SoJeong Yi

Pharmacokinetic interaction of fimasartan, a new angiotensin II receptor antagonist, with amlodipine in healthy volunteers.

Aim: Fimasartan (BR-A-657) is a new angiotensin II receptor antagonist used as antihypertensive agent. The objective of this study was to investigate the effect of the coadministration of fimasartan and amlodipine on the steady-state pharmacokinetics of each drug. Methods: This study comprised 2 separate parts, A and B; each was a multiple-dose, open-label, 2-period crossover study in healthy male volunteers. In part A, 20 subjects were administered 120 mg of fimasartan alone in period I and fimasartan with 10 mg of amlodipine in period II. In part B, 14 subjects were administered amlodipine alone, followed by coadministration with fimasartan. Blood samples for pharmacokinetics were collected up to 24 hours after the last dosing. The pharmacokinetics of the coadministration of fimasartan and amlodipine were compared with that of each drug alone. Results: The geometric mean ratio and 90% confidence intervals for Cmax,ss and area under the plasma concentration-time curve (AUC)τ,ss of fimasartan (with/without amlodipine) were 1.096 (0.746-1.610) and 1.163 (1.001-1.351), respectively. The geometric mean ratios (90% confidence interval) for Cmax,ss and AUCτ,ss of amlodipine (with/without fimasartan) after coadministration with fimasartan were 1.037 (0.969-1.110) and 0.975 (0.920-1.033), respectively. Conclusions: Coadministration of fimasartan and amlodipine did not result in clinically relevant changes in the systemic exposure of fimasartan or amlodipine.

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

AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Reduced valproic acid serum concentrations due to drug interactions with carbapenem antibiotics: overview of 6 cases.

Background: The plasma concentrations of valproic acid (VPA) are known to decrease during the concomitant administration of carbapenem antibiotics, such as meropenem, imipenem, and ertapenem. This study summarizes 6 cases of drug–drug interactions between VPA and carbapenem antibiotics. Methods: To investigate the onset and severity of the reductions in the concentration of VPA in patients with or without the coadministration of carbapenem antibiotics, the authors performed a retrospective evaluation of therapeutic drug monitoring (TDM) reports that described a decrease in the serum concentrations of VPA during the concomitant use of carbapenem antibiotics from January 2008 to December 2010 in the Seoul National University Hospital. The evaluated TDM reports included 6 cases. The decrement ratio of the VPA serum concentration was calculated from the TDM reports, and the change in the half-life of the VPA was also estimated. Results: Six cases presented with changes in the VPA serum concentration before and after the administration of carbapenem antibiotics. (Three cases were treated with meropenem, 2 were treated with ertapenem, and 1 was treated with imipenem.) The VPA concentrations reduced by (mean ± SD) 88.7 ± 5.3% (3 cases of meropenem), 74.0 ± 9.8% (2 cases of ertapenem), and 73.3% (1 case of imipenem), respectively, and the half-life of VPA reduced by 80.1 ± 9.0%, 64.4 ± 24.2%, and 50.6%, respectively. Conclusion: The interaction between VPA and carbapenem antibiotics caused decreases in the VPA serum concentrations; the extent of this decrease was greater in the meropenem-treated patients than in the imipenem-treated or ertapenem-treated cases. Because the therapeutic effect of VPA depends on its serum concentration, it should be recognized that there may be a loss of seizure control in patients using VPA with carbapenem antibiotics.

Comparative Pharmacokinetics and Tolerability of Branded Etanercept (25 mg) and Its Biosimilar (25 mg): A Randomized, Open-Label, Single-Dose, Two-Sequence, Crossover Study in Healthy Korean Male Volunteers

BACKGROUND The biosimilar is a recombinant dimeric tumor necrosis factor receptor (TNFR) under development for the treatment of rheumatoid arthritis. OBJECTIVE The aim of this study was to compare the pharmacokinetics and/or tolerability of branded etanercept and its biosimilar in healthy Korean men before investigating the clinical efficacy of the biosimilar in subjects. METHODS Etanercept (reference, 25 mg) or its biosimilar (test, 25 mg) was subcutaneously injected to the periumbilical area of healthy volunteers in a randomized, open-label, single-dose, active-controlled, two-sequence, crossover study. Plasma concentrations of TNFR in serial blood samples for 480 hours after dosing were measured by ELISA. The primary outcome, pharmacokinetic characteristics, was assessed via geometric mean ratios (GMRs) of the log-transformed pharmacokinetic parameters. The second outcome, tolerability, was evaluated using physical examinations, electrocardiograms, clinical laboratory tests, vital sign measurements, and adverse events (AEs) by unmasked investigators. RESULTS Twenty-three men of mean age (%CV) 25.8 years (17.1%) and weight 70.5 kg (12.8%) were administered study medication. Four subjects dropped out after the first period; their data were included in the analysis. Both test and reference drugs were absorbed with a median T(max) of 72 (range, 36-144) hours and eliminated with mean (%CV) t(½) of 92.7 (20.9%) and 87.4 (16.6%) hours, respectively. The GMRs (90% CIs) of the test to reference drug for C(max), AUC(0-t), and AUC(0-∞) were 0.99 (0.83-1.17), 0.95 (0.79-1.13), and 0.95 (0.80-1.13), respectively. Eleven of 21 (52.4%) and 8 of 21 (38.1%) subjects administered the test and reference drugs reported 22 and 21 AEs, respectively. Common AEs were headache (14.3%), throat irritation (8.5%), and epistaxis (9.5%). Three serious AEs related to a traffic accident (back, neck, and musculoskeletal pain) were reported in a test drug-treated subject. CONCLUSIONS In this select group of Korean healthy male volunteers, the reference drug and the test biosimilar met the standard criteria for assuming bioequivalence as defined by Korean regulatory authorities. Because the reference drug is a biological product, further trials for assessment of its efficacy are still required by Korean authorities. World Health Organization International Clinical Trials Registry Platform identifier: KCT0000118.

