Healthy Korean Subjects Research Articles

Pharmacokinetics of a New Orally Disintegrating Tablet Formulation of Aripiprazole 15 mg Administered Without Water in Healthy Middle-aged Korean Subjects

PurposeThe main objective of this study was to compare the pharmacokinetic properties and relative bioavailability of two 15-mg aripiprazole formulations (an orally disintegrating tablet [ODT] as the test drug and a conventional tablet as the reference drug) in healthy middle-aged Korean subjects. MethodsThis study was conducted in a population of healthy middle-aged Korean subjects as a randomized, open-label, single-dose, 2-sequence, 2-period crossover trial. After administration of a single dose of a 15-mg aripiprazole standard tablet with 240 mL water or an aripiprazole 15-mg ODT without water, blood samples were collected at specific time intervals from 0 to 240 hours. Concentrations of aripiprazole in plasma were analyzed by using a LC-MS/MS method of detection. Data on the pharmacokinetic parameters were recorded, and the 90% CIs of the ratios of the geometric means of the parameters were determined from the logarithmically transformed data by using an ANOVA model. FindingsThirty-nine healthy middle-aged Korean subjects were enrolled (mean age, 52.7 years; mean height, 167 cm; mean weight, 67.6 kg); 33 participants completed the study (29 male subjects and 4 female subjects). The 90% CIs of the geometric means ratio (test drug/reference drug) of Cmax, AUC0–last, and AUC0–∞ values were 0.95 to 1.14, 0.98 to 1.09, and 0.97 to 1.08, respectively. All of the subjects who experienced adverse events recovered without sequelae, and no serious adverse events were observed. ImplicationsThe aripiprazole pharmacokinetics was similar for the ODT and standard tablet of 15-mg aripiprazole in these healthy middle-aged Korean subjects. The aripiprazole ODT formulation is therefore expected to offer a convenient alternative for patients who have difficulty swallowing tablets without water. The study was registered at http://cris.nih.go.kr (registration number: KCT0001677).

Pharmacokinetic Interaction Between Amlodipine and Lobeglitazone, a Novel Peroxisome Proliferator–activated Receptor-γ Agonist, in Healthy Subjects

PurposeLobeglitazone, a peroxisome proliferator–activated receptor-γ agonist, was developed for the treatment of diabetes mellitus. Because the prevalence of hypertension is high among patients with diabetes mellitus, lobeglitazone is likely to be used with the antihypertensive drug amlodipine. We evaluated the pharmacokinetic interactions between lobeglitazone and amlodipine in healthy male Korean subjects. MethodsThe study used a randomized, open-label, multiple-dose, 3-treatment, 3-period, 6-sequence crossover design. A total of 24 healthy subjects were enrolled. Blood samples for pharmacokinetic analysis were collected according to a planned schedule after 0.5 mg of lobeglitazone and 10 mg of amlodipine were administered alone or concomitantly once per day for 10 days. FindingsA total of 24 healthy male subjects participated in the study (mean [SD] age, 26.6 [3.9] years; weight, 67.8 [5.7] kg; and height, 173.6 [6.4] cm). Three participants voluntarily withdrew after the second period, and 1 participant dropped out because of increased creatinine kinase levels caused by strenuous exercise before the start of the third period. Thus, 21 participants completed the study schedule to compare the pharmacokinetic parameters of lobeglitazone, and 22 participants completed the study of amlodipine. The geometric mean ratio (with 90% CIs) of Cmax,ss and AUCτ,ss for lobeglitazone administered concomitantly with amlodipine versus lobeglitazone administered alone was 1.01 (0.93–1.09) and 1.06 (0.92–1.23), respectively. The geometric mean ratio (with 90% CIs) of Cmax,ss and AUCτ,ss for amlodipine administered concomitantly with lobeglitazone versus amlodipine administered alone was 0.98 (0.94–1.02) and 1.00 (0.96–1.05). No serious drug-induced adverse events were reported in the study, and no clinically significant changes in vital signs, physical examination results, clinical laboratory results, or ECGs were noted. ImplicationsThe coadministration of lobeglitazone and amlodipine did not affect the pharmacokinetics of lobeglitazone or amlodipine in these healthy male Korean subjects. ClinicalTrials.gov identifier: NCT01341392.

