253 (0.9185 - 1.1443) and 1.0425 (0.9986 - 1.0883) for gliclazide, and 0.9887 (0.9137 - 1.0697), 0.9915 (0.9189 - 1.0697) and 0.9882 (0.9295 - 1.0505) for metformin, respectively, satisfying the bioequivalence criteria of 80 - 125% as proposed by the US FDA and the Korean legislation. Significant F test values were found between the subjects and subject nested sequence (SEQ) for AUC0-t and Cmax, indicating substantial inter-subject variation in the pharmacokinetics of gliclazide and metformin. However, a SEQ effect in the two-way crossover design did not impair the bioequivalence conclusion. No statistically significant differences were found for tmax and blood glucose concentration between two treatments. The combination tablet of gliclazide/metformin is bioequivalent to co-administration of individual tablets. As a result, the combination tablets are regarded therapeutically equivalent and exchangeable to the co-administration of individual tablets in clinical practice. Moreover, the combination tablets are expected to improve convenience and adherence to prescribed therapy and to contribute to better blood glucose control for patients with Type 2 diabetes.

Pharmacokinetics and bioequivalence of two formulations of rebamipide 100-mg tablets: A randomized, single-dose, two-period, two-sequence crossover study in healthy Korean male volunteers

Background: Rebamipide is a quinolinone-derived gastroprotective agent approved in Korea for the treatment of gastric ulcers, acute gastritis, and exacerbated chronic gastritis. Objectives: The aims of this study were to evaluate the pharmacokinetics and bioequivalence of a reference (branded) and test (generic) formulation of rebamipide 100-mg tablets in healthy Korean male volunteers for the purposes of generic substitution and to evaluate the relationship between genetic polymorphisms in the ABCB1 gene (exons 21 and 26) and rebamipide pharmacokinetics. Methods: This study had a 2-period crossover design, with a 7-day washout between formulations. Healthy Korean male volunteers were randomly assigned to receive a single 100-mg dose of the test or reference formulation, administered with 240 mL of water after a 12-hour overnight fast. Serum concentrations of rebamipide up to 12 hours after administration were determined using a validated HPLC method with fluorescence detection. Vital signs (temperature, blood pressure, and heart rate) were measured before and after dosing in both periods. Adverse events were monitored by clinic staff on the days of study drug administration and were recorded for up to 1 week after the last dose of study medication. Pharmacokinetic parameters were determined using a noncompartmental method. The formulations were considered bioequivalent if the log-transformed ratios of AUC 0−t, AUC 0−∞), and C max were within the predetermined bioequivalence range (80%–125%) established by the US Food and Drug Administration and Korean legislation. The in vitro dissolution profiles of the 2 formulations were examined, and the influence on rebamipide pharmacokinetics of genetic polymorphisms in the ABCB1 gene (P-glycoprotein) was investigated. Results: Thirty healthy Korean male volunteers (mean [SD] age, 22.97 [1.67] years [range, 20–27 years]; height, 174.56 [6.27] cm [range, 159.1–184.8 cm]; and weight, 69.44 [8.32] kg [range, 54.7–90.2 kg]) were enrolled in and completed the study. No adverse events were reported. The 2 formulations had comparable in vitro dissolution profiles. The mean AUC 0−t for the test and reference formulations was 831.09 (329.52) and 903.46 (419.17) ng/mL/h, respectively; the AUC 0−∞ was 851.68 (332.62) and 923.58 (423.21) ng/mL/h; the C max was 218.12 (93.90) and 220.57 (107.48) ng/mL; the T max was 2.05 (1.15) and 2.10 (0.76) hours; and the t ½ was 1.96 (0.52) and 1.93 (0.49) hours. No significant sequence, subject, formulation, or period effects were detected for any pharmacokinetic parameter. The point estimates for AUC 0−t, AUC 0−∞, and C max were 0.95 (90% CI, 0.84–1.06), 0.95 (90% CI, 0.84–1.06), and 1.01 (90% CI, 0.89–1.15), respectively, satisfying the criterion for bioequivalence. There was no statistically significant difference in T max. No significant differences in rebamipide AUC 0−t, AUC 0−∞, or C max were found among the ABCB1 2677 GG, GT, or TT groups, or among the ABCB1 3435 CC, CT, or TT groups. There was no evidence that genetic polymorphisms in the ABCB1 gene influenced the pharmacokinetics of rebamipide. Conclusions: The results of this study in healthy Korean male volunteers suggest that the 2 rebamipide 100-mg tablet formulations administered in the fasted state met the regulatory criterion for bioequivalence. There was no evidence that rebamipide pharmacokinetic parameters were influenced by genetic polymorphisms in the ABCB1 gene (exons 21 and 26). ClinicalTrials.gov identifier: NCT00997789

