Background: Amlodipine is a third-generation dihydropyridine calcium channel blocker, which has proven to be a useful drug against hypertension or angina. Methods: This randomized, open-label, two-period, two-treatment, single-dose, crossover study was conducted in twenty healthy male volunteers. Subjects were administered 5 mg of the test or reference formulation. After 2-week washout period, the other formulation was administered. Blood samples were collected up to 144 hours after drug administration, and plasma amlodipine concentrations were determined by validated liquid chromatography-tandem mass spectrometry. Drug safety was assessed using measurement of vital signs, physical examinations, laboratory test, electrocardiograms, and adverse event monitoring. Results: All subjects were completed this study. The geometric mean ratios of $C_{max}$ and $AUC_{last}$ were 1.078 (90 % CI, 0.968 - 1.200) and 1.095 (90 % CI, 1.011 - 1.186), respectively. There were no serious adverse events were reported by both formulations. Conclusion: This study showed the test and reference formulations had similar pharmacokinetics and safety profiles.

Background: Cefcapene pivoxil hydrochloride (CFPN-PI) is an oral ester cephalosporin antibiotic with a broad spectrum. In this study, we investigated the pharmacokinetics (PK) and tolerability of CFPN-PI following single oral administration in healthy Korean subjects. Methods: An open label, dose escalation, parallel group study was conducted in 18 healthy male volunteers. A single dose of CFPN-PI was administered to 6 subjects in each treatment group of 100, 150 and 200 mg. Serial blood and urine samples were collected up to 12 h and 24 h after dosing, respectively. Plasma and urine concentrations of cefcapene were measured by HPLC-UV. PK parameters were estimated using non-compartmental analysis. For the safety evaluation, adverse event monitoring, clinical laboratory tests and physical examination were performed throughout the study. Results: Median values of time to peak plasma concentration were observed around 1.5 to 2.0 h. Maximum plasma concentrations ($C_{max}$) were $1.04{\pm}0.22$, $1.24{\pm}0.46$ and $1.56{\pm}0.43$ mg/L ($mean{\pm}SD$), and area under the plasma concentration time curve ($AUC_{inf}$) were $2.94{\pm}0.46$, $3.97{\pm}1.28$ and $4.70{\pm}1.19h{\times}mg/L$ in 100, 150 and 200 mg dose groups, respectively. The differences of dose normalized $C_{max}$ and $AUC_{inf}$ among three groups were not statistically significant. The fractions of drug excreted in urine unchanged were 31.5 % - 42.9 %. There were no serious adverse events or clinically significant abnormalities related to CFPN-PI. Conclusion: CFPN-PI was well tolerated with single oral administration and showed a linear PK property within 100 - 200 mg in healthy Korean male subjects.

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 ($C_{ss,max}$) of levodropropizine syrup and levodropropizine CR were 313.28 ng/mL and 285.31 ng/mL and time to reach $C_{ss,max}$ ($T_{max,ss}$) 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 $hr{\times}ng/mL$ and 2553.81 $hr{\times}ng/mL$, 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 $C_{ss,max}$ and $AUC_{ss,24hr}$ 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.

Background: This clinical study was conducted to compare pharmacokinetics of eperisone and aceclofenac of HCP1104, a new fixed dose combination drug with those in co-administration of eperisone 50 mg and aceclofenac 100 mg. The study used a partial replicated study design to characterize intra-subject variability of eperisone when co-administrated with aceclofenac. Methods: A partial replicated crossover design was employed in 30 subjects. Each subject received a single dose of co-administration of eperisone 50 mg and aceclofenac 100 mg on two occasions and a single dose of 1 capsule of HCP1104. Blood samples were obtained for 24 hrs after dosing, and plasma was assayed for eperisone and aceclofenac by Liquid chromatography-electrospray ionization-mass spectrometry. Results: Using an average bioequivalence criterion, the 90 % confidence limits for Ln-transformed $C_{max}$ and $AUC_{last}$ for aceclofenac fell wihin the acceptable range of 80 - 125 %. Point estimates of eperisone $AUC_{last}$ and $C_{max}$ were 1.0152 and 1.0490, respectively and the 90 % confidence interval for $C_{max}$ was 0.8499 - 1.3025. The within-subject coefficient of variation of Cmax for the reference was 50.198 %. Acceptance range for eperisone $C_{max}$ based on new bioequivalence guidance for highly variable drugs was extended to 0.6984 - 1.4319. Conclusion: The extent of exposure and rate of absorption of both eperisone and aceclofenac with a single dose of HCP1104 capsule were equivalent to those with co-administration of a marketed eperisone 50 mg tablet and a marketed aceclofenac 100 mg tablet under fasting conditions in healthy adult males.

