Publications by authors named "Ki Young Huh"

10 Publications

  • Page 1 of 1

Contrast-enhanced MRI T1 Mapping for Quantitative Evaluation of Putative Dynamic Glymphatic Activity in the Human Brain in Sleep-Wake States.

Radiology 2021 Jun 22:203784. Epub 2021 Jun 22.

From the Departments of Radiology (S.L., R.E.Y., S.H.C., J.Y.L., I.H., K.M.K., T.J.Y., J.H.K., C.H.S.) and Clinical Pharmacology and Therapeutics (K.Y.H.), Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehangno, Jongno-gu, Seoul 03080, Republic of Korea; Center for Nanoparticle Research, Institute for Basic Science, Seoul, Republic of Korea (S.H.C.); School of Chemical and Biological Engineering (S.H.C.) and Department of Electrical and Computer Engineering (S.J., J.L.), Seoul National University, Seoul, Republic of Korea; and Department of Biomedical Engineering, Hankuk University of Foreign Studies, Yongin-si, Republic of Korea (S.H.O.).

Background Evaluation of the glymphatic system with intrathecal contrast material injection has limited clinical use. Purpose To investigate the feasibility of using serial intravenous contrast-enhanced T1 mapping in the quantitative evaluation of putative dynamic glymphatic activity in various brain regions and to demonstrate the effect of sleep on glymphatic activity in humans. Materials and Methods In this prospective study from May 2019 to February 2020, 25 healthy participants (mean age, 25 years ± 2 [standard deviation]; 15 men) underwent two cycles of MRI (day and night cycles). For each cycle, T1 maps were acquired at baseline and 0.5, 1, 1.5, 2, and 12 hours after intravenous contrast material injection. For the night cycle, participants had a normal night of sleep between 2 and 12 hours. The time () to reach the minimum T1 value (T1), the absolute difference between baseline T1 and T1 (peak ΔT1), and the slope between two measurements at 2 and 12 hours (slope) were determined from T1 value-time curves in cerebral gray matter (GM), cerebral white matter (WM), cerebellar GM, cerebellar WM, and putamen. Mixed-model analysis of variance (ANOVA), Friedman test, and repeated-measures ANOVA were used to assess the effect of sleep on slope and to compare and peak ΔT1 among different regions. Results The slope increased from the day to night cycles in cerebral GM, cerebellar GM, and putamen (geometric mean ratio [night/day] = 1.4 [95% CI: 1.2, 1.7], 1.3 [95% CI: 1.1, 1.4], and 2.4 [95% CI: 1.6, 3.6], respectively; = .001, < .001, and < .001, respectively). Median values were 0.5 hour in cerebral and cerebellar GM and putamen for both cycles. Cerebellar GM had the highest mean peak ΔT1, followed by cerebral GM and putamen in both day (159 msec ± 6, 99 msec ± 4, and 62 msec ± 5, respectively) and night (152 msec ± 6, 104 msec ± 6, and 58 msec ± 4, respectively) cycles. Conclusion Clearance of a gadolinium-based contrast agent was greater after sleep compared with daytime wakefulness. These results suggest that sleep was associated with greater glymphatic clearance compared with wakefulness. © RSNA, 2021 . See also the editorial by Anzai and Minoshima in this issue.
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http://dx.doi.org/10.1148/radiol.2021203784DOI Listing
June 2021

Evaluation of safety and pharmacokinetics of bismuth-containing quadruple therapy with either vonoprazan or lansoprazole for Helicobacter pylori eradication.

Br J Clin Pharmacol 2021 Jun 3. Epub 2021 Jun 3.

Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.

Aims: Helicobacter pylori (Hp) eradication plays a key role in the treatment and prevention of peptic ulcer diseases. Increasing clarithromycin resistance in Hp necessitates more effective treatments for eradication, such as bismuth-containing quadruple therapy. We aimed to compare the safety and pharmacokinetics (PK) of bismuth between vonoprazan- and lansoprazole-containing quadruple therapy in Hp-positive subjects.

Methods: In this randomised, double-blind, parallel-group study, Hp-positive subjects were randomised to receive vonoprazan- or lansoprazole-containing quadruple therapy. Each subject received vonoprazan 20 mg or lansoprazole 30 mg combined with bismuth 220 mg, clarithromycin 500 mg and amoxicillin 1000 mg twice daily for 14 days. Blood sampling and urine collection for bismuth PK were conducted predose and up to 12 hours postdose at steady-state. The PK parameters of bismuth were derived using a noncompartmental method and compared between treatments. An exploratory breath test for Hp was conducted at screening and at the follow-up visit on day 42. Safety was assessed by adverse event monitoring, physical examinations, vital signs, 12-lead electrocardiograms and clinical laboratory tests.