Relative bioavailability of generic and branded 250-mg and 500-mg oral chlorphenesin carbamate tablets in healthy Korean volunteers: A single-dose, randomized-sequence, open-label, two-period crossover trial

Background: Chlorphenesin carbamate is a skeletal muscle relaxant approved in Korea for use in the treatment of pain and discomfort related to skeletal muscle trauma and inflammation. Objective: The aim of this study was to assess the bioequivalence of a generic formulation of chlorphenesin carbamate at doses of 250 and 500 mg and 2 branded formulations of the same doses in healthy Korean adults. Methods: This single-dose, randomized-sequence, open-label, 2-period crossover study was conducted in healthy Korean male and female volunteers. Subjects were assigned to receive, in a randomized sequence, a single dose of the generic (test) and branded (reference) formulations of chlorphenesin carbamate at a dose of 250 or 500 mg. Blood samples were drawn at 0, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 9, 12, and 15 hours after administration. Pharmacokinetic properties (C max, T max, AUC 0−t AUC 0-∞, t 1/2, and ke) were determined using HPLC. The formulations were to be considered bioequivalent if the 90% CIs of the treatment ratios of the geometric means of C max and AUC 0−t were within a predetermined range of log 0.80 to log 1.25 based on regulatory criteria. Tolerability was assessed by monitoring for adverse events (AEs) on physical examination and/or e-mail and personal interview at the beginning and end of each study period. Results: Twenty-eight subjects (22 men, 6 women) received chlorphenesin carbamate at the 250-mg dose, and 24 male subjects received the 500-mg dose. The mean (SD) ages of the subjects were 24.0 (2.6) and 24.0 (1.9) years in the 250- and 500-mg groups, respectively. No significant differences were found between the test and reference formulations (90% CIs: C max, 1.0048–1.1153 with the 250-mg dose and 0.9630–1.1189 with the 500-mg dose; AUC 0−t, 0.9882–1.0546 and 0.9842–1.0578, respectively). No clinically significant AEs (upper gastric pain, abdominal bloating, pyrexia, edema, nausea, heartburn, constipation, headache, dizziness, drowsiness, or fatigue) were reported throughout the study. Conclusion: In this single-dose study in these healthy Korean subjects, the generic and branded formulations of chlorphenesin carbamate 250 and 500 mg met the regulatory criteria for bioequivalence. All formulations were well tolerated.

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 Cmax, Tmax, t½, AUC0−∞, and AUC0−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 Cmax 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) Tmax of ticlopidine was 1.5 (0.5–2.0) hours in both groups. The mean (SD) t½ 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 AUC0−last, AUC0–∞, and Cmax 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

Potential interactions between cilostazol and probucol: A two-part, single-dose, open-label study in healthy Korean male volunteers