Tolerability and Pharmacokinetics of Lobeglitazone (CKD-501), a Peroxisome Proliferator-Activated Receptor-γ Agonist: A Single- and Multiple-Dose, Double-Blind, Randomized Control Study in Healthy Male Korean Subjects

BACKGROUND Lobeglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist with partial PPAR-α affinity, was developed to treat type 2 diabetes mellitus. OBJECTIVE This studys aim was to evaluate the tolerability and pharmacokinetic (PK) properties of lobeglitazone to satisfy regulatory requirements for marketing approval in Korea. METHODS A block-randomized, double-blind, placebo-controlled, single- and multiple-dose study was conducted in healthy subjects. In the pilot study, 4 subjects were administered 0.5 mg, including 1 receiving a placebo. Then, the single-dose study was conducted with 1, 2, 4, and 8 mg doses (8 subjects in each group, including 2 receiving placebos), followed by the multiple-dose study with 1, 2, and 4 mg doses (once daily for 7 days; 8 subjects in each group, including 2 receiving placebos). Serial samples of blood and urine were collected and drug concentrations were determined by high turbulence liquid chromatography-LC/MS/MS. Tolerability assessments were performed throughout the study. Adverse events (AEs) were determined from general health-related questions and self-reports. RESULTS Thirty-six (mean [SD]; age, 23.6 [2.7] years; weight, 70.0 [6.9] kg) and 25 Korean male subjects (age, 23.5 [3.1] years; weight 69.4 [9.4] kg) were enrolled in the single- and multiple-dose studies, respectively. The data from subjects administered lobeglitazone who completed the study (27, single; 18, multiple) was included in the PK analyses. In the single-dose study, the AUC and C(max) of lobeglitazone increased with the dose. After repeated dosing for 7 days, the accumulation ratio ranged from 1.1 to 1.4. A total of 25 AEs were reported by 11 (30.6%) and 8 subjects (33.3%) in the single- and multiple-dose studies, respectively. All AEs were mild in intensity and not serious. CONCLUSIONS Lobeglitazone was well tolerated in this small, selected group of healthy male Korean volunteers. The AUC and C(max) of lobeglitazone increased in a dose-proportional manner from 1 to 4 mg.

Increased Systemic Exposure of Fimasartan, an Angiotensin II Receptor Antagonist, by Ketoconazole and Rifampicin

The authors studied the effects of ketoconazole and rifampicin on the pharmacokinetics of a single dose of fimasartan (BR‐A‐657), a newly developed angiotensin II receptor antagonist for the treatment of hypertension, in 22 healthy participants. Ketoconazole increased the maximumplasma concentration (Cmax) and area under the plasma concentration vs time curve to infinity (AUC⧝ of fimasartan by 2.47‐fold (90% confidence interval [CI], 1.61‐3.79) and 2.03‐fold (1.56‐2.64), respectively. Concomitant administration of rifampicin increased the Cmax and AUC∞ of fimasartan by 10.33‐fold (90% CI, 6.74‐15.81) and 4.60‐fold (3.54‐5.97). In vitro studies indicated that ketoconazole inhibited the uptake of fimasartan into cells expressing OATP1B1 with a Ki of 107.7 µM, and rifampicin inhibited OAT1‐ and OATP1B1‐mediated fimasartan transport with a Ki of 212 µM and 12.2 µM, respectively. The systemic exposure of fimasartan was significantly increased by coadministration of ketoconazole or rifampicin in healthy volunteers. This is consistent with the in vitro results, in which fimasartan is a substrate of CYP3A and OATP1B1.

Pharmacokinetics and pharmacodynamics of oral tolvaptan administered in 15- to 60-mg single doses to healthy Korean men.

Abstract: Tolvaptan is a selective arginine vasopressin V2-receptor antagonist that is used as an aquaretic agent. This trial investigated the pharmacokinetics and pharmacodynamics of 15- to 60-mg single oral doses of tolvaptan in healthy Korean men. A dose block–randomized, placebo-controlled, double-blind, single ascending dose trial was conducted with 46 subjects receiving tolvaptan (15, 30, or 60 mg) or placebo. To determine pharmacokinetics and pharmacodynamics, blood and urine samples were collected at baseline and up to 48 hours after drug administration. Urine volume and fluid intake were measured for 24 hours starting the day before dosing (day −1) as baseline, and on the day of drug administration (day 1). Tolvaptan showed dose-linear pharmacokinetic characteristics regarding area under the concentration–time curve. Changes from baseline in 24-hour urine volume and 24-hour fluid balance correlated significantly with area under the concentration–time curve from time 0 to the last measurable time. Dose-dependent increases were observed in serum osmolality, serum sodium concentration, and free water clearance in the 4- to 8-hour interval after dosing, and these increases were maintained for at least 24 hours. Single 15- to 60-mg doses of tolvaptan exhibited linear pharmacokinetics and resulted in substantial, dose-dependent aquaresis in healthy Korean men.

