Background: Cilostazol is widely used as an antiplatelet drug in patients with intermittent claudication and peripheral arterial disease. Ginkgo biloba extract is prescribed in the management of circulatory disorders in peripheral arteries. Thus a fixed-dose combination of the two drugs has been under clinical development. The pharmacokinetics of cilostazol and safety profiles were compared between coadministration of cilostazol and Ginkgo biloba extract, and that of a fixed-dose combination of the two drugs. Methods: A randomized, open-label, single-dose, two-treatment, two-period, two-sequence crossover study was conducted in 26 healthy male volunteers. Subjects were administered cilostazol 100 mg and Ginkgo biloba extract 80 mg concomitantly and a fixed-dose combination of the two drugs with a 7-day washout in between. Plasma concentrations of cilostazol were determined by liquid chromatography-tandem mass spectrometry. Safety profiles were assessed by physical examinations, electrocardiograms, vital signs, laboratory testings, and monitoring adverse events. Results: Median $T_{max}$ of cilostazol was 3.0 and 4.0 hours after administration of cilostazol and Ginkgo biloba extract concomitantly and fixed-dose combination of the two drugs, respectively. The geometric mean ratio (90% confidence intervals) of the fixed dose combination to the coadministration for $C_{max}$ was 0.95 (0.87-1.05) and that for $AUC_{last}$ was 1.03 (0.96-1.10). The most frequently reported adverse event was headache, reported by 14 subjects. There was no difference of adverse event occurrences between two treatment groups. No serious adverse events were reported. Conclusion: Pharmacokinetics of cilostazol and safety were comparable between coadministration of cilostazol and Ginkgo biloba extract, and administration of a fixed-dose combination of the two drugs.

Background: Theobromine (3,7-dimethylxanthine) has various clinical properties including vasodilation, bronchodilation, and diuresis in humans. It is currently under clinical investigation for cough suppression. The aim of this study was to evaluate the safety and pharmacokinetic characteristics after multiple oral administrations of theobromine 500 mg capsules in healthy male volunteers. Methods: A single-arm, multiple-dosing study was conducted in 12 healthy male volunteers. All subjects orally received the study drug every 12 hours for 7 days. Blood samples were collected up to 12 hours after first dosing and up to 48 hours after last dosing. Plasma concentrations of theobromine were analyzed using high-performance liquid chromatography. Safety assessments, including monitoring adverse events, laboratory tests, vital signs, ECGs, and physical examinations, were performed throughout the study. Results: Pharmacokinetic steady-state was achieved before the last dosing. Median time to peak concentration at steady state ($T_{max,ss}$) was 1.8 hr. Mean terminal half-life was 13.4 hr, and mean peak-trough fluctuation was 47.5% at steady state. At steady state, mean peak concentration ($C_{max,ss}$) and area under the plasma concentration-time curve during a dosing interval ($AUC_{\tau,ss}$) was $22.0\;{\mu}g/mL$ (coefficient of variation, CV: 13.8%) and $213.9\;{\mu}g{\ast}h/mL$ (CV: 17.6%), respectively. Mean accumulation ratio ranged from 1.8 to 2.8 after multiple administrations. There were neither any serious adverse events nor remarkable findings regarding safety. Conclusion: Theobromine capsules were safe and well-tolerated when administered twice daily at dose of 500 mg for 7 days. This study showed the relatively low inter-individual variation in terms of $C_{max}$ and AUC, and moderate accumulation after multiple dosing. This study provided evidence for a twice-a-day dosing regimen of theobromine 500 mg capsules for treatment of chronic cough.

Aims: This study was aimed to characterize the population pharmacokinetics of $Arimidex^{(R)}$ (anastrozole) which has been administered to healthy Korean male volunteers. Methods: We have committed population pharmacokinetic analysis using $NONMEM^{(R)}$ VII with 408 plasma concentration data obtained from subjects who were administered with reference drug $Arimidex^{(R)}$ in a randomized, double-blind, two-way crossover bioequivalence trial conducted in Asan Medical Center. We estimated the parameters by first-order conditional estimation (FOCE) method, and then, observed the change of objective function values which had been calculated by using different compartment models, and explored the significant covariates. To evaluate the suitability and stability of final population model, we performed bootstrapping and visual/numerical predictive checks using Wings for NONMEM and Perl-speaks-NONMEM software. We simulated the plasma concentration corresponding to daily doses of anastrozole 1 mg through 10 days. Results: The plasma concentration data of $Arimidex^{(R)}$ is best fitted by first-order two-compartment linear model. The estimated absorption rate constant value is $0.23\;h^{-1}$, and the final estimates for the volume of distribution of central and peripheral compartment is calculated as 5.12 L and 319 L, respectively. Conclusions: We successfully constructed the final population pharmacokinetic model of $Arimidex^{(R)}$ in this study, which could be useful for various purposes such as Monte-Carlo simulation for the plasma concentration-time profiles of $Arimidex^{(R)}$.