Background: Combined therapy with cilostazol, an antiplatelet agent, and probucol, an antihyperlipidemic agent, has been reported to prevent restenosis after percutaneous transluminal coronary angioplasty. However, the potential for pharmacokinetic drug interactions between the 2 agents has not been evaluated.Objectives: The aims of this study were to compare the pharmacokinetic properties of cilostazol and probucol administered alone and together in healthy Korean male volunteers.Methods: This open-label study in healthy adult (age 20–40 years) male volunteers consisted of 2 parts. Part A had a 1-sequence, 2-period crossover design in which each subject received cilostazol 100 mg (1 tablet) in period 1 and cilostazol 100 mg (1 tablet) plus probucol 500 mg (2 tablets) in period 2. Part B had a parallel-group design in which one group received probucol 250 mg (1 tablet) and the other received probucol 250 mg (1 tablet) and cilostazol 100 mg (1 tablet). Geometric mean ratios for Cmax and AUC were compared by ANOVA, and pharmacokinetic parameters were also compared by t tests. Tolerability was evaluated based on adverse events, ECGs, vital signs, and clinical laboratory test results.Results: Twelve healthy volunteers completed part A; their mean age was 24.1 years (range, 21–29 years), mean height 171.8 cm (range, 163–177 cm), and mean weight 65.2 kg (range, 56.3–77.6 kg). Of the 20 healthy volunteers enrolled in part B, 19 completed the study; their mean age was 25.1 years (range, 21–34 years), mean height 173.2 cm (range, 162–183 cm), and mean weight 65.5 kg (54.0–78.0 kg). The pharmacokinetic parameters of cilostazol and probucol did not differ significantly when the 2 agents were administrated alone or together. In part A, the geometric mean ratios for Cmax and AUC0–60h between coadministration and single administration of cilostazol were 0.8882 (90% CI, 0.7873–1.002) and 1.013 (90% CI, 0.8643–1.188), respectively, for cilostazol; 0.8758 (90% CI, 0.7584–1.011) and 0.9785 (90% CI, 0.7600–1.260) for the OPC-13015 metabolite; and 0.8730 (90% CI, 0.7486–1.018) and 1.004 (90% CI, 0.8847–1.140) for the OPC-13213 metabolite. In part B, the geometric mean ratios for Cmax and AUC0–648h between coadministration and single administration of probucol were 1.134 (90% CI, 0.8177–1.572) and 1.070 (90% CI, 0.7364–1.555), respectively. Twenty-five adverse events were reported by 9 subjects in part A; the most frequently reported were headache (10 events) and nausea (4 events). Twenty adverse events were reported by 10 subjects in part B; the most frequently reported were headache (4 events) and productive cough (3 events). No clinically significant changes were noted in vital signs, ECGs, or laboratory values.Conclusion: In these healthy Korean male volunteers, coadministration of single doses of cilostazol and probucol had no significant effects on the pharmacokinetics of either drug. ClinicalTrials.gov identifier: NCT00549978

Simultaneous quantification of rosiglitazone and its two major metabolites, N-desmethyl and p-hydroxy rosiglitazone in human plasma by liquid chromatography/tandem mass spectrometry: Application to a pharmacokinetic study

We present a simple, rapid, and sensitive liquid chromatography (LC)–tandem mass spectrometry (MS/MS) method for the simultaneous quantification of rosiglitazone and its two major metabolites via CYP2C8/9, N -desmethyl and p-hydroxy rosiglitazone, in human plasma. The procedure was developed and validated using rosiglitazone-d 3 as the internal standard. Plasma samples (0.1 ml) were prepared using a simple deproteinization procedure with 0.2 ml of acetonitrile containing 40 ng/ml of rosiglitazone-d 3. Chromatographic separation was carried out on a Luna C 18 column (100 mm × 2.0 mm, 3-μm particle size) using an isocratic mobile phase consisting of a 60:40 (v/v) mixture of acetonitrile and 0.1% formic acid (aq). Each sample was run at 0.2 ml/min for a total run time of 2.5 min per sample. Detection and quantification were performed using a mass spectrometer in selected reaction-monitoring mode with positive electrospray ionization at m/ z 358.1 → 135.1 for rosiglitazone, m/ z 344.2 → 121.1 for N -desmethyl rosiglitazone, m/ z 374.1 → 151.1 for p-hydroxy rosiglitazone, and m/ z 361.1 → 138.1 for rosiglitazone-d 3. The linear ranges of concentration for rosiglitazone, N -desmethyl rosiglitazone, and p-hydroxy rosiglitazone were 1–500, 1–150, and 1–25 ng/ml, respectively, with a lower limit of quantification of 1 ng/ml for all analytes. The coefficient of variation for assay precision was less than 14.4%, and the accuracy was 93.3–112.3%. No relevant cross-talk and matrix effect were observed. This method was successfully applied to a pharmacokinetic study after oral administration of a 4-mg rosiglitazone tablet to healthy male Korean volunteers.

