The influence of dietary sodium content on the pharmacokinetics and pharmacodynamics of fimasartan

Gu, Namyi,Cho, Joo-Youn,Shin, Kwang-Hee,Jang, In-Jin,Rhee, Moo-Yong Dove Medical Press 2016 Drug design, development and therapy Vol.10 No.-

<P>A low sodium diet enhances the hemodynamic effect of renin–angiotensin system blockers. It was suggested that the substrates of P-glycoprotein or cytochrome P450 3A4 were reduced on a high sodium diet. This study aimed to investigate the influence of high sodium diet on the pharmacokinetics and pharmacodynamics of fimasartan, which is a substrate of cytochrome P450 3A4 but not P-glycoprotein. The study design was a two-diet, two-period, two-sequence, randomized, open-label, and crossover with 1-week washout for diet. Eligible subjects were fed with either low sodium (50 mEq/day) diet or high sodium diet (300 mEq/day) for 7 days in the first hospitalization period and the other diet in the second period. On the seventh morning of each period, subjects received a single dose of fimasartan 60 mg in a fasted state. The serial plasma concentrations of fimasartan, serum aldosterone concentration (SAC), and plasma renin activity (PRA) were measured for pharmacokinetic–pharmacodynamic analysis. Sixteen subjects completed the study satisfying the compliance test for diets. Although the mean systemic exposure of fimasartan is slightly (≈10%) decreased on a high sodium diet, the difference was not statistically or clinically significant (<I>P</I>>0.05). The SAC and PRA after fimasartan administration were highly dependent on their baseline levels. The dietary sodium content influenced the baseline of SAC and PRA, but did not influence the ratio change of SAC and PRA after fimasartan treatment. The ratio change of SAC after fimasartan treatment was correlated to the systemic exposure of fimasartan (<I>P</I><0.05), while the correlation between the ratio change of PRA after fimasartan treatment and the individual systemic exposure of fimasartan was not significant (<I>P</I>>0.05). In conclusion, the pharmacokinetics of fimasartan and ratio changes of SAC and PRA after fimasartan treatment were not significantly influenced by dietary sodium content.</P>

Pharmacokinetics of Lacosamide in Healthy Korean Male Volunteers

Kim, Sung Eun,Gu, Namyi,Kim, Bo-Hyung,Fitchner, Andreas,Elshoff, Jan-Peer,Cawello, Willi,Jang, In-Jin,Yu, Kyung-Sang S. Karger AG 2012 Pharmacology Vol.89 No.3

<P>Abstract</P><P><I>Aim: </I>The aim of this study was to evaluate the pharmacokinetics (PK) of single and repeated doses of lacosamide in healthy male Korean volunteers and to compare the PK profile of lacosamide in Korean and Caucasian populations. <I>Methods:</I> In a double-blind, placebo-controlled, parallel-group, dose-escalation trial, 16 volunteers received a single dose (50 mg) of lacosamide or placebo, and 32 volunteers were administered single/repeated twice-daily doses (100 or 200 mg) of lacosamide or placebo. <I>Results:</I> For multiple doses of 100 and 200 mg twice daily, the geometric means C<SUB>max,ss</SUB> were 6.23 (15.0) and 13.13 (8.9) μg/ml respectively, and AUC<SUB>τ</SUB><SUB>,s</SUB><SUB>s</SUB> values were 52.10 (17.0) and 112.35 (13.0) μg·h/ml, respectively. Values for both parameters were relatively higher than those seen in Caucasians. To further describe ethnic differences, population PK analysis was assessed. A one-compartment model with first-order absorption and elimination was selected and effects of CL<SUB>creatinine</SUB> on CL/F and body surface area on V/F were included in the final model. <I>Conclusion:</I> There were no other ethnic differences in the PK profile of lacosamide between Koreans and Caucasians based on the population PK analysis, except for the demographic differences.</P><P>Copyright © 2012 S. Karger AG, Basel</P>

Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity

Oh, Jaeseong,Yi, Sojeong,Gu, Namyi,Shin, Dongseong,Yu, Kyung-Sang,Yoon, Seo Hyun,Cho, Joo-Youn,Jang, In-Jin Korea Genome Organization 2018 Genomics & informatics Vol.16 No.3