An assessment of the Pharnacokinetics of DW1029M in Healthy Korean Subjects

An assessment of the Pharnacokinetics of DW1029M in Healthy Korean Subjects

Coadministration of duloxetine and tolperisone in relation to CYP2C19 genotype in Korean subjects

Tolperisone is a centrally acting muscle relaxant is prescribed for the treatment of muscle spasm. Tolperisone is predominantly biotransformed by CYP2D6, and to a lesser extent by CYP2C19 and CYP1A2. Duloxetine is a potent dual reuptake inhibitor of serotonin and norepinephrine and acts as an inhibitor of CYP2D6. As CYP2C19 is one of the most important polymorphic CYPs, the aim of study was to determine pharmacokinetic changes of tolperisone after coadministration of duloxetine according to CYP2C19 genotype. Twenty four healthy Korean subjects were volunteered and classified into three different groups in relation to CYP2C19 genotype: CYP2C19EM (CYP2C19*1/*1, n = 9), CYP2C19IM (CYP2C19*1/*2 or CYP2C19*1/*3, n = 8) and CYP2C19PM (CYP2C19*2/*2, CYP2C19*2/*3 or CYP2C19*3/*3, n = 7). In the control phase, all subjects received a single 150 mg oral dose of tolperisone after overnight fasting. After administration of 30 mg duloxetine twice in a day for consecutive three days, 150 mg oral dose of tolperisone was administered one hour after administration of a single 30 mg oral dose of duloxetine in test phase. Blood samples were collected up to 12 hours after drug administration, and plasma concentrations of tolperisone were determined by using liquid chromatography-tandem mass spectrometry system. Cmax of test phase increased by 1.93-fold, 1.80-fold, and 1.57-fold, respectively in CYP2C19EM, CYP2C19IM, and CYP2C19PM group, compared to control phase (P = 0.045, P = 0.027, and P = 0.031, respectively). AUC0-∞ of test phase was significantly higher in CYP2C19EM and CYP2C19IM group than that of control phase (P = 0.034 and P = 0.005, respectively), but there was no significant difference in CYP2C19PM group between control phase and test phase (P = 0.124). Coadministration of tolperisone and duloxetine has significant effects on the pharmacokinetics of tolperisone according to CYP2C19 genotype.

The effects of Environmental and clinical factors on basal platelet Aggregation and coagulation in Korean Healthy Subjects

The effects of Environmental and clinical factors on basal platelet Aggregation and coagulation in Korean Healthy Subjects

Cyp2d6*10 Allele Has Significant Effects on The Pharmacokinetics of Tramadol and Its Metabolite

Tramadol is a centrally acting analgesic used to treat moderate to severe pain. Tramadol exerts its activity by binding to the μ-opioid receptor and inhibiting the reuptake of serotonin and norepinephrine. Tramadol is metabolized to its active metabolite, Ο-desmethyltramadol, by CYP2D6. About 20 to 30% of drugs in clinical use are metabolized by CYP2D6 and CYP2D6 genetic polymorphism have been associated with altered enzyme activity. As CYP2D6*10 allele is the most common allele in the Asian population, we investigated the effect of CYP2D6*10 allele on the pharmacokinetics of tramadol and its active metabolite. Forty-four healthy Korean subjects were recruited and divided into 3 different groups according to CYP2D6 genotype: CYP2D6*wt/*wt (*w t= *1 or *2, n = 15), CYP2D6*wt/*10 (n = 14) and CYP2D6*10/*10 (n = 15). After overnight fasting, each subject received a single oral dose of 100 mg tramadol. Blood samples were collected up to 30 hours after drug intake, and plasma concentrations of tramadol and its metabolite were determined by using validated liquid chromatography-tandem mass spectrometry system. Although Cmax of tramadol was not significantly different among 3 different groups, AUC0-∞ of tramadol in CYP2D6*10/*10 group was 1.56-fold higher than that in CYP2D6*wt/*wt group (P < 0.001) and apparent oral clearance (CL/F) of tramadol in CYP2D6*10/*10 group was 32.9% lower, compared to CYP2D6*wt/*wt group. In terms of its active metabolite, Cmax and AUC0-∞ in CYP2D6*10/*10 group were significantly higher than those in CYP2D6*wt/*wt group (both, P < 0.001). CYP2D6*10 allele has significant effects on the plasma exposure of tramadol and its active metabolite.