액토스TM정(염산 피오글리타존 15 mg)에 대한 피로스TM정의 생물학적 동등성

The purpose of the present study was to evaluate the bioequivalence of two pioglitazone HCl tablets, , tablets (Lilly Korea. Ltd., Korea) as a reference drug and , tablets (Reyon Pharm. Co., Ltd., Korea) as test drug, according to the guideline of Korea Food and Drug Administration (KFDA). Twenty-four healthy male Korean volunteers received one tablet containing pioglitazone HCl 15 mg in a crossover study. There was a one-week washout period between the doses. Plasma concentrations of pioglitazone were monitored for over a period of 36 hr after administration by using a high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The area under the plasma concentration-time curve from time zero to 36 hr (), maximum plasma drug concentration () and time to reach () were complied from the plasma concentration-time data. Analysis of variance (ANOVA) test was utilized for the statistical analysis of the parameters using logarithmically transformed and . The 90% confidence intervals of the ratio and the ratio for /. were log 0.8753-log 1.1286 and log 0.8669-log 1.1734, respectively. These values were within the acceptable bioequivalence intervals of log 0.80-log 1.25, recommended by KFDA. In all of these results, we concluded that the . tablet was bioequivalent to the . tablet, based on the rate and extent of absorption.

An open-label, single-dose, parallel-group, dose-increasing study comparing the pharmacokinetics and tolerability of pilsicainide hydrochloride in healthy Korean and Japanese male subjects

Background: Pilsicainide hydrochloride is a class IC antiarrhythmic agent used for the treatment of supraventricular and ventricular arrhythmias. Objective: The objective of this study was to compare the pharmacokinetics and tolerability of pilsicainide in healthy Korean and Japanese male volunteers to satisfy regulatory requirements for marketing pilsicainide in the Republic of Korea. Methods: This was an open-label, single-dose, parallel-group, dose-increasing study. It was simultaneously conducted in healthy Korean and Japanese volunteers from September 2005 through May 2006; pilsicainide was approved for use in the Republic of Korea in 2007. Subjects for the 100-mg group were enrolled after the performance of tolerability evaluations in the 50-mg dose group. Serial blood and urine samples were collected up to 24 hours after dosing, and drug concentrations in plasma and urine were determined by high-performance liquid chromatography. Tolerability was evaluated by monitoring adverse events (AEs), clinical laboratory parameters, and results of 12-lead electrocardiograms (ECGs). Results: Sixteen healthy Korean male subjects (mean [SD] age, 24.5 [4.2] years; weight, 71.8 [5.5] kg; height, 176.6 [6.3] cm) and 16 healthy male Japanese subjects (age, 24.7 [4.9] years; weight, 60.2 [4.4] kg; height, 171.9 [6.4] cm) were enrolled in the study. Values for AUC and C max of pilsicainide increased proportionally with dose escalation in all subjects. Pilsicainide reached C max 0.5 to 1.5 hours after dosing in both the Korean and Japanese subjects. The mean (SD) dose-normalized values for C max for the Korean and Japanese subjects were 9.4 (1.9) and 9.2 (1.6) ng/mL/mg, respectively. The mean (SD) dose-normalized values for AUC 0-∞ were 56.0 (8.0) ng · h/mL/mg in the Korean subjects and 53.8 (8.1) ng · h/mL/mg in the Japanese subjects. None of these findings were statistically significant. A total of 9 AEs occurred in 7 of the 16 Korean subjects; they included dizziness, feeling of being hot, somnolence, and atrioventricular block. All of the AEs were mild in severity and were considered possibly related to pilsicainide. Two of the 16 Japanese subjects had a total of 4 AEs. All of the AEs occurred in the subjects treated with 50 mg. Of the 2 subjects with AEs, 1 subject had a decrease in blood pressure, a sense of discomfort, and PR-interval prolongation on ECG, while the other developed a premature ventricular contraction (PVC). The PR-interval prolongation and PVC were determined to be possibly related to pilsicainide, and these were mild in severity. The other AEs (ie, decreased blood pressure, sense of discomfort) were moderate in severity. Conclusions: The results of this study suggest that the pharmacokinetic profile of pilsicainide was not significantly different between these healthy Korean and Japanese male volunteers. A single dose (50 or 100 mg) of pilsicainide was well tolerated in both ethnic groups.