In this report, we present a case study of how pharmacogenomics and pharmacometabolomics can be useful to characterize safety and pharmacokinetic profiles in early phase new drug development clinical trials. During conducting a first-in-human trial for a new molecular entity, we were able to determine the mechanism of dichotomized variability in plasma drug concentrations, which appeared closely related to adverse drug reactions (ADRs) through integrated omics analysis. The pharmacogenomics screening was performed from whole blood samples using the Affymetrix DMET (Drug-Metabolizing Enzymes and Transporters) Plus microarray, and confirmation of genetic variants was performed using real-time polymerase chain reaction. Metabolomics profiling was performed from plasma samples using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. A GSTM1 null polymorphism was identified in pharmacogenomics test and the drug concentrations was higher in GSTM1 null subjects than GSTM1 functional subjects. The apparent drug clearance was 13-fold lower in GSTM1 null subjects than GSTM1 functional subjects (p < 0.001). By metabolomics analysis, we identified that the study drug was metabolized by cysteinylglycine conjugation in GSTM functional subjects but those not in GSTM1 null subjects. The incidence rate and the severity of ADRs were higher in the GSTM1 null subjects than the GSTM1 functional subjects. Through the integrated omics analysis, we could understand the mechanism of inter-individual variability in drug exposure and in adverse response. In conclusion, integrated multi-omics analysis can be useful for elucidating the various characteristics of new drug candidates in early phase clinical trials.

Comparative Pharmacokinetics of a Controlled-release Pregabalin Tablet (GLA5PR GLARS-NF1) and an Immediate-release Pregabalin Capsule in Healthy Male Volunteers

Kim, Tae-Eun,Jeon, Ji-Young,Gu, Namyi,Chang Kwon, Min,Kim, Min-Gul Elsevier 2018 Clinical therapeutics Vol.40 No.12

<P><B>Abstract</B></P> <P><B>Purpose</B></P> <P>Pregabalin is a widely used drug for the management of neuropathic pain. This study compared the pharmacokinetics of the GLA5PR GLARS-NF1 tablet, a 150-mg controlled-release formulation of pregabalin taken once daily, with those of a 75-mg immediate-release (IR) capsule formulation of pregabalin taken twice daily with a 12-h interval between doses.</P> <P><B>Methods</B></P> <P>Two separate studies, single dose and multiple dose, were conducted with a sequence-randomized, open-label crossover design. In the single-dose study, 30 participants each received 3 treatments: two 75-mg IR capsules taken 12 h apart, each after a high-fat meal (SRF treatment); a single 150-mg GLA5PR GLARS-NF1 tablet taken after a high-fat meal (STF treatment); and a single 150-mg GLAR5PR GLARS-NF1 tablet taken in an overnight-fasted state (ST treatment). In the multiple-dose study, 24 participants each received 2 treatments, both of which occurred over 3 days: one 75-mg IR capsule in the evening after a standardized meal and a second 75-mg IR capsule the following morning after a standardized meal, for 3 days (MRF treatment); and a single 150-mg GLA5PR GLARS-NF1 tablet in the evening after a standardized meal, for 3 days (MTF treatment). Blood samples for pharmacokinetic assessments were collected over the 36 h following drug administration in each treatment period.</P> <P><B>Findings</B></P> <P>In the single-dose study, the geometric mean ratios (GMRs) of the Cmax and the AUC<SUB>last</SUB> values of the GLA5PR GLARS-NF1 tablet to those of the IR capsules (STF/SRF) were 1.047 (90% CI, 0.971–1.129) and 0.757 (90% CI, 0.694–0.826), respectively. In the multiple-dose study, the GMRs (MTF/MRF) of the Cmax and the AUC values over the dosing interval were 1.277 (90% CI, 1.210–1.348) and 0.974 (90% CI, 0.933–1.017), respectively. The systemic pregabalin exposure from the GLA5PR GLARS-NF1 tablet was higher in the fed state than in the fasted state; GMRs (STF/ST): <I>C</I> <SUB>max</SUB>, 1.458 (90% CI, 1.353–1.573) and AUC<SUB>last</SUB>, 1.655 (90% CI, 1.518–1.804).</P> <P><B>Implications</B></P> <P>The overall pregabalin exposure after multiple administrations of GLA5PR GLARS-NF1 tablets was comparable to that after multiple administrations of the IR capsules. A single administration of the GLA5PR GLARS-NF1 tablet produced lower overall pregabalin exposure than that of the same dose administered in 2 IR capsules taken every 12 h. A high-fat diet significantly increased the bioavailability of the GLA5PR GLARS-NF1 tablet. ClinicalTrials.gov identifiers: NCT01638273 and NCT02326987.</P>

Relationship between 24-h urine sodium/potassium ratio and central aortic systolic blood pressure in hypertensive patients

Rhee, Moo-Yong,Shin, Sung-Joon,Gu, Namyi,Nah, Deuk-Young,Kim, Byong-Kyu,Hong, Kyung-Soon,Cho, Eun-Joo,Sung, Ki-Chul,Lee, Sim-Yeol,Kim, Kwang-Il Springer Science and Business Media LLC 2017 Hypertension research Vol.40 No.4

