건강한 남성 자원자에서 실데나필 제제인 플리즈구강용해필름과 비아그라®의 약동학적 특성 및 안전성의 비교평가

홍태곤,이종태,전상일,백정기,김현일,곽성신,박수준,한승훈,임동석 대한임상약리학회 2013 Translational and Clinical Pharmacology Vol.21 No.1

Background: The objective of this study was to compare the pharmacokinetics and safety between newly developed sildenafil (Please Orally Soluble Film) and sildenafil citrate (VIAGRAⓇ) after single oral administration in healthy Korean male subjects. Methods: A randomized, open-label, single dose, 2-way crossover study was conducted in 50 healthy male subjects. Each sequence group consisted of 25 subjects, received a single oral 50 mg dose of Please Orally Soluble Film (test formulation) or VIAGRAⓇ (reference formulation) by study period. Blood samples were obtained during a 24-hour period after dosing. Sildenafil and its metabolite concentrations were determined using validated LC-MS/MS. A non-compartmental pharmacokinetic analysis was performed. Safety was assessed through monitoring of adverse events, vital sign check-up, physical examination, laboratory tests and electrocardiography. Results: All enrolled participants completed the study. The point estimates and 90 % confidence intervals of log transformed Cmax and AUClast of the test formulation in comparison to those of reference formulation were 0.9294(0.8353 - 1.0341) and 0.9415 (0.8869 – 0.9994) respectively. The analysis of variance showed no significant influences of formulation, sequence and period on the pharmacokinetic parameters. The frequencies of adverse events were not statistically different between the formulations. No serious adverse event was observed or reported.Conclusion: Please Orally Soluble Film could be considered bioequivalent to VIAGRAⓇ and had similar safety properties in healthy Korean male subjects.

On comparison of SAS codes with GLM and MIXED for the crossover studies with QT interval data

KyungmeeChoi,홍태곤,이종태 대한임상약리학회 2014 Translational and Clinical Pharmacology Vol.22 No.2

The structural complexity of crossover studies for bioequivalence test confuses analysts and leavesthem a hard choice among various programs. Our study reviews PROC GLM and PROC MIXED inSAS and compares widely used SAS codes for crossover studies. PROC MIXED based on REML ismore recommended since it provides best linear unbiased estimator of the random between-subjecteffects and its variance. Our study also considers the covariance structure within subject over periodwhich most PK/PD studies and crossover studies ignore. The QT interval data after the administrationof moxifloxacin for a fixed time point are analyzed for the comparison of representative SAScodes for crossover studies.

건강한 성인 남성을 대상으로 Levodropropizine CR정반복 투여시의 약동학적 특성 및 안전성에 관한 연구

전상일,이종태,홍태곤,백정기,한승훈,임동석 대한임상약리학회 2013 Translational and Clinical Pharmacology Vol.21 No.2

Background: Levodropropizine is non-opioid agent whose peripheral antitussive action may result from its modulation of sensory neuropeptide levels. Currently, levodropropizine 60 mg is taken three-times daily. A controlled release formulation of levodropropizine (levodropropizine CR) 90 mg was developed, which can be taken twice daily. The aim of this study was to evaluate the safety and pharmacokinetic characteristics after multiple oral administrations of levodropropizine CR 90 mg tablets in healthy male volunteers. Methods: A randomized, open-label, cross-over study was conducted in 24 healthy male volunteers. Each subject received levodropropizine syrup 60 mg three times daily or levodropropizine CR 90 mg twice daily for 3 days. Blood samples for pharmacokinetic analysis were collected pre-dose and up to 24 hours on day 4. Pharmacokinetic analysis was conducted by non-compartmental method. Safety assessments including monitoring adverse events, laboratory tests, vital signs, physical examinations and ECGs were performed throughout the study. Results: A total of 20 male volunteers completed the study. The maximum steady-state plasma concentration (Css,max) of levodropropizine syrup and levodropropizine CR were 313.28 ng/mL and 285.31 ng/mL and time to reach Css,max (Tmax,ss) were 0.48 hr and 0.88 hr, respectively. The area under the concentration-time curve to the last measured concentration of two groups were 2345.36 hr × ng/mL and 2553.81 hr × ng/mL, respectively. There was no serious adverse event. Conclusion: Levodropropizine CR 90 mg tablet was safe and well-tolerated when administered twice daily for 3 days. No statistically significant differences were seen in Css,max and AUCss,24hr between the two formulations. This study provided pharmacokinetic evidences that the twice-daily dosing regimen of levodropropizine 90 mg may substitute the conventional 3-times-daily regimen of levodropropizine 60 mg.