배경: 본 연구는 건강한 한국인 자원자를 대상으로 공복상태에서 5일간 탐스로신을 투여한 뒤 약동학적 특성을 평가하고자 하였다. 방법: 무작위배정, 공개, 반복 투여, 2기 교차 시험 설계로 수행된 본 연구는, 총 44명의 시험대상자를 1:1로 무작위 배정하여 제 1기에 시험약으로 탐수로이신$^{(R)}$ 캡슐 0.2 mg 또는 대조약인 하루날$^{(R)}$ 캡슐 0.2 mg을 각각 투여하고 10일간의 휴약기를 거친 후 제 2기에는 1기와 반대로 해당 임상시험용 의약품을 투여하였다. 탐스로신의 혈장 농도는 HPLC-MS/MS를 사용하여 측정하였다. 안전성 평가를 위하여 임상실험실 검사, 이상반응 모니터링, 신체검진 등을 수행하였다. 결과: 시험약과 대조약의 약동학적 파라미터는 다음과 같았다(평균(표준편차)). $C_{ss,max}$는 시험약이 9.0 (2.9) ng/mL, 대조약은 8.4 (2.6) ng/mL이었고, $t_{max}$(중앙값(최소값-최대값))는 시험약이 4 (2-6), 대조약은 5 (2-7) hours이었다. $AUC_{\tau}$는 시험약이 93.7 (31.5) $ng{\times}h/mL$, 대조약은 88.2 (29.3) $ng{\times}h/mL$이었으며, $t_{1/2}$의 경우 시험약은 9.5 (2.6), 대조약은 10.0 (2.7) hours이었다. 탐스로신 경구 투여 후 volume of distribution 과 clearance는 각각 0.5 L/kg, 0.04 L/h/kg이었고, 탐스로신 0.2 mg 1일 1회 용법에 대한 accumulation ratio는 1.2였다. 로그 변환한 $AUC_{\tau}$와 $C_{ss,max}$ 변수의 대조약에 대한 시험약의 기하평균비의 90 % 신뢰구간은 각각 1.005-1.131, 1.000-1.136으로 동등성 범위 이내에 속하였다. 시험기간 동안 중대한 이상반응은 발생하지 않았고 시험약과 대조약 모두 내약성이 우수하였다. 결론: 공복상태에서 탐스로신을 투약한 후 $C_{ss,max}$와 $AUC_{\tau}$는 타 연구에서 음식물과 함께 탐스로신을 복용한 경우보다 증가하였고 tmax는 감소하였다.

Background: JES9501 is dehydroevodiamine, the extract of Evodia rutaecarpa, expected to be a new therapeutic for Alzheimer disease. This study aims to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of JES9501 after single or multiple dosing. Methods: A double-blind, randomized, placebo-controlled, dose ascending, parallel study was conducted in healthy subjects. A single dose of JES9501 50 100 200 400 or 800 mg and multiple doses of JES9501 100 200 or 400 mg once-daily for 7days was administered. Serial blood and urine samples for PK evaluation were collected. Acetylcholinesterase (AChE) activity was measured for PD evaluation in multiple dose group. Results: In the single dose study, means of dose-normalized peak concentration ($C_{max}$) of 100 200 400 and 800 mg dose group are comparable except 50 mg dose group. Means of dose-normalized area under the plasma concentration-time curve (AUC) from dosing to the last quantifiable concentration of corresponding dose group were similar. At steady state in the multiple dose study, means of dose-normalized $C_{max}$ and AUC for dosing interval of 100 200 and 400 mg dose group decreased as the dose increased, however those were not relevant. There was no significant difference of AChE activity between three dosage groups and placebo group. Adverse events related to study drug were all mild and there were no remarkable findings. Conclusion: JES9501 was safe and well-tolerated after single or multiple doses in healthy male subjects. Further studies are warranted to evaluate the PK of optimized dosage form and to prove the drug effect in clinical trials for Alzheimer disease patients.

