Pharmacokinetic and pharmacodynamic interaction between gemigliptin and metformin in healthy subjects.

Shin, Dongseong,Cho, Young Min,Lee, SeungHwan,Lim, Kyoung Soo,Kim, Jeong-Ae,Ahn, Ji-Yung,Cho, Joo-Youn,Lee, Howard,Jang, In-Jin,Yu, Kyung-Sang Adis International 2014 Clinical drug investigation Vol.34 No.6

<P>Gemigliptin is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor used in the treatment of type 2 diabetes mellitus. This study evaluated possible pharmacodynamic and pharmacokinetic interactions between gemigliptin and metformin and investigated their tolerability.</P>

Pharmacokinetics and tolerability of DA-8031, a novel selective serotonin reuptake inhibitor for premature ejaculation in healthy male subjects

Shin, Dongseong,Lee, SeungHwan,Yi, Sojeong,Yoon, Seo Hyun,Cho, Joo-Youn,Bahng, Mi Young,Jang, In-Jin,Yu, Kyung-Sang Dove Medical Press 2017 Drug design, development and therapy Vol.11 No.-

<P><B>Objective</B></P><P>DA-8031 is a selective serotonin reuptake inhibitor under development for the treatment of premature ejaculation. This is the first-in-human study aimed at evaluating the pharmacokinetics and tolerability of DA-8031 and its metabolites (M1, M2, M4, and M5) in the plasma and urine after administration of a single oral dose in healthy male subjects.</P><P><B>Methods</B></P><P>A dose block-randomized, double-blind, placebo-controlled, single ascending dose study was conducted. Subjects received either placebo or a single dose of DA-8031 at 5, 10, 20, 40, 60, 80, or 120 mg. DA-8031 and its four metabolites were analyzed in the plasma and urine for pharmacokinetic evaluation. The effect of genetic polymorphisms of cytochrome-P450 (CYP) enzymes on the pharmacokinetics of DA-8031 was evaluated.</P><P><B>Results</B></P><P>After a single dose, plasma DA-8031 reached the maximum concentration at a median of 2–3 h and was eliminated with terminal elimination half-life of 17.9–28.7 h. The mean renal clearance was 3.7–5.6 L/h. Dose-proportional pharmacokinetics was observed over the dose range of 20–80 mg. Among the metabolites, M4 had the greatest plasma concentration, followed by M5 and M1. Subjects with CYP2D6 intermediate metabolizer had significantly greater dose-normalized <I>C</I><SUB>max</SUB> and AUC<SUB>0–</SUB><I><SUB>t</SUB></I> of DA-8031 as well as smaller metabolic ratios than those subjects with CYP2D6 extensive metabolizer. The most common adverse events were nausea, dizziness, and headache, and no serious adverse events were reported.</P><P><B>Conclusion</B></P><P>In conclusion, the systemic exposure of DA-8031 was increased proportionally to the dose within 20–80 mg. Genetic polymorphisms of CYP2D6 had an effect on the systemic exposure of DA-8031. DA-8031 was well tolerated after single doses of 80 mg or less.</P>

Influence and analysis of a commercial ZigBee module induced by gamma rays

Shin, Dongseong,Kim, Chang-Hwoi,Park, Pangun,Kwon, Inyong Korean Nuclear Society 2021 Nuclear Engineering and Technology Vol.53 No.5

Many studies are undertaken into nuclear power plants (NPPs) in preparation for accidents exceeding design standards. In this paper, we analyze the applicability of various wireless communication technologies as accident countermeasures in different NPP environments. In particular, a commercial wireless communication module (WCM) is investigated by measuring leakage current and packet error rate (PER), which vary depending on the intensity of incident radiation on the module, by testing at a Co-60 gamma-ray irradiation facility. The experimental results show that the WCMs continued to operate after total doses of 940 and 1097 Gy, with PERs of 3.6% and 0.8%, when exposed to irradiation dose rates of 185 and 486 Gy/h, respectively. In short, the lower irradiation dose rate decreased the performance of WCMs more than the higher dose rate. In experiments comparing the two communication protocols of request/response and one-way, the WCMs survived up to 997 and 1177 Gy, with PERs of 2% and 0%, respectively. Since the request/response protocol uses both the transmitter and the receiver, while the one-way protocol uses only the transmitter, then the electronic system on the side of the receiver is more vulnerable to radiation effects. From our experiments, the tested module is expected to be used for design-based accidents (DBAs) of "Category A" type, and has confirmed the possibility of using wireless communication systems in NPPs.