Bioequivalence Study of Toriem®Tablet to Motilium-M®Tablet (Domperidone Maleate 12.72 mg) Evaluated by Liquid Chromatography/Tandem Mass Spectrometry

The aim of the present study was to evaluate the bioequivalence of two domperidone maleate tablets, Motilium- Tablet (Janssen Korea Ltd., reference product) and Tablet (Daewon Pharm. Co., Ltd., test product). Domperidone was extracted by liquid-liquid extraction using tert-butyl methyl ether and separated in less than 3 min on reverse-phase column using an isocratic elution. A tandem mass spectrometer, as detector, was used for quantitative analysis in positive mode by a multiple reaction monitoring mode to monitor the m/z and the m/z transitions for domperidone and the internal standard (roxithromycin), respectively. Calibration curves, from ng/mL of domperidone, showed correlation coefficients (r) higher than 0.9941. Intra day and inter day precision (C.V. %) for quality control were ranged from 10.04 to 16.09% and from 10.87 to 18.69%, respectively. The lower limit of quantification (LLOQ) of domperidone was 0.05 ng/mL. The method described is precise and sensitive and has been successfully applied to the study of bioequivalence of domperidone in 24 healthy Korean volunteers. Twenty-four healthy male Korean volunteers received a single dose of each medicine ( domperidone maleate) in a crossover study. There was a one-week washout period between the doses. Plasma concentrations of domperidone were monitored for over a period of 24 hr after the administration. (the area under the plasma concentration-time curve) was calculated by the linear trapezoidal rule. (maximum plasma drug concentration) and (time to reach ) were compiled from the plasma concentration-time data. The 90% confidence intervals for the log transformed data were within acceptable range of log 0.8 to log 1.25 (e.g., for , for ). The major parameters, and met the criteria of KFDA for bioequivalence indicating that tablet is bioequivalent to Motilium- tablet.

Pharmacokinetics and bioequivalence of 20 mg omeprazole capsule in 24 healthy Korean male volunteers

A randomized, two-way, crossover bioequivalence study in 24 healthy Korean male volunteers was conducted to compare bioequivalence of two brands of 20 mg omeprazole capsules, Hutex omeprazole (Hutex Pharm Co. Korea) as a test and Yuhan Losec (Yuhan Co. Ltd., Korea) as a reference drug. Subjects were administered single dosage of 1 capsule of 20 mg of each formulation with 240 ml of water after 10 hs overnight fasting on 2 treatment days separated by one-week washout period. After dosing, serial blood sampling was held during 9 hs. Plasma was analyzed for omeprazole by a validated HPLC method with ultraviolet detection in the range of 10 approximately 1,000 ng/ml with the lowest limit of quantification of 10 ng/ml. Several pharmacokinetic (PK) parameters were determined from the plasma samples, and data from reference and test formulations in the plasma were represented such as AUC0-t (1,223.3 vs 1,284.3 ng x h/ml), [formula in text](1,311.1 vs 1,410.0 ng x h/ml), Cmax (598.7 vs 598.1 ng/ml), tmax (1.9 vs 1.9 h), t1/2 (1.3 vs 1.4 h) and Ke (0.67 vs 0.67 h-1), respectively. AUC0-t, [formula in text] and Cmax were tested for bioequivalence after log-transformation of plasma data. PK parameters with 90% confidence interval (CI) of test/reference ratio based on ANOVA analysis were 0.961 approximately 1.135 for AUC0-t, 0.968 approximately 1.144 for [formula in text] and 0.951 approximately 1.117 for Cmax. PK parameters with 90% CI were within the bioequivalence range of 80 - 125% of FDA statistical limit. Therefore, both omeprazole formulations were bioequivalent during fasting state in these healthy Korean male volunteers.