Influence of alcohol on the hemodynamic effects and pharmacokinetic properties of mirodenafil: A single-dose, randomized-sequence, open-label, crossover study in healthy male volunteers in Korea

BACKGROUND Mirodenafil is a phosphodiesterase type 5 (PDE-5) inhibitor developed for the treatment of erectile dysfunction. Mirodenafil has the possibility of being administered with alcohol. OBJECTIVE This study assessed the hemodynamic effects and pharmacokinetic properties of mirodenafil administered with alcohol. METHODS This single-dose, randomized-sequence, open-label, crossover study was conducted in healthy male volunteers at the Clinical Trials Center, Seoul National University Hospital, Seoul, Korea. Volunteers were randomly allocated to 1 of 3 randomized-sequence groups, each of which consisted of 3 administration phases, each separated by a 1-week washout period: oral mirodenafil 100 mg, alcohol 0.5 g/kg, and both. Vital signs (systolic blood pressure [SBP], dia-stolic BP [DBP], and pulse rate) were measured before (baseline) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours after administration. Because volunteers were given a standardized meal at 4 hours after mirodenafil and/or alcohol administration, hemody-namic results were assessed using the maximum decrease from baseline during a period of up to 4 hours after administration. For pharmacokinetic assessment, serial blood samples were collected before (baseline) and at 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after administration. Tolerability was assessed using monitoring of adverse events (AEs), clinical laboratory parameters, and results of 12-lead electrocardiography. RESULTS A total of 20 subjects participated in the study (mean [range] age, 25.5 years [20-41 years]; weight, 69.8 kg [57.4-87.2 kg]; and height, 174.7 cm [168-186 cm]). Up to 4 hours after the administration of mirodenafil, alcohol, and mirodenafil + alcohol, the mean (SD) maximum decreases in SBP were 8.5 (3.5), 13.5 (7.8), and 15.1 (6.7) mm Hg, respectively, and the maximum decreases in DBP were 6.4 (4.8), 13.3 (7.4), and 13.8 (5.2) mm Hg. Simultaneous administration of mirodenafil + alcohol was associated with additional mean (95% CI) decreases in SBP and DBP of 1.7 mm Hg (-6.0 to 2.6 mm Hg) and 0.6 mm Hg (-4.7 to 3.6 mm Hg) compared with alcohol alone. Pharmacokinetic parameters of mirodenafil were not significantly different when the drug was administered with or without alcohol. The mean (SD) AUC(0-t) values were 842.0 (434.7) ng/mL/h with mirodenafil and 833.4 (398.2) ng/mL/h with mirodenafil + alcohol. The most common AEs considered at least possibly related to study drug were nasal congestion (7 subjects [35%]), headache (3 [15%]), nausea (1 [5%]), and hiccups (1 [5%]). CONCLUSIONS The concurrent administration of mirodenafil with alcohol was not associated with clinically significant hemodynamic changes in these healthy male volunteers in Korea. The pharmacoki-netics of mirodenafil were not significantly altered by this concurrent administration. Mirodenafil administered with alcohol had a tolerability profile comparable to that of mirodenafil alone.

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.

Effect of multiple doses of fimasartan, an angiotensin II receptor antagonist, on the steady-state pharmacokinetics of digoxin in healthy volunteers.

UNLABELLED Fimasartan (BR-A-657) is an angiotensin II receptor antagonist, recently approved as an antihypertensive agent. OBJECTIVE This study aimed to investigate whether administration of fimasartan has an effect on the steady-state pharmacokinetics of digoxin. METHODS An open-label, two-period, two-treatment, single-sequence, crossover study was conducted in 14 healthy male volunteers. On the first day of each 7-day treatment period, subjects received a loading dose of digoxin 0.5 mg, either alone or together with fimasartan 240 mg in the morning, followed by an additional dose of digoxin 0.25 mg after 6 h. On the subsequent 6 days, digoxin 0.25 mg, either alone or with fimasartan 240 mg was administered once daily. Serial blood samples for pharmacokinetics were collected up to 24 h after the last administration in each period. RESULTS The geometric mean ratio and 90% confidence intervals (CI) for the Cmax,ss and AUCτ,ss of digoxin (with/without fimasartan) were 1.307 (1.123 - 1.520) and 1.087 (1.015 - 1.165), respectively. Study medications were well-tolerated without serious adverse events or clinically meaningful changes. CONCLUSIONS Coadministration of fimasartan with digoxin does not result in clinically significant changes of digoxin pharmacokinetics at steady-state in healthy subjects.