Coadministration of Fluvoxamine and Tolperisone in relation to CYP2D6 genotype

Tolperisone, a piperidine derivate, is used to relieve spasticity of neurological origin and muscle spasm. CYP2D6 was identified as the key enzyme in the metabolism of tolperisone and CYP1A2 and CYP2C19 were also involved in the metabolism of tolperisone. Fluvoxamine is an antidepressants and known as one of CYP2C19 inhibitors. As CYP2D6 is very high polymorphic and causes large interindividual differences in drug response, we investigated the effects fluvoxamine, a CYP2C19 inhibitor, on the pharmacokinetic parameters of tolperisone. Thirty healthy Korean subjects were volunteered and divided into three different groups according to CYP2D6 genotype: CYP2D6*wt/*wt (*wt = *1 or *2, n = 10), CYP2D6*wt/*10 (n = 10), and CYP2D6*10/*10 (n = 10). All subjects received a single oral dose of 150 mg tolperisone in the control phase after overnight fasting. Before study day (day 6), a 50 mg oral dose of fluvoxamine was administered once a day for five days. On day 6, subjects received a single oral dose of tolperisone one hour after the administration of fluvoxamine. Blood samples were collected up to 12 hours after drug administration, and plasma concentrations of tolperisone were determined by using liquid chromatography-tandem mass spectrometry system. Cmax and AUCinf of tolperisone was significantly different in each group between control phase and study day (P < 0.01). On study day, Cmax increased by 3.6-fold, 2.0-fold, and 5.0-fold, respectively in the CYP2D6*wt/*wt, CYP2D6*wt/*10, and CYP2D6*10/*10 group, compared to control phase. Also, apparent oral clearance (CL/F) of tolperisone on study day decreased by 74.2%, 72.0%, and 86.2%, respectively in CYP2D6*wt/*wt, CYP2D6*wt/*10, and CYP2D6*10/*10 group, compared to control phase Significant differences in the pharmacokinetics of tolperisone were observed after coadministration of fluvoxamine in relation to CYP2D6 genotype.

Determination of DPYD enzyme activity in Korean population.

Dihydropyrimidine dehydrogenase (DPYD) is an enzyme that regulates the rate-limiting step in pyrimidine metabolism, especially catabolism of fluorouracil. This study was performed to analyze the association between DPYD genetic variants and DPYD enzyme activity in the Korean population. We screened the genetic variants and analyzed the enzyme activity in 73 healthy Korean subjects (69 men and 4 women; mean age, 22.6 years). Direct sequencing was conducted using the ABI 3730XL system, and enzyme activity was determined using high-performance liquid chromatography. A total of 83 genetic variants were observed. Among the identified genetic variants, 32 were polymorphic including 3 core and 11 novel genetic variants. Association analysis between each genetic variant and enzyme activity in Korean subjects showed that 2 novel genetic variants, -832 G>A and -131 C>A, induced a significant difference in enzyme activity (P < 0.05). To our knowledge, this is the first study that has examined the association between enzyme activity and DPYD genetic variants in the Korean population. In this study, we identified novel genetic variants that are associated with the enzyme activity. These findings will be valuable for further pharmacogenetic studies and especially useful for personalized medicine.

Pharmacokinetic Properties and Tolerability of Rotigotine Transdermal Patch After Repeated-Dose Application in Healthy Korean Volunteers