임상시험에서 사용되는 기본통계개념에 관한 고찰

이종태,최경미,전상일,홍태곤,백정기,한승훈,임동석 대한임상약리학회 2012 Translational and Clinical Pharmacology Vol.20 No.2

Statistical analysts engaged in typical clinical trials often have to confront a tight schedule to finish massive statistical analyses specified in a Standard Operation Procedure (SOP). Thus, statisticians or not, most analysts would want to reuse or slightly modify existing programs. Since even a slight misapplication of statistical methods or techniques can easily drive a whole conclusion to a wrong direction, analysts should arm themselves with well organized statistical concepts in advance. This paper will review basic statistical concepts related to typical clinical trials. The number of variables and their measurement scales determine an appropriate method. Since most of the explanatory variables in clinical trials are designed beforehand, the main statistics we review for clinical trials include univariate data analysis, design of experiments, and categorical data analysis. Especially, if the response variable is binary or observations collected from a subject are correlated, the analysts should pay special attention to selecting an appropriate method. McNemar’s test and multiple McNemar’s test are respectively recommended for comparisons of proportions between correlated two samples or proportions among correlated multi-samples.

임상시험에서 사용되는 기본통계개념에 관한 고찰

최경미,이종태,전상일,홍태곤,백정기,한승훈,임동석,Choi, Kyungmee,Lee, Jongtae,Jeon, Sangil,Hong, Taegon,Paek, Jeongki,Han, Seunghoon,Yim, Dong-Seok 대한임상약리학회 2012 臨床藥理學會誌 Vol.20 No.2

Statistical analysts engaged in typical clinical trials often have to confront a tight schedule to finish massive statistical analyses specified in a Standard Operation Procedure (SOP). Thus, statisticians or not, most analysts would want to reuse or slightly modify existing programs. Since even a slight misapplication of statistical methods or techniques can easily drive a whole conclusion to a wrong direction, analysts should arm themselves with well organized statistical concepts in advance. This paper will review basic statistical concepts related to typical clinical trials. The number of variables and their measurement scales determine an appropriate method. Since most of the explanatory variables in clinical trials are designed beforehand, the main statistics we review for clinical trials include univariate data analysis, design of experiments, and categorical data analysis. Especially, if the response variable is binary or observations collected from a subject are correlated, the analysts should pay special attention to selecting an appropriate method. McNemar's test and multiple McNemar's test are respectively recommended for comparisons of proportions between correlated two samples or proportions among correlated multi-samples.

Immunogenicity and Safety of Trivalent Split Influenza Vaccine in Healthy Korean Adults with Low Pre-Existing Antibody Levels: An Open Phase I Trial