Background: Iguratimod is a new type of disease modifying anti-rheumatic drug, which reduced the production of inflammatory cytokines. The purpose of this study was to evaluate pharmacokinetic characteristics and safety profiles of iguratimod after a single oral administration in healthy Korean volunteers. Methods: A randomized, double-blind, placebo-controlled, parallel group, single oral dose study was conducted in 24 healthy male volunteers. Three groups of eight subjects each received 25 mg, 50 mg, or 100 mg dosage, respectively. Two subjects in each dose group were administered matching placebo. Plasma concentrations of iguratimod were measured till 72 hours after drug administration. Tolerability was evaluated by monitoring adverse events, clinical laboratory tests, and 12-lead electrocardiograms. Results: The mean area under the concentration-time curve from 0 to 72 hours ($AUC_{last}$) were 11.9, 25.2, and 51.8 $mg{\times}h/L$ and the maximum plasma concentration ($C_{max}$) were 1.15, 2.33, and 4.78 mg/L in 25, 50 and 100 mg dose groups, respectively. All doses of iguratimod were well tolerated without serious adverse events or clinically meaningful changes. Conclusion: $C_{max}$ and $AUC_{last}$ values of iguratimod proportionally increased with incremental dose. Iguratimod was generally safe and well tolerated.

Background: Erlotinib is a tyrosine kinase inhibitor prescribed for the treatment of non-small cell lung cancer and pancreatic cancer. The aim of this study was to compare the safety and pharmacokinetics (PK) of a generic (test) formulation of erlotinib with those of a reference formulation in healthy volunteers. Methods: A randomized, open-label, single-dose two-treatment, two-period, two-sequence, crossover study was conducted in Clinical Trials Center, Chungnam National University Hospital with 40 healthy men. Subjects orally received either one 150 mg tablet of the test or the corresponding dose of the reference, and crossover phases were separated by 14-day washout. Plasma samples were collected up to 72 hr post-dose. Plasma erlotinib concentrations were determined by liquid chromatography-tandem mass spectrometry. PK parameters were calculated by non-compartmental analysis. The safety was monitored throughout the study. Results: A total of 21 cases of adverse events were reported. They are mild and relieved without an intervention. There was no serious adverse event. Median times to peak concentration of two formulations were 3.0. Means [SD] for peak concentration ($C_{max}$) and area under the plasma concentration-time curve (AUC) of the test were 1,298 [346] ${\mu}g/L$ and 25,318 [7,668] $hr{\times}{\mu}g/L$. Those of the reference were 1,193 [378] ${\mu}g/L$ and 24,853 [8,419] $hr{\times}{\mu}g/L$. Geometric mean ratios (90 % confidence intervals) for the test to the reference were 1.10 (1.02-1.18) for $C_{max}$ and 1.02 (0.97-1.09) for AUC. Conclusion: Two formulations were safe and well-tolerated. PK findings suggest that the test formulation is equivalent to the reference in terms of pharmacokinetics.

Background: Bivalirudin is a direct thrombin inhibitor for patients with unstable angina undergoing percutaneous coronary intervention. Methods: A sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) method was developed and validated for the determination of bivalirudin, in human plasma using nafarelin as internal standard (IS). Chromatographic separation was performed using a Shiseido MG3 mm column ($2.0{\times}50$ mm) with a gradient mobile phase consisting of water and acetonitrile containing 0.1 % formic acid at a flow rate of 0.4 mL/min, and total run time was within 5 min. Detection and quantification was performed by the mass spectrometer using a multiple reaction-monitoring mode at m/z $1091.0{\rightarrow}650.3$ for bivalirudin, and m/z $662.1{\rightarrow}249.3$ for IS. Results: The assay was linear over a concentration range of 10 - 10000 ng/mL with a lower limit of quantification of 10 ng/mL in human plasma. Conclusion: This method was successfully applied for pharmacokinetics study after intravenous administration of bivalirudin to healthy Korean male volunteers.