Comparison of the pharmacokinetics and tolerability of HCP1004 (a fixed-dose combination of naproxen and esomeprazole strontium) and VIMOVO ^® (a marketed fixed-dose combination of naproxen and esomeprazole magnesium) in healthy volunteers

Choi, YoonJung,Han, HyeKyung,Shin, Dongseong,Lim, Kyoung Soo,Yu, Kyung-Sang Dove Medical Press 2015 Drug design, development and therapy Vol.9 No.-

<P><B>Background</B></P><P>HCP1004 is a newly developed fixed-dose combination of naproxen (500 mg) and esomeprazole strontium (20 mg) that is used in the treatment of rheumatic diseases and can reduce the risk of nonsteroidal anti-inflammatory drug-associated ulcers. The aim of this study was to evaluate the pharmacokinetics (PK) and safety of HCP1004 compared to VIMOVO<SUP>®</SUP> (a marketed fixed-dose combination of naproxen and esomeprazole magnesium).</P><P><B>Subjects and methods</B></P><P>An open-label, randomized, two-treatment, two-sequence crossover, single-dose clinical study was conducted in 70 healthy volunteers. In each period, a reference (VIMOVO<SUP>®</SUP>) or test (HCP1004) drug was administered orally, and serial blood samples for PK analysis were collected up to 72 hours after dosing. To evaluate the PK profiles, the maximum plasma concentration (C<SUB>max</SUB>) and the area under the concentration–time curve from 0 to the last measurable time (AUC<SUB>0−t</SUB>) were estimated using a noncompartmental method. Safety profiles were evaluated throughout the study.</P><P><B>Results</B></P><P>Sixty-six of the 70 subjects completed the study. The C<SUB>max</SUB> (mean ± standard deviation) and AUC<SUB>0−t</SUB> (mean ± standard deviation) for naproxen in HCP1004 were 61.67±15.16 µg/mL and 1,206.52±166.46 h·µg/mL, respectively; in VIMOVO<SUP>®</SUP>; these values were 61.85±14.54 µg/mL and 1,211.44±170.01 h·µg/mL, respectively. The C<SUB>max</SUB> and AUC<SUB>0−t</SUB> for esomeprazole in HCP1004 were 658.21±510.91 ng/mL and 1,109.11±1,111.59 h·ng/mL, respectively; for VIMOVO<SUP>®</SUP>, these values were 595.09±364.23 ng/mL and 1,015.12±952.98 h·ng/mL, respectively. The geometric mean ratios and 90% confidence intervals (CIs) (HCP1004 to VIMOVO<SUP>®</SUP>) of the C<SUB>max</SUB> and AUC<SUB>0−t</SUB> of naproxen were 0.99 (0.94–1.06) and 1.00 (0.98–1.01), respectively. For esomeprazole, the geometric mean ratios (90% CI) for the C<SUB>max</SUB> and AUC<SUB>0−t</SUB> were 0.99 (0.82–1.18) and 1.04 (0.91–1.18), respectively. The overall results of the safety assessment showed no clinically significant issues for either treatment.</P><P><B>Conclusion</B></P><P>The PK of HCP1004 500/20 mg was comparable to that of VIMOVO<SUP>®</SUP> 500/20 mg for both naproxen and esomeprazole after a single oral dose. Both drugs were well-tolerated without any safety issues.</P>

[가솔린엔진부문] CNG 엔진의 피스톤 기계적 및 열 응력 유한요소해석

이병훈(Byunghun Lee),신동성(Dongseong Shin) 한국자동차공학회 2000 한국자동차공학회 춘 추계 학술대회 논문집 Vol.- No.-