임동석,강규리,한승훈,홍태곤,전상일,백정기,강진한 연세대학교의과대학 2016 Yonsei medical journal Vol.57 No.6

Purpose: A phase I clinical trial was conducted to evaluate the immunogenicity and safety of newly developed egg-cultivated trivalentinactivated split influenza vaccine (TIV) in Korea. Materials and Methods: The TIV was administered to 43 healthy male adults. Subjects with high pre-existing titers were excluded in a screening step. Immune response was measured by a hemagglutination inhibition (HI) assay. Results: The seroprotection rates against A/California/7/2009 (H1N1), A/Perth/16/2009 (H3N2) and B/Brisbane/60/2009 were 74.42% [95% confidence interval (CI): 61.38–87.46], 72.09% (95% CI: 58.69–85.50), and 86.05% (95% CI: 75.69–96.40), respectively. Calculated seroconversion rates were 74.42% (95% CI: 61.38–87.46), 74.42% (95% CI: 61.38–87.46), and 79.07% (95% CI: 66.91–91.23), respectively. There were 25 episodes of solicited local adverse events in 21 subjects (47.73%), 21 episodes of solicited generaladverse events in 16 subjects (36.36%) and 5 episodes of unsolicited adverse events in 5 subjects (11.36%). All adverse events were grade 1 or 2 and disappeared within three days. Conclusion: The immunogenicity and safety of TIV established in this phase I trial are sufficient to plan a larger scale clinical trial.

Decreased potency of fimasartan in liver cirrhosis was quantified using mixed-effects analysis

김춘옥,전상일,한승훈,홍태곤,박민수,윤영란,임동석 대한임상약리학회 2017 Translational and Clinical Pharmacology Vol.25 No.1

Fimasartan is a nonpeptide angiotensin II receptor blocker. In a previous study that compared thepharmacokinetics (PK) of fimasartan between patients with hepatic impairment (cirrhosis) andhealthy subjects, the exposure to fimasartan was found to be higher in patients, but the decrease ofblood pressure (BP) was not clinically significant in those with moderate hepatic impairment. Theaims of this study were to develop a population PK-pharmacodynamic (PD) model of fimasartanand to evaluate the effect of hepatic function on BP reduction by fimasartan using previously publisheddata. A 2-compartment linear model with mixed zero-order absorption followed by firstorderabsorption with a lag time adequately described fimasartan PK, and the effect of fimasartanon BP changes was well explained by the inhibitory sigmoid function in the turnover PK-PD modeloverlaid with a model of circadian rhythm (NONMEM version 7.2). According to our PD model,the lower BP responses in hepatic impairment were the result of the increased fimasartan EC50 inpatients, rather than from a saturation of effect. This is congruent with the reported pathophysiologicalchange of increased plasma ACE and renin activity in hepatic cirrhosis.

Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans

배수현,박완수,한승훈,박갑진,이종태,홍태곤,전상일,임동석 대한약리학회 2018 The Korean Journal of Physiology & Pharmacology Vol.22 No.3

It was recently reported that the Cmax and AUC of rosuvastatin increases when it is coadministered with telmisartan and cyclosporine. Rosuvastatin is known to be a substrate of OATP1B1, OATP1B3, NTCP, and BCRP transporters. The aim of this study was to explore the mechanism of the interactions between rosuvastatin and two perpetrators, telmisartan and cyclosporine. Published (cyclosporine) or newly developed (telmisartan) PBPK models were used to this end. The rosuvastatin model in Simcyp (version 15)’s drug library was modified to reflect racial differences in rosuvastatin exposure. In the telmisartan–rosuvastatin case, simulated rosuvastatin CmaxI/Cmax and AUCI/AUC (with/without telmisartan) ratios were 1.92 and 1.14, respectively, and the Tmax changed from 3.35 h to 1.40 h with coadministration of telmisartan, which were consistent with the aforementioned report (CmaxI/Cmax: 2.01, AUCI/AUC:1.18, Tmax: 5 h → 0.75 h). In the next case of cyclosporine–rosuvastatin, the simulated rosuvastatin CmaxI/Cmax and AUCI/AUC (with/without cyclosporine) ratios were 3.29 and 1.30, respectively. The decrease in the CLint,BCRP, intestine of rosuvastatin by telmisartan and cyclosporine in the PBPK model was pivotal to reproducing this finding in Simcyp. Our PBPK model demonstrated that the major causes of increase in rosuvastatin exposure are mediated by intestinal BCRP (rosuvastatin–telmisartan interaction) or by both of BCRP and OATP1B1/3 (rosuvastatin–cyclosporine interaction).

