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Background: A controlled-release (CR) formulation of simvastatin was recently developed in Korea. The formulation is expected to yield a lower Cmax and similar AUC values compared with the immediate-release (IR) formulation. Objective: The goal of this study was to compare the pharmacokinetics of the new CR formulation and an IR formulation of simvastatin after single- and multiple-dose administration in healthy Korean subjects. This study was developed as part of a product development project at the request of the Korean regulatory agency. Methods: This was a randomized, open-label, parallelgroup, 2-part study. Eligible subjects were healthy male or female volunteers between the ages of 19 and 55 years and within 20% of their ideal weight. In part I, each subject received a single dose of the CR or IR formulation of simvastatin 40 mg orally (20 mg × 2 tablets) after fasting. In part II, each subject received the same dose of the CR or IR formulation for 8 consecutive days. Blood samples were obtained for 48 hours after the dose in part I and after the first and the last dose in part II. Pharmacokinetic parameters were determined for both simvastatin (the inactive prodrug) and simvastatin acid (the active moiety). An adverse event (AE) was defined as any unfavorable sign (including an abnormal laboratory finding) or symptom, regardless of whether it had a causal relationship with the study medication. Serious AEs were defined as any events that are considered life threatening, require hospitalization or prolongation of existing hospitalization, cause persistent or significant disability or incapacity, or result in congenital abnormality, birth defect, or death. AEs were determined based on patient interviews and physical examinations. Results: Twenty-four healthy subjects (17 men, 7 women; mean [SD] age, 29 [7] years; age range, 22–50 years) were enrolled in part I, and 29 subjects (17 men, 12 women; mean age, 33 [9] years; age range, 19–55 years) were enrolled in part II. For simvastatin acid, Cmax was significantly smaller (1.68 vs 3.62 ng/mL; P < 0.013) and Tmax and apparent t½ significantly longer (10.33 vs 4.04 hours [P < 0.001] and 11.41 vs 4.16 hours [P < 0.011]) for the CR formulation compared with the IR formulation, respectively, after the single-dose administration. After the multiple-dose administration, for simvastatin acid, the Cmax for the CR formulation was significantly smaller (3.40 vs 5.16 ng/mL; P < 0.037), while the values for Tmax and apparent t½ were significantly longer (8.40 vs 4.57 hours and 13.09 vs 4.52 hours; both, P < 0.001) compared with the IR formulation. There was no significant difference between the CR and