Background: LB80380 is a prodrug of LB80317 developed for the treatment of wild type and lamivudine resistant hepatitis B. This study was conducted to evaluate the pharmacokinetics of LB80380 and that of LB80920 and LB80331 which are the metabolites of LB80380 in healthy volunteers. Methods: This was an open-label, 1-sequence, 2-treatment crossover study. LB80380 90 mg was administered in period 1 and LB80380 240 mg was given in period 2. Blood samples for pharmacokinetics were collected up to 24 hours after each dosing. LB80380, LB80920 and LB80331 were analyzed by liquid chromatography-tandem mass spectrometry. Safety was assessed by monitoring for adverse events (AEs), vital signs, ECGs, physical examination, and laboratory tests. Results: LB80380 was not detected during all sampling times in all subjects. LB80920 was detected up to 3 hours with a median peak time of 0.5 hr for 90 mg and 0.75 hr for 240 mg. LB80331 reached peak plasma concentration at 2.0 hr for both 90 mg and 240 mg. $C_{max}$ of LB80331 were $215.4{\pm}29.4\;{\mu}g/L$ (mean ${\pm}$ SD) and $421.4{\pm}140.1\;{\mu}g/L$; AUCinf was $1280.2{\pm}285.3\;{\mu}g{\ast}h/L$ for 90 mg and $2555.4{\pm}508.3{\mu}g{\ast}h/L$ for 240 mg. A total of 3 adverse events were reported and judged as mild intensity. Conclusion: Pharmacokinetic profiles after administration of LB80380 were in accordance with invitro data in which LB80380 was rapidly metabolized to LB80920 and then to LB80331. A single administration of LB80380 was generally safe and well tolerated.

Background: Garenoxacin is a des-F(6) quinolone antimicrobial drug with broad-spectrum activity. We investigated the safety and pharmacokinetic (PK) characteristics of garenoxacin after a single oral dose in healthy Korean male volunteers, and compared them to those of Japanese. Methods: A parallel, single ascending dose (200, 400 and 600 mg), dose-block randomized, double-blind, placebo-controlled study was conducted in 24 healthy Korean male volunteers. Subjects were randomized into each dose group (6 for active drug, 2 for placebo). For safety assessment, vital signs, laboratory tests, 12-lead electrocardiograms and adverse events were monitored. Plasma concentrations of garenoxacin were measured till 72 hours after drug administration. Concentration-time data was analyzed by noncompartmental methods and the results were compared to Japanese data from the previous study performed under the same protocol. Results: Regarding safety, all doses of garenoxacin were well tolerated without serious adverse events or clinically meaningful changes. The mean area under the concentration-time curve from 0 hour to the last measured concentration over the limit of quantitation ($C_{last}$) ($AUC_{last}$) were 43.9, 101.8, 155.7 mg*h/L and the maximum plasma concentration ($C_{max}$) were 4.7, 8.9, 13.6 mg/L in 200, 400 and 600 mg dose groups, respectively. The range of mean elimination half-life by dose groups was 12.3 to 12.4 h. Increases in systemic exposure to garenoxacin in terms of $AUC_{last}$ and $C_{max}$ were dose proportional over the dose range of 200 to 600 mg. The geometric mean ratios (90% confidence interval) for Koreans to Japanese were 0.97 (0.87-1.08) for dose-normalized $AUC_{last}$ and 1.08 (0.96-1.22) for dose-normalized $C_{max}$. Conclusion: Single oral doses of garenoxacin were well tolerated. Systemic exposures of garenoxacin were linear according to dose increments up to 600 mg dose. Comparison of the PK between Koreans and Japanese indicates that the pharmacokinetic characteristics were similar, which suggests that no dosage adjustment is required for garenoxacin in Koreans compared to Japanese.

Backgrounds: The style and contents of information sheet is very important to make the subjects understand appropriately the information provided in the information sheet. However, the conventional forms of information sheets are still mostly difficult to read and understand for the subjects who are mostly unfamiliar to the complex clinical research process. We performed a prospective comparative evaluation of comprehension and preference between a conventional versus a new modified information sheets, in which both styles are different but the contents are same each other. Methods: The 66 participants were divided into two groups. The control group read the conventional information sheet (CIS) and the other test group read the modified information sheet (MIS). After reading the information sheet, both groups answered the questionnaire to evaluate their comprehension on the clinical research presented in the information sheet. By having the control group read MIS and the test group CIS resp., both groups could compare MIS with CIS and expressed their preference one over the other. Results: The population had a mean age of 21.5 years. The average speed of reading MIS (4.13 words/sec) was faster than that of CIS (3.48 words/sec). The score of comprehension on MIS (the percentage of correct answers: 71.4%) was significantly greater than that on CIS (correct answers: 64.3%). The 8 items newly adopted in MIS modified from CIS in this study were 1) bold style and underlining of characters, 2) increasing font size of characters, 3) using diagrams, 4) widening the interval between lines, 5) using colors, 6) inserting a table of contents, 7) using the cover page, and 8) using header symbols. In a preference study, 87.9% of participants preferred MIS to CIS. Conclusions: Improvement of participants' comprehension was observed through using a new modified information sheet over the conventional information sheet, suggesting a new efficient information sheet.