Results: A total of 30 subjects were randomised and 26 subjects completed the study (12 in the vonoprazan group and 14 in the lansoprazole group). The systemic exposure of bismuth in the 2 treatments was comparable (~5% difference). All subjects turned negative for Hp at the follow-up visit. No significant difference in safety profiles was noted between the 2 treatments.

Conclusion: The systemic exposure of bismuth was similar between vonoprazan- and lansoprazole-containing quadruple therapy. Vonoprazan-containing quadruple therapy was safe and well tolerated.
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http://dx.doi.org/10.1111/bcp.14934DOI Listing
June 2021

Current Bioequivalence Study Designs in South Korea: A Comprehensive Analysis of Bioequivalence Study Reports Between 2013 and 2019.

Front Pharmacol 2021 4;12:651790. Epub 2021 May 4.

Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Gyeonggi-do, South Korea.

Demonstration of bioequivalence (BE) is mandatory while developing generic drugs. The scientific concept of BE applies equally to different regulatory agencies. However, the application of the concept may differ for each agency, which can affect the design of BE studies. To evaluate the study practices in terms of the BE concept in South Korea, we retrospectively analyzed BE study reports available from Ministry of Food and Drug Safety between 2013 and 2019. Statistical estimation of the pharmacokinetic parameters, including peak concentration and area under the concentration-time curve to the last measurable concentration, as well as study design, number of subjects in a study, study duration, fasting status, and formulation of specific drugs were obtained. The drugs were classified per World Health Organization Anatomical Therapeutic Chemical Classification and Biopharmaceutics Classification System. Post-hoc intrasubject coefficient of variation and corresponding sample sizes were calculated from the 90% confidence intervals of pharmacokinetic parameters. A total of 143 generic drugs in 588 BE studies were analyzed. The largest number of studies were performed in the area of Cardiovascular system (172 studies), followed by Nervous system (143 studies) and Alimentary tract and metabolism (92 studies). Overall, BE studies in South Korea were conducted in accordance with the global guideline despite the differences in details. BE studies were focused on the several therapeutic areas and conducted in a similar manner. The number of subjects was generally larger than that estimated with 90% power.
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http://dx.doi.org/10.3389/fphar.2021.651790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147690PMC
May 2021

Pharmacokinetics and tolerability of apremilast in healthy Korean adult men.

Clin Transl Sci 2021 Jul 1;14(4):1505-1511. Epub 2021 May 1.

Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.

We performed a two-part study to evaluate the pharmacokinetics, safety, and tolerability of oral apremilast, a phosphodiesterase 4 inhibitor indicated for the treatment of psoriasis, in healthy Korean adult men. In part 1, there were 12 subjects who randomly received a single oral dose of apremilast at 20, 30, or 40 mg in each of 3 periods in a crossover fashion. In part 2, there were 16 subjects who randomly received 30 mg of apremilast or its matching placebo in a ratio of 3:1 twice daily for 14 days. Apremilast was rapidly absorbed (maximum concentration: ~2-3 h postdose), and eliminated according to a monoexponential pattern with a terminal-phase elimination half-life of 8-9 h. The exposure to apremilast increased in a dose-proportional manner and accumulation was 1.6-fold at steady-state. Apremilast was well-tolerated after a single oral administration and multiple oral administrations in Korean adult men; all of the treatment-emergent adverse events were mild and recovered without sequelae. In conclusion, apremilast was safe and well-tolerated in healthy Korean adult men when administered single oral doses of 20, 30, or 40 mg or when administered multiple oral doses of 30 mg b.i.d. for 14 days. Overall exposures increased in an approximate dose proportional manner in healthy Korean adult men.
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http://dx.doi.org/10.1111/cts.13013DOI Listing
July 2021

Population Pharmacokinetic Modelling and Simulation to Determine the Optimal Dose of Nanoparticulated Sorafenib to the Reference Sorafenib.

Pharmaceutics 2021 Apr 28;13(5). Epub 2021 Apr 28.

Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Gyeonggi-do 13620, Korea.