PurposeRotigotine, a nonergolinic dopamine receptor agonist, is a once-daily transdermal patch developed for the treatment of Parkinson’s disease and restless legs syndrome. The objective of the present study was to determine the pharmacokinetic characteristics and tolerability of rotigotine transdermal patch after repeated-dose application in healthy male and female Korean subjects. MethodsIn this randomized, double-blind, placebo-controlled, repeated-dose study, subjects were randomly assigned to receive either rotigotine or placebo (ratio, 20 rotigotine to 4 placebo, per sex). Rotigotine patches were applied once daily at a dose of 2 mg/24 h on days 1 to 3, followed by 4 mg/24 h on days 4 to 6. Serial blood and urine samples were collected on days 1 to 9 for the determination of the concentrations of rotigotine and its metabolites. Tolerability was evaluated by adverse events determined using physical examination, including vital signs with orthostatic measurements; ECG; and clinical laboratory testing. FindingsA total of 48 healthy Korean subjects were enrolled (24 men, 24 women; mean age, 24 years). Approximately 50% of the total drug content was delivered within 24 hours. The mean plasma concentration of unconjugated rotigotine increased proportionally with dose. At the 2 mg/24 h dose at steady state, the geometric mean AUC0–24h and Cmax values of unconjugated rotigotine were 5.88 ng·h/mL and 0.347 ng/mL, respectively; at the 4 mg/24 h dose, the corresponding values were 13.74 ng·h/mL and 0.838 ng/mL. The mean t½ of rotigotine was 4.96 hours. At the 2 mg/24 h dose at steady state, the geometric mean AUC0–24h and Cmax values of total rotigotine were 14.02 ng·h/mL and 0.776 ng/mL; at the 4-mg/24 h dose, 32.38 ng·h/mL and 1.867 ng/mL. Common adverse events reported in the rotigotine-treated subjects included nausea (17 subjects, 42.5%), headache (11, 27.5%), and dizziness (9, 22.5%). No clinically significant changes in blood pressure, ECG, or laboratory values were observed. ImplicationsThe mean plasma exposures of unconjugated rotigotine increased proportionally with dose. Repeated daily application of the rotigotine patch was well tolerated in these healthy Korean volunteers. ClinicalTrials.gov identifier: NCT01964573.

A pharmacokinetic and pharmacodynamic drug interaction between rosuvastatin and valsartan in healthy subjects.

PurposeValsartan, an angiotensin-receptor blocker, and rosuvastatin, a competitive inhibitor of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, are frequently coadministered to treat patients with hypertension and dyslipidemia. The study reported here sought to evaluate the pharmacokinetic and pharmacodynamic interactions between rosuvastatin and valsartan in healthy Korean subjects.Subjects and methodsThirty healthy male Korean subjects were administered with rosuvastatin (20 mg/day), valsartan (160 mg/day), and both drugs concomitantly for 4 days in a randomized, open-label, multiple-dose, three-treatment, three-period crossover study. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and valsartan were determined using validated high-performance liquid chromatography with tandem mass spectrometry. Lipid profiles and vital signs (systolic and diastolic blood pressure and pulse rate) were measured for the pharmacodynamic assessment.ResultsFor rosuvastatin, the geometric mean ratios (90% confidence intervals [CIs]) of coadministration to mono-administration were 0.8809 (0.7873−0.9857) for maximum plasma concentration at steady state and 0.9151 (0.8632−0.9701) for area under the concentration–time curve (AUC) over a dosing interval at steady state. For valsartan, the geometric mean ratios (90% CIs) of those were 0.9300 (0.7946−1.0884) and 1.0072 (0.8893−1.1406), respectively. There were no significant differences in the metabolic ratio of N-desmethyl rosuvastatin AUC to rosuvastatin AUC between coadministration and rosuvastatin alone. No interaction was found in terms of systolic or diastolic blood pressure or lipid profiles. Combined treatment with valsartan and rosuvastatin was generally well tolerated without serious adverse events.ConclusionThe pharmacokinetic profiles of rosuvastatin and valsartan in combination were comparable with those of rosuvastatin and valsartan administered individually, suggesting that their individual pharmacokinetics were not affected by their coadministration. No dose adjustment was required and the results are supportive of a study in a larger patient population.

Multiplex genotyping of cytokine gene SNPs using fluorescence bead array.

Single nucleotide polymorphisms (SNPs) of genes that affect cytokine production and function are known to influence the susceptibility and progression of immune-related conditions such as infection, autoimmune diseases, transplantation, and cancer. We established a multiplex genotyping method to analyze the SNPs of cytokine genes by combining the multiplex PCR and bead array platform. Thirteen cytokine gene regions, including 20 SNPs, were amplified, and allele-specific primer extension was performed in a single tube. High-quality allele-specific primers were selected for signals greater than 1000 median fluorescence intensity (MFI) for positive alleles, and less than 500 MFI for negative alleles. To select and improve the extension primers, modifications for the reverse direction, length or refractory were performed. 24 primers in the forward or reverse direction step and 12 primers in length or refractory modifications were selected and showed high concordance with results by nucleotide sequencing. Among the 13 candidate cytokine genes, the SNPs of 12 cytokine genes, including IL-1α, IL-1R, IL-1RA, IL-1β, IL-2, IL-4, IL-4Rα, IL-6, IL-10, IL-12, TGF-β1, and TNF-α, were successfully defined with the selected allele-specific primers in healthy Korean subjects. Our genotyping system provides a fast and accurate detection for SNPs of multiple cytokine genes to investigate their association with immune-related diseases and transplantation outcomes.