건일로딘 캡슐(에토돌락 200mg)에 대한 에토딘 캡슐의 생물학적동등성

The purpose of the present study was to evaluate the bioequivalence of two etodolac capsules, Kuhnillodin capsule (Kuhnil. Co., Ltd., Seoul, Korea) as reference drug and Etodin capsule (Myungmun Pharm. Co., Ltd., Seoul, Korea) as test drug, according to the guidelines of Korea Food and Drug Administration (KFDA). Twenty-three healthy male Korean volunteers received one capsule at the dose of 200 mg etodolac in a crossover study. There was a one-week washout period between the doses. Plasma concentrations of etodolac were monitored by a high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) for over a period of 24 hr after the administration. was calculated by the linear trapezoidal rule method. and were compiled from the plasma concentration-time data. Analysis of variance (ANOVA) was carried out using logarithmically transformed and . The 90% confidence intervals of the ratio and the ratio for Etodin/Kuhnillodin were and , respectively. These values were within the acceptable bioequivalence intervals of . Thus, our study demonstrated that Etodin was bioeqiovalent to Kuhnillodin preparation when the rate and extent of absorption between two preparations were compared.

Pharmacokinetic interaction of flecainide and paroxetine in relation to the CYP2D6*10 allele in healthy Korean subjects

The objectives were to evaluate the effect of CYP2D6 genetic polymorphism on the pharmacokinetics of flecainide, and also on the extent of drug interaction with paroxetine as a CYP2D6 inhibitor after a single oral administration in healthy subjects. An open-label, two-period, single-sequence, cross-over study was performed in 21 healthy Korean male volunteers (seven for CYP2D6*1/*1 or *1/*2, group 1; seven for CYP2D6*1/*10, group 2; seven for CYP2D6*10/*10 or *10/*36, group 3). Subjects were administered 200 mg of flecainide on day 1. After a 7-day wash-out period, subjects were administered 20 mg of paroxetine from day 8 to 14, and 200 mg of flecainide on day 15. Blood sampling was performed up to 72 h after flecainide administration. Terminal elimination half-life and mean residence time (MRT) were significantly different among three genotype groups after a single oral administration of flecainide (P = 0.021, 0.011, respectively). Area under the concentration-time curve, terminal elimination half-life and MRT increased significantly after paroxetine co-administration only in groups 1 and 2. This study reports that the extent of drug interaction between flecainide and paroxetine is influenced by the CYP2D6*10 allele in healthy subjects, which is frequent in Asians.

Bioequivalence of Cyclosporine A 100 mg Soft Capsules (Cipol-N®vs. Sandimmun Neoral®) in Healthy Korean Volunteers

The bioequivalence of two cyclosporine A (CyA) 100 mg soft capsules (Chong Kun Dang's as the test drug; Korea Novartis' Sandimmun as the reference drug) was assessed in healthy male Korean volunteers after oral administration of 200 mg CyA according to a randomized crossover design. The whole blood samples were analyzed for the determination of parent CyA in the blood by using a validated HPLC/diode array detector method. The mean values for reference and test products were and , respectively. The mean values were for the reference product, and for the test product. was for the reference and for the test product. The differences of , and were -3.35, -13.28 and +10.63%, respectively. The point estimates and 90% confidence intervals for and were 0.981 (0.9171 to 1.0514) and 0.876 (0.8229 to 0.9336), respectively. Based on the pharmacokinetic and statistical data, we conclude that these two products are bioequivalent and can be considered interchangeable in the medical practice.