Sorafenib, an oral multikinase inhibitor, exhibits a highly variable absorption profile due to enterohepatic reabsorption and poor solubility. SYO-1644 improved the solubility of sorafenib by nanoparticulation technology leading to enhanced bioavailability. To evaluate the pharmacokinetically equivalent dose of SYO-1644 to the reference Nexavar 200 mg, a randomized, open-label, replicated two-period study was conducted in healthy volunteers. A total of 32 subjects orally received a single dose of the following assigned treatment under a fasted state in the first period and repeated once more in the second period with a two-week washout: SYO-1644 100, 150 and 200 mg and Nexavar 200 mg. Pharmacokinetic (PK) samples were collected up to 168 h post-dose. The PK profile was evaluated by both non-compartmental analysis and population PK method. With the final model, 2 × 2 crossover trial scenarios with Nexavar 200 mg and each dose of SYO-1644 ranging from 100 to 150 mg were repeated 500 times by Monte Carlo simulation, and the proportion of bioequivalence achievement was assessed. Transit absorption compartments, followed by a one-compartment model with first-order elimination and enterohepatic reabsorption components were selected as the final model. The simulation results demonstrated that the SYO-1644 dose between 120 and 125 mg could yielded the highest proportion of bioequivalence.
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http://dx.doi.org/10.3390/pharmaceutics13050629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145937PMC
April 2021

Pharmacokinetic Interaction Among Ezetimibe, Rosuvastatin, and Telmisartan.

Clin Pharmacol Drug Dev 2021 Mar 1. Epub 2021 Mar 1.

Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.

To evaluate the pharmacokinetic interactions among rosuvastatin, ezetimibe, and telmisartan, a randomized, open-label, 3-period, 6-sequence crossover study was conducted in healthy subjects. Subjects received one of the following treatments once daily for 7 days in each period with a 1-week washout: a fixed-dose combination of ezetimibe/rosuvastatin 10/20 mg, telmisartan 80 mg, combination therapy of ezetimibe/rosuvastatin 10/20 mg, or telmisartan 80 mg. Blood samples were collected up to 24 hours postdose at steady state. Geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) of the combination therapy to monotherapy for the maximum plasma concentration (C ), and the area under the time-concentration curve within a dosing interval at steady state (AUC ) were estimated. Among the 36 randomized subjects, 31 subjects completed the study. The GMRs and 90%CIs of C and AUC of total ezetimibe were not significantly altered. The C of free ezetimibe was increased (GMR, 1.85; 90%CI, 1.56-2.19) but not for the AUC (GMR, 1.16; 90%CI, 1.06-1.26). Similarly, the C of rosuvastatin was increased (GMR, 2.13; 90%CI, 1.88-2.43) without a change in the AUC (GMR, 1.09; 90%CI, 1.03-1.15). The C (GMR, 1.16; 90%CI, 1.01-1.32) and AUC (GMR, 1.26; 90%CI, 1.17-1.37) of telmisartan were slightly increased. Considering the therapeutic range of the components, the interaction would have limited clinical impact.
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http://dx.doi.org/10.1002/cpdd.926DOI Listing
March 2021

Comparison of the Pharmacokinetics of a Fixed-Dose Combination of Rosuvastatin/Metformin Sustained-Release (10/1000 mg) and Separate Tablets in Healthy Male Subjects.

Clin Pharmacol Drug Dev 2021 02 24;10(2):207-213. Epub 2020 Jun 24.

Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.

Fixed-dose combination (FDC) drugs with various dose combinations for the treatment of type 2 diabetes mellitus and dyslipidemia are currently in demand. We compared the pharmacokinetic (PK) profiles of the rosuvastatin/metformin sustained-release (10/1000 mg) FDC and separate tablets and evaluated the effect of food by randomized, open-label, 3-period, 6-sequence crossover studies conducted in healthy male subjects. Subjects were randomly assigned to one of the following treatments: separate tablets of 10 mg rosuvastatin and 1000 mg metformin sustained release in the fed state and the FDC in the fasted and fed states. PK samples were collected up to 72 hours postdose for rosuvastatin, N-desmethyl rosuvastatin, and metformin. The PK parameters were determined using a noncompartmental method, and the geometric mean ratio (GMR) and the 90% confidence interval (CI) of the treatments were calculated. A total of 35 subjects completed the study. The GMR and 90%CI of the peak concentration (C ) and area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC ) of the FDC and the separate tablets were within the bioequivalence criteria (0.8-1.25) for both rosuvastatin and metformin. The effect of food was statistically significant for both rosuvastatin and metformin but not expected to be of clinical significance.
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http://dx.doi.org/10.1002/cpdd.841DOI Listing
February 2021

Pharmacokinetics and pharmacodynamics of a fixed-dose combination of gemigliptin/metformin sustained release 25/500 mg compared to the loose combination in healthy male subjects.

Transl Clin Pharmacol 2020 Mar 30;28(1):43-54. Epub 2020 Mar 30.

Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Korea.