<P>Studies evaluating the relationship between measured 24-h urine sodium (24HUNa), potassium (24HUK) and aortic blood pressure (BP) are rare, and no such study has been performed with an Asian population. We evaluated the relationship between 24HUNa, 24HUK, casual BP, 24-h ambulatory BP and aortic BP by analyzing data from 524 participants with valid 24-h urine collection, 24-h ambulatory BP and central BP measurements (mean age 48.1 +/- 9.8 years, 193 men). Hypertension was defined as a 24-h ambulatory BP >= 130/80 mm Hg or current treatment for hypertension (n = 219). The participants with hypertension and high 24HUNa (mean 210.5 +/- 52.0 mmol per day, range 151.0-432.0) showed higher 24-h systolic (P = 0.037) and diastolic BP (P = 0.037) and aortic systolic BP (AoSBP, P = 0.038) than the participants with hypertension and low 24HUNa (mean 115.7 +/- 25.0 mmol per day, range 45.6-150.0), adjusted for confounders. The participants with hypertension and a high ratio of 24HUNa and 24HUK (24HUNa/24HUK, mean 4.03 +/- 1.00, range 2.93-7.96) had higher AoSBP than the participants with hypertension and a low 24HUNa/24HUK ratio (mean 2.13 +/- 0.54, range 0.53-2.91), adjusted for confounders (P = 0.026). The participants with hypertension demonstrated a significant linear relationship between AoSBP and 24HUNa/24HUK ratio that was independent of 24HUNa, according to the multiple regression analysis (P = 0.047). In hypertensive patients, 24HUNa/ 24HUK was positively and more strongly related to AoSBP compared with 24HUNa alone. The result indicates that high sodium and low potassium intake may increase the subsequent risk of cardiovascular disease by elevating AoSBP.</P>

Visual Fatigue Induced by Viewing a Tablet Computer with a Highresolution Display

Dong Ju Kim,Chi-Yeon Lim,Namyi Gu,Choul Yong Park 대한안과학회 2017 Korean Journal of Ophthalmology Vol.31 No.5

Purpose: In the present study, the visual discomfort induced by smart mobile devices was assessed in normal and healthy adults. Methods: Fifty-nine volunteers (age, 38.16 ± 10.23 years; male : female = 19 : 40) were exposed to tablet computer screen stimuli (iPad Air, Apple Inc.) for 1 hour. Participants watched a movie or played a computer game on the tablet computer. Visual fatigue and discomfort were assessed using an asthenopia questionnaire, tear film break-up time, and total ocular wavefront aberration before and after viewing smart mobile devices. Results: Based on the questionnaire, viewing smart mobile devices for 1 hour significantly increased mean total asthenopia score from 19.59 ± 8.58 to 22.68 ± 9.39 (p < 0.001). Specifically, the scores for five items (tired eyes, sore/aching eyes, irritated eyes, watery eyes, and hot/burning eye) were significantly increased by viewing smart mobile devices. Tear film break-up time significantly decreased from 5.09 ± 1.52 seconds to 4.63 ± 1.34 seconds (p = 0.003). However, total ocular wavefront aberration was unchanged. Conclusions: Visual fatigue and discomfort were significantly induced by viewing smart mobile devices, even though the devices were equipped with state-of-the-art display technology.

Estimating 24-Hour Urine Sodium From Multiple Spot Urine Samples

Rhee, Moo-Yong,Kim, Ji-Hyun,Shin, Sung-Joon,Gu, Namyi,Nah, Deuk-Young,Park, Ju-Hyun,Kim, Sun-Woong,Kim, Hyun Ja.,Oh, Kyung Won.,Kim, Ji-Hyeon,Lee, Sim-Yeol Le Jacq Communications 2017 Journal of Clinical Hypertension Vol.19 No.4

A first-in-human, double-blind, placebo-controlled, randomized, dose escalation study of DWP05195, a novel TRPV1 antagonist, in healthy volunteers

Lee, Jieon,Kim, Bo-Hyung,Yu, Kyung-Sang,Kim, Hee Sun,Kim, Ji Duck,Cho, Joo-Youn,Lee, SeungHwan,Gu, Namyi Dove Medical Press 2017 Drug design, development and therapy Vol.11 No.-