In this study, three dimensional finite element model of the piston of a CNG engine was made to accomplish thermal and also mechanical stress and deformation analysis. Not only steady state temperatures but also gas pressure were measured. In pu1icular, steady st.1te temperatures measured using standard N' 3-type templug were applied to finite element analysis of thermal stress. 1llennal and mechanical stresses of combustion bowl in open dish-type piston were investigated using Smith diagram of a cast aluminium alloy.<br/> The Following Conclusion can be derived;<br/> (1) The thermal stress distribution in the piston was not critical, but at its combustion bowl lip area, the stress due to thermal and mechanical load were concentrated.<br/> (2) The deformation generated in the area of the crown edge and top land was insignificant under durability test.<br/>

Stress-based vs. Strain-based safety evaluations of spent nuclear fuel transport casks in energy-limited events

Kim, Seung-Pil,Kim, Jeongho,Sohn, Dongseong,Kwon, Hyukjoo,Shin, Myoungsu Elsevier 2019 Nuclear engineering and design Vol.355 No.-

<P><B>Abstract</B></P> <P>The stress-based criteria specified in ASME Section III (American Society of Mechanical Engineers, 2010) have long been used to evaluate the structural safety of mechanical structures, systems, and components (SSC) associated with nuclear power plants. These evaluation criteria, however, have inevitable limitations in accounting for the structural behaviors of spent nuclear fuel (SNF) transport casks, which likely undergo significant plastic deformations in extreme accidents. Hence, the stress-based evaluation criteria are considered inappropriate for energy-limited events that involve a high impact load, such as an accidental drop.</P> <P>This study evaluates the effectiveness of strain-based criteria, which were recently added in ASME Section III, Nonmandatory Appendix FF (American Society of Mechanical Engineers, 2015) and provides critical comparative study over traditional stress-based criteria for assessing the structural safety of SNF transport casks. Horizontal and vertical accidental drop events specified in NUREG-1536 (US Nuclear Regulatory Commission, 1997) are simulated using nonlinear dynamic finite-element analysis (FEA). Four SNF cask models with different impact-limiter designs are numerically simulated. The design of the impact limiter varies with wood types (redwood and balsa wood) and grain directions (transverse and longitudinal with respect to the loading direction). The FEA stress and strain results for the basket and canister parts are examined according to both stress-based and strain-based criteria. The strain-based criteria provide less conservative and more sensitive estimation than the stress-based criteria.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Four spent nuclear-fuel cask models with different impact-limiter designs are numerically simulated. </LI> <LI> The baskets and canister were successfully protected from drop impact loads by the energy absorption of the impact limiters. </LI> <LI> The cask design satisfied both the stress-based and strain-based acceptance criteria. </LI> <LI> The stress-based design criteria are deemed quite more conservative than the strain-based design criteria. </LI> </UL> </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.

Pharmacokinetic and pharmacodynamic interaction between ezetimibe and rosuvastatin in healthy male subjects

Kim, Chang Hee,An, Hyungmi,Kim, Sung Hye,Shin, Dongseong Dove Medical Press 2017 Drug design, development and therapy Vol.11 No.-

<P><B>Background and objective</B></P><P>Rosuvastatin and ezetimibe are commonly applied in lipid-lowering pharmacotherapy. However, the pharmacokinetic (PK) interaction was not clear by the coadministration of rosuvastatin and ezetimibe. This study investigated the pharmacodynamic (PD) and PK interactions between rosuvastatin and ezetimibe through a crossover clinical trial.</P><P><B>Subjects and methods</B></P><P>A randomized, open-label, multiple-dose, two-treatment, two-period, two-sequence crossover study with two treatment parts was conducted in healthy male subjects. Study part A involved rosuvastatin, and study part B involved ezetimibe. A total of 25 subjects in both parts completed the PK and PD evaluations. Rosuvastatin (20 mg) or ezetimibe (10 mg) was administered once daily for 7 days as monotherapy or co-therapy. The plasma concentrations of rosuvastatin, total ezetimibe and free ezetimibe were measured for 72 h after day 7. Low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC) were investigated for the PD assessments on day 1 (pretreatment) and day 8.</P><P><B>Results</B></P><P>Rosuvastatin and ezetimibe presented multiple peaks. The 90% confidence intervals (CIs) of the geometric mean ratios for the peak plasma concentration at steady state (C<SUB>max,ss</SUB>) and area under the plasma concentration–time curve during the dosing interval at steady state (AUC<SUB>τ,ss</SUB>) of rosuvastatin and total ezetimibe were within the range 0.8–1.25. However, the coadministration increased the systemic exposure of free ezetimibe. In the PD assessments, rosuvastatin and ezetimibe monotherapy reduced the LDL-C and TC levels effectively. In addition, the lipid-lowering effects of the coadministration corresponded to an approximate summation of the effects of rosuvastatin and ezetimibe monotherapy. However, no significant changes in HDL-C were observed with rosuvastatin or ezetimibe treatment. No significant safety issue was noted.</P><P><B>Conclusion</B></P><P>The coadministration of rosuvastatin and ezetimibe revealed a bioequivalent PK interaction. Additional lipid-lowering effects, including decreased LDL-C and TC, were observed as expected in combination therapy without significant safety concern.</P>