A fixed-dose combination (FDC) of gemigliptin/metformin can improve the medication adherence in patients with type 2 diabetes mellitus (T2DM). In this study, the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of gemigliptin and metformin were compared between FDC and the corresponding loose combination under fasted and fed states. A two-part, randomized, open label, single-dose, two-way crossover study was conducted in healthy male subjects. Under fasted (part 1) or fed (part 2) state, 2 FDC tablets of gemigliptin/metformin sustained release (SR) 25/500 mg or loose combination with one tablet of gemigliptin 50 mg and two tablets of metformin extended release (XR) 500 mg were orally administered in each period with a 7-day washout. Serial blood samples were collected up to 48 hours to determine the drug concentration and the dipeptidyl peptidase 4 (DPP-4) activity. The concentration-time profiles of gemigliptin and metformin were similar between FDC and loose combination in both the fasted and fed states. Geometric mean ratios and 90% confidence intervals of FDC to loose combination for area under the concentration-time curve and maximum plasma concentration of gemigliptin and metformin were within the bioequivalence range (0.8-1.25) in both states. DPP-4 activity-time profiles of FDC were comparable to that of the loose combination, showing similar area under the DPP-4 inhibition-time curve and maximum DPP-4 inhibition between FDC and loose combination, regardless of the fasted or fed state. In conclusion, the PK/PD characteristics of gemigliptin and metformin were similar in FDC tablets and loose combination both in fasted and fed states.

Trial Registration: ClinicalTrials.gov Identifier: NCT03355014.
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http://dx.doi.org/10.12793/tcp.2020.28.e2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136079PMC
March 2020

Safety, tolerability and pharmacokinetics and pharmacodynamics of HL2351, a novel hybrid fc-fused interleukin-1 receptor antagonist, in healthy subjects: A first-in-human study.

Br J Clin Pharmacol 2020 02 3;86(2):372-379. Epub 2020 Jan 3.

Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.

Aims: We performed a first-in-human study with HL2351, a novel hybrid Fc-fused interleukin (IL)-1 receptor antagonist, to evaluate its tolerability, pharmacokinetics and pharmacodynamics (PD) after a single subcutaneous (SC) administration in healthy subjects.

Methods: A randomized, double-blind, placebo- and active-controlled, dose-escalation study was conducted. Eligible subjects randomly received a single SC administration of HL2351 (1, 2, 4, 8 and 12 mg/kg) or placebo in a ratio of 8:2. Subjects in the active-controlled group received a single SC administration of anakinra at 100 mg. Serial blood samples were collected for pharmacokinetics and PD analyses. An ex-vivo activation test was performed to evaluate the PD using peripheral blood mononuclear cells treated with IL-1β. Anti-HL2351 antibodies were determined at baseline and 29 days postdose. Tolerability was assessed throughout the study.

Results: HL2351 was eliminated more slowly than anakinra (terminal half-life: 27.21-45.28 vs 3.97 h). Serum concentrations of HL2351 were increased dose-proportionally. The mean apparent clearance of HL2351 were 0.6, 0.66, 0.75, 0.51, 0.65 L/h at 1, 2, 4, 8 and 12 mg/kg, respectively. The percent inhibition of IL-6 expression varied widely (range: 0-92.1%), showing no clear trend or discernible difference between HL2351, anakinra and placebo. HL2351 was well tolerated after a single SC administration.

Conclusion: HL2351 was well tolerated and showed linear pharmacokinetic characteristics after a single SC administration at doses up to 12 mg/kg in healthy subjects. HL2351 remained in the body 7-11 times longer than anakinra. HL2351 can be developed as a potential therapeutic alternative to anakinra.
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http://dx.doi.org/10.1111/bcp.14161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015738PMC
February 2020

Trends of clinical trials from 2014 to 2016 in South Korea.

Transl Clin Pharmacol 2018 Dec 19;26(4):172-176. Epub 2018 Dec 19.

Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Republic of Korea.

Mandatory registration of clinical trials in public registry can ensure the transparency of clinical trials. Public clinical trial registry of can provide current chronological and geographical distribution of clinical trial throughout the country. We used public clinical trial registry provided by Ministry of Food and Drug Safety to analyze current status of clinical trial from 2014 to 2016 in South Korea. The number of clinical trials in antineoplastic and immunomodulating agents area was the greatest, followed by cardiovascular system and antiinfectives for systemic use as a whole. From 2014 to 2016, overall number of clinical trials decreased while the number of phase I clinical trials increased. Seoul accounted for more than half number of clinical trials in Korea. Supports for clinical trials in non-metropolitan area needs to be considered.
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http://dx.doi.org/10.12793/tcp.2018.26.4.172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989249PMC
December 2018
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