<P><B>Objectives</B></P><P>DWP05195 is a transient receptor potential vanilloid 1 (TRPV1) antagonist developed for managing pain. The purpose of this study was to evaluate the pharmacodynamics pharmacokinetics, safety, and tolerability of DWP05195 in healthy subjects. This was a first-in-human randomized, double-blinded, placebo-controlled, dose escalation study.</P><P><B>Subjects and methods</B></P><P>DWP05195 or placebo was administered as a single dose of 10–600 mg in the single-dose study and as 100–400 mg once daily for 8 days in the multiple-dose studies. Each study group consisted of 10 subjects (study drug-to-placebo ratio was 8:2). For pharmacodynamics assessment, the heat pain threshold (HPtr), heat pain tolerance (HPtol), perfusion intensity, and flare area ratio of cutaneous blood flow were measured. Safety and tolerability were evaluated throughout the study.</P><P><B>Results</B></P><P>The maximum plasma concentrations and area under the plasma concentration–time curve from zero to the last measurable time dose-dependently increased. HPtr and HPtol tended to increase more after DWP05195 administration than after placebo administration. HPtr and HPtol tended to dose-dependently increase after administration of DWP05195. Cutaneous blood flow was reduced as the dose of DWP05195 increased during the multiple-dose study. DWP05195 was well tolerated up to 600 and 400 mg single- and multiple-dose administrations, respectively.</P><P><B>Conclusion</B></P><P>The pharmacological activity of DWP05195, measured using HPtr and HPtol, increased as expected in a dose-dependent manner owing to increased systemic exposure, indicating that DWP05195 can be used as a TRPV1 antagonist for pain management.</P>

Prevalence of Masked Hypertension: a Population-Based Survey in a Large City by Using 24-Hour Ambulatory Blood Pressure Monitoring

Moo-Yong Rhee,Sun-Woong Kim,Eun-Hee Choi,김지현,Deuk-Young Nah,Sung-Joon Shin,Namyi Gu 대한심장학회 2016 Korean Circulation Journal Vol.46 No.5

Background and Objectives: We estimated the prevalence of hypertension and hypertension subtypes in a large semi-urban city in Korea, using 24-hour ambulatory blood pressure monitoring (ABPM) in a randomly selected sample population. Subjects and Methods: A random sample (aged 20-65 years) from a city with an adult population of approximately 600000 was selected by using a list-assisted random digit dialing method. The 24-hour ABPM and conventional blood pressure measurement (CBPM) of these individuals were obtained. Results: Among the 496 participants, valid 24-hour ABPM and CBPM were obtained from 462 (93%) individuals. The estimated prevalence of hypertension in Goyang was 17.54% by CBPM and 32.70% by 24-hour ABPM (p<0.01). In the age stratified analysis, both CBPM and 24-hour ABPM showed increased prevalence of hypertension with age. The estimated prevalence of masked hypertension was 16.22% and that of white-coat hypertension was 1.08%. Men had a higher prevalence of masked hypertension than women (20.79% vs. 11.86%, p=0.0295). The estimated prevalence of masked hypertension was 17.5%, 20.58%, 24.34%, and 13.29% in the age categories of 30s, 40s, 50s, and 60s, respectively. The estimated prevalence of masked uncontrolled hypertension was 26.79% in patients with hypertension who were taking antihypertensive medications. Conclusion: The estimated prevalence of hypertension by 24-hour ABPM was higher than that by CBPM, revealing high prevalence of masked hypertension. The high prevalence of masked hypertension supports the adoption of ABPM in the national population survey and clinical practice to improve public health and reduce health care costs.

Elevation of heart-femoral pulse wave velocity by short-term low sodium diet followed by high sodium diet in hypertensive patients with sodium sensitivity

Ji-Hyun Kim,Sang-Hoon Na,Jin-Wook Chung,Jun-Ho Bae,Deuk-Young Nah,Namyi Gu,Hae-Young Kim,Moo-Yong Rhee 대한지역사회영양학회 2016 Nutrition Research and Practice Vol.10 No.3

BACKGROUND/OBJECTIVES: We compared changes in heart-femoral pulse wave velocity (hfPWV) in response to low sodium and high sodium diet between individuals with sodium sensitivity (SS) and resistance (SR) to evaluate the influence of sodium intake on arterial stiffness. SUBJECTS/METHODS: Thirty-one hypertensive and 70 normotensive individuals were given 7 days of low sodium dietary approach to stop hypertension (DASH) diet (LSD, 100 mmol NaCl/day) followed by 7 days of high sodium DASH diet (HSD, 300 mmol NaCl/day) during 2 weeks of hospitalization. The hfPWV was measured and compared after the LSD and HSD. RESULTS: The hfPWV was significantly elevated from LSD to HSD in individuals with SS (P = 0.001) independently of changes in mean arterial pressure (P = 0.037). Conversely, there was no significant elevation of hfPWV from LSD to HSD in individuals with SR. The percent change in hfPWV from the LSD to the HSD in individuals with SS was higher than that in individuals with SR. Subgroup analysis revealed that individuals with both SS and hypertension showed significant elevation of hfPWV from LSD to HSD upon adjusted analysis using changes of the means arterial pressure (P = 0.040). However, there was no significant elevation of hfPWV in individuals with SS and normotension. CONCLUSION: High sodium intake elevated hfPWV in hypertensive individuals with SS, suggesting that high sodium intake increases aortic stiffness, and may contribute to enhanced cardiovascular risk in hypertensive individuals with SS.