Pharmacokinetic-pharmacodynamic analysis to evaluate the effect of moxifloxacin on QT interval prolongation in healthy Korean male subjects.

A single 400 mg dose of moxifloxacin has been the standard positive control for thorough QT (TQT) studies. However, it is not clearly known whether a 400 mg dose is also applicable to TQT studies in Asian subjects, including Koreans. Thus, we aimed to develop a pharmacokinetic (PK)-pharmacodynamic (PD) model for moxifloxacin, to evaluate the time course of its effect on QT intervals in Koreans. Data from three TQT studies of 33 healthy male Korean subjects who received 400 and 800 mg of moxifloxacin and placebo (water) were used. Twelve-lead electrocardiograms were taken for 2 consecutive days: 1 day to record diurnal changes and the next day to record moxifloxacin or placebo effects. Peripheral blood samples were also obtained for PK analysis. The PK-PD data obtained were analyzed using a nonlinear mixed-effects method (NONMEM ver. 7.2). A two-compartment linear model with first-order absorption provided the best description of moxifloxacin PK. Individualized QT interval correction, by heart rate, was performed by a power model, and the circadian variation of QT intervals was described by two mixed-effect cosine functions. The effect of moxifloxacin on QT interval prolongation was well explained by the nonlinear dose-response (Emax) model, and the effect by 800 mg was only slightly greater than that of 400 mg. Although Koreans appeared to be more sensitive to moxifloxacin-induced QT prolongation than were Caucasians, the PK-PD model developed suggests that a 400 mg dose of moxifloxacin is also applicable to QT studies in Korean subjects.

Inverse association between central obesity and arterial stiffness in Korean subjects with metabolic syndrome: a cross-sectional cohort study.

BackgroundMetabolic syndrome (MetS) is associated with increased risks of diabetes and atherosclerotic cardiovascular disease. Whether central obesity (CeO) is a prerequisite for the diagnosis of MetS in the International Diabetes Federation (IDF) definition is a substantial issue because it may influence the clinical value of MetS for predicting subclinical atherosclerosis.MethodsWe investigated the relation between MetS, as defined by the National Cholesterol Education Program–Adult Treatment Panel (NCEP–ATP) III criteria, and arterial stiffness according to CeO status in 2,560 healthy Korean subjects who participated in a community-based cohort study. Arterial stiffness was measured using brachial-ankle pulse wave velocity (baPWV).ResultsThe prevalence of MetS was 37%; 84% of MetS subjects had CeO. The prevalence of diabetes was significantly higher in MetS subjects than in non-MetS subjects (30 vs. 8%, p <0.001). The number of MetS components was significantly correlated with baPWV (r = 0.311, p <0.001). In a subgroup analysis of MetS subjects, the prevalence of diabetes was not significantly different in MetS subjects with and without CeO. MetS subjects without CeO had significantly higher baPWV than those with CeO (1654 ± 315 vs. 1578 ± 270 cm/s, p = 0.002). Multiple regression models revealed that waist circumference was independently associated with decreased baPWV in MetS subjects.ConclusionsDespite the significant correlation between the number of MetS components and arterial stiffness, there appeared to be an inverse association between CeO and arterial stiffness in MetS subjects. In contrast to the IDF definition, our findings suggest that CeO is not crucial for the diagnosis of MetS in otherwise healthy Koreans having multiple metabolic risk factors with respect to subclinical atherosclerosis reflected in arterial stiffness.

Impact of hypothyroidism on the development of non-alcoholic fatty liver disease: A 4-year retrospective cohort study

Background/AimsHypothyroidism is reported to contribute to the development of nonalcoholic fatty liver disease (NAFLD). We compared the risk of the development of NAFLD among three groups with different thyroid hormonal statuses (control, subclinical hypothyroidism, and overt hypothyroidism) in a 4-year retrospective cohort of Korean subjects.MethodsApparently healthy Korean subjects without NAFLD and aged 20-65 years were recruited (n=18,544) at health checkups performed in 2008. Annual health checkups were applied to the cohort for 4 consecutive years until December 2012. Based on their initial serum-free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels, they were classified into control, subclinical hypothyroidism (TSH >4.2 mIU/L, normal fT4), and overt hypothyroidism (TSH >4.2 mIU/L, fT4 <0.97 ng/dL) groups. NAFLD was diagnosed on the basis of ultrasonography findings.ResultsNAFLD developed in 2,348 of the 18,544 subjects, representing an overall incidence of 12.7%: 12.8%, 11.0%, 12.7% in the control, subclinical hypothyroidism, and overt hypothyroidism groups, respectively. The incidence of NAFLD did not differ significantly with the baseline thyroid hormonal status, even after multivariate adjustment (subclinical hypothyroidism group: hazard ratio [HR]=0.965, 95% confidence interval [CI]=0.814-1.143, P=0.67; overt hypothyroidism group: HR=1.255, 95% CI=0.830-1.899, P=0.28).ConclusionsOur results suggest that the subclinical and overt types of hypothyroidism are not related to an increased incidence of NAFLD.

Serious adverse events during clinical trial for pharmacokinetic interaction between telmisartan and chlorthalidone in healthy Korean subjects: A case report

Sook Jin Seong, Young-Ran Yoon and Mi-sun Lim* Department of Biomedical Science, BK21 Plus KNU Bio-Medical Convergence Program for Creative Talent and Clinical Trial Center, Kyungpook National University Graduate School and Hospital, Daegu 41944, Republic of Korea, College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan, Gyeongbuk 42415, Republic of Korea *Correspondence: M. Lim; Tel: +82-53-810-2823, Fax: +82-53-810-4654, E-mail: mslim@ynu.ac.kr

Head position and intraocular pressure in the lateral decubitus position.

To investigate the effects of different head positions in the lateral decubitus posture on intraocular pressure (IOP). Seventeen healthy Korean subjects were included in this prospective observational study. Intraocular pressure measurements were taken with the subjects in the sitting position and the recumbent positions including supine, right lateral decubitus, and left lateral decubitus positions. In right and left lateral decubitus positions, IOP measurements were taken with three different head positions (30 degrees higher, 30 degrees lower, and parallel to the center of the thoracic vertebra) in a randomized sequence. Intraocular pressure was measured using the ICare Pro tonometer in both eyes 5 minutes after assuming each posture. The eye on the lower side in the lateral decubitus position was termed as the dependent eye. We assessed differences in the IOP of the dependent and nondependent eyes in the lateral decubitus positions with different head positions. Regardless of the head position, the dependent eyes showed higher IOP than the nondependent eyes in the lateral decubitus positions except in the left lateral decubitus with high head position (p < 0.001 for all positions except left lateral decubitus, p = 0.083). Low head position significantly increased the IOP of dependent eyes, compared with the neutral or high head positions in lateral decubitus posture. Low head position elevates the IOP of the dependent eyes compared with neutral head position in the lateral decubitus posture. Proper adjustment of the height of a pillow may help mitigate IOP elevations resulting from lying on the side with a low pillow or with no pillow.

Cross-Sectional Study between Anthropometric Obesity Indices and Intraocular Pressure

3 , Yangsan, Korea Purpose: To investigate the cross sectional study association of intraocular pressure (IOP) with anthropometric obesity indices. Methods: We classified study subjects into three groups--normal, overweight and obesity, and investigated the correlation of IOP with age, gender and anthropometric obesity indices such as obesity Index, body mass index (BMI), a body shape index (ABSI) and waist to height ratio (WHtR) on healthy subjects. Results: Of a total of 63,385 participants, 30,288 were male and 33,097 were female. Mean IOP was 15.13 ± 3.24 mm Hg for men and 14.44 ± 3.02 mm Hg for women. The obesity index and BMI in the normal, overweight and obesity groups were sig- nificantly different in both men and women (p < 0.05). Mean IOP increased to a higher degree in the obesity group. In the normal, overweight and obesity group divided by ABSI, there were no significant differences in both men (p = 0.66) and women (p = 0.28). Between the normal and overweight group and the normal and obesity group divided by WHtR, there were significant dif- ferences in men (p < 0.05) and women (p < 0.05). Multiple linear regression analysis showed the significant relationship between obesity index, BMI, ABSI, WHtR and IOP in men and women. Receiver operating characteristic curve showed that the obesity in- dex was the highest value following BMI, WHtR and ABSI. Conclusions: Korean healthy subjects showed a correlation between IOP and anthropometric obesity indices regardless of gen- der, and the obesity index had the highest correlation. J Korean Ophthalmol Soc 2015;56(3):379-387