Determination of donepezil in human plasma using ultra performance liquid chromatography-tandem mass spectrometry

정현철,Jeong-Eun Park,Ji-Yeon Hyun,Min-Kyu Park,Dongseong Shin,신광희 대한임상약리학회 2018 Translational and Clinical Pharmacology Vol.26 No.2

An ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methodwas developed and validated for the quantification of donepezil in human plasma. Donepeziland donepezil-D4 were extracted from human plasma by liquid-liquid extraction using a mixture ofhexane and ethyl acetate (70:30 v/v). The extracted samples were analyzed using a Thermo HypersilGold C18 column with 5% acetic acid in 20 mM ammonium acetate buffer (pH 3.3) and 100%acetonitrile as a mobile phase with the 60:40 (v:v) isocratic method, at a flow rate of 0.3 mL/min. The injection volume was 3 μL, and the total run time was 3 min. Inter- and intra-batch accuraciesranged from 98.0% to 110.0%, and the precision was below 8%. The developed method was successfullyapplied to the quantification of donepezil in human plasma. The mean (standard deviation)maximum concentration and the median (range) time to maximum concentration were 8.6 (2.0)ng/mL and 2.0 h (1.0~5.0 h), respectively, in healthy Koreans after oral administration of 5 mg donepezil.

Evaluation of the pharmacokinetic and pharmacodynamic drug interactions between cilnidipine and valsartan, in healthy volunteers

Lee, Jieon,Lee, Howard,Jang, Kyungho,Lim, Kyoung Soo,Shin, Dongseong,Yu, Kyung-Sang Dove Medical Press 2014 Drug design, development and therapy Vol.8 No.-

<P><B>Purpose</B></P><P>Although cilnidipine and valsartan are widely coadministered to patients with hypertension, their drug–drug interaction potential has not been investigated. This study compared the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles of cilnidipine and valsartan, both alone and in combination, in healthy male subjects.</P><P><B>Patients and methods</B></P><P>Fifty-four subjects, enrolled into an open-label, single-dose, three-treatment, three-period crossover study, randomly received cilnidipine (10 mg), valsartan (160 mg), or both according to one of six sequences. Blood samples were collected at baseline and up to 24 hours after drug administration in each period. Plasma concentrations of cilnidipine and valsartan were determined by liquid chromatography with tandem mass spectrometry. Maximum plasma concentration (C<SUB>max</SUB>) and area under the concentration-time curve from 0 to the last measurable time (AUC<SUB>last</SUB>) were estimated using a noncompartmental method. Tolerability was evaluated by assessing adverse events (AEs), vital signs, electrocardiograms, and clinical laboratory tests. Blood pressure was also measured for PD assessment.</P><P><B>Results</B></P><P>A total of 51 subjects completed the study. The PK profile of cilnidipine was not significantly affected by coadministered valsartan; the geometric mean ratio and 90% confidence interval (90% CI) of AUC<SUB>last</SUB> for cilnidipine with and without valsartan was 1.04 (0.98–1.10). Likewise, cilnidipine did not affect the PK of valsartan; the geometric mean ratio (90% CI) of AUC<SUB>last</SUB> for valsartan with and without cilnidipine was 0.94 (0.83–1.07). Coadministration of cilnidipine and valsartan reduced blood pressure in an additive way. No serious AEs were reported, and both cilnidipine and valsartan were well tolerated.</P><P><B>Conclusion</B></P><P>Coadministered cilnidipine and valsartan do not cause a significant PK or PD interaction, and they are well tolerated.</P>