Pharmacokinetic drug interaction between atorvastatin and ezetimibe in healthy Korean volunteers

박정신,김춘옥,진병학,양승원,박민수,홍태곤 대한임상약리학회 2017 Translational and Clinical Pharmacology Vol.25 No.4

Atorvastatin and ezetimibe are frequently co-administered to treat patients with dyslipidemia forthe purpose of low-density lipoprotein cholesterol control. However, pharmacokinetic (PK) druginteraction between atorvastatin and ezetimibe has not been evaluated in Korean population. Theaim of this study was to investigate PK drug interaction between two drugs in healthy Korean volunteers. An open-label, randomized, multiple-dose, three-treatment, three-period, Williams designcrossover study was conducted in 36 healthy male subjects. During each period, the subjects receivedone of the following three treatments for seven days: atorvastatin 40 mg, ezetimibe 10 mg, ora combination of both. Blood samples were collected up to 96 h after dosing, and PK parameters ofatorvastatin, 2-hydroxyatorvastatin, total ezetimibe (free ezetimibe + ezetimibe-glucuronide), andfree ezetimibe were estimated by non-compartmental analysis in 32 subjects who completed thestudy. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) of the maximum plasmaconcentration (Cmax,ss) and the area under the curve within a dosing interval at steady state (AUCτ,ss)of atorvastatin when administered with and without ezetimibe were 1.1087 (0.9799–1.2544) and1.1154 (1.0079–1.2344), respectively. The corresponding values for total ezetimibe were 1.0005(0.9227–1.0849) and 1.0176 (0.9465–1.0941). There was no clinically significant change in safetyassessment related to either atorvastatin or ezetimibe. Co-administration of atorvastatin and ezetimibeshowed similar PK and safety profile compared with each drug alone. The PK interaction betweentwo drugs was not clinically significant in healthy Korean volunteers.

Evaluation of pharmacokinetic interactions between amoxicillin, clarithromycin, and the potassium-competitive acid blocker YH4808 in healthy subjects

이우열,오은실,Mengqi Cui,김춘옥,Yeji Lim,Hunam Kim,Hyeonsoo Park,Sukyong Yoon,박민수,홍태곤 대한임상약리학회 2020 Translational and Clinical Pharmacology Vol.28 No.1

YH4808 is a novel potassium-competitive acid blocker that was developed as a therapeutic agent for gastric acid-related diseases; it may replace proton pump inhibitors, which are widely used in combination with amoxicillin and clarithromycin for Helicobacter pylori eradication. We compared the pharmacokinetic (PK) profiles and safety of amoxicillin, clarithromycin, and YH4808 used as monotherapies or in combination for evaluating potential drug interactions. An open-label, randomized, single-dose, Latin-square (4 × 4) crossover study was conducted in 32 healthy Korean volunteers. Subjects were randomly assigned to one of the 4 treatment sequences that consisted of 4 periods separated by 21-day washout intervals. PK parameters of YH4808, amoxicillin and clarithromycin administered in combination were compared with those of the respective monotherapies. The geometric mean ratios of the maximum concentration (Cmax) and the area under the time-concentration curve from time zero to time of the last quantifiable concentration (AUClast) of YH4808 increased during the triple therapy by 48.6% and 29.1%, respectively. Similarly, the Cmax and AUClast of M3 (active metabolite of YH4808) increased by 23.3% and 16.0%, respectively. The Cmax and AUClast of clarithromycin increased by 27.4% and 30.5%, and those of 14-hydroxyclarithromycin were increased by 23.1% and 32.4%, respectively. The corresponding amoxicillin values decreased during the triple therapy by 21.5% and 15.6%, respectively. There was no clinically significant change in safety assessment related to either monotherapies or triple therapy. In conclusion, amoxicillin, clarithromycin and YH4808 administered as triple therapy did not exhibit significant PK interactions and were not associated with safety issues.