Population Pharmacokinetic Analysis of Diurnal and Seasonal Variations of Plasma Concentrations of Cilostazol in Healthy Volunteers

The background of this study was (1) to examine factors influencing cilostazol pharmacokinetics by developing a population model incorporating diurnal variation and other covariate effects and (2) to assess the feasibility of applying the developed model to determine the optimal dosing times. Data obtained from a cilostazol pharmacokinetic study consisting of 2 clinical trials (a single twice-a-day (BID) dosing trial in winter and a multiple BID dosing trial in summer) conducted in healthy Korean subjects were used for model building. A basic model was built, followed by a diurnal variation model, and then a final model was built incorporating covariates, including a seasonal difference. The optimal morning and evening dosing times were determined from simulations. Diurnal variation in cilostazol pharmacokinetics was explained by the morning absorption rate constant being faster than in the evening, yielding values of 0.278 versus 0.234/h in summer, when 24- and 12-hour circadian rhythms were included in the model. The seasonal variation was explained by a 26.9% and a 31.8% decrease in the absorption rate constant and clearance, respectively, in winter compared with summer. Based on twice-a-day (BID) dosing, dosing times of 9 AM and 5 PM in summer and 10 AM and 7 PM in winter were expected to produce the smallest peak-to-peak fluctuations in cilostazol concentration, possibly minimizing unwanted effects of the drug. This study demonstrated the intraday and interseasonal time-varying nature of cilostazol pharmacokinetics using a population modeling approach and developed a strategy for optimizing dosing times. It is suggested that these methods can be similarly applied to analyses and controls of other drugs that exhibit characteristics of time-varying pharmacokinetics.

한방 외용제 개발을 위한 건강한 성인 남녀 25명의 피부 특성 분석

Abstract Objectives : The aim of present study was to investigate the skin characteristics of twenty-five healthy Korean subjects. These results can be used as basic data for the development of future herbal applications. Methods : Skin type, hair and scalp condition, water content, sebum content were investigated through the measurement of skin conditions and subjective questionnaire survey to know the skin characteristics of subjects. Results : Most of subject has 'Dry Skin' and they have trouble about their keratin(dandruff), scalp itching, alopecia, hair texture, scalp moisture. Conclusions : More studies are needed to investigate the skin characteristics of healthy Korean subjects.Key words : Skin characteristic; Skin type; Hair condition; Scalp condition; Water content; Sebum content ⓒ 2014 the Society of Korean Medicine Ophthalmology & Otolaryngology & DermatologyThis is an Open Access journal distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/license/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Effect of voglibose on the pharmacokinetics of metformin in healthy Korean subjects.

The objective of this study was to evaluate the effects of voglibose on the pharmacokinetics of metformin. A randomized, open-label, two-way crossover study with a 7-day washout period was conducted. All subjects were given an oral dose of metformin with or without voglibose 3 x daily for 7 days. Plasma concentrations of metformin on day 7 were measured using high performance liquid chromatography (HPLC) with UV detection for pharmacokinetic assessment Vital signs and adverse events were monitored, and physical examinations and laboratory tests were conducted to evaluate safety. 22 subjects completed the study. The geometric mean ratios for C(ss,max) of metformin (metformin plus voglibose vs. metformin only) were 0.98 (90% CI, 0.92 - 1.05; p > 0.05) and for AUC-τ, the ratio was 0.99 (90% CI, 0.92 - 1.06; p > 0.05). There were no significant differences in adverse drug reactions between metformin with and without voglibose. However, the incidence of adverse events was higher in period 1 than in period 2 (16 cases vs. 1 case, p < 0.001). Co-administration of metformin and voglibose had no statistically or clinically significant effects on the pharmacokinetics of metformin in healthy subjects. The pharmacodynamic interaction study to evaluate the effect of metformin on the pharmacodynamics of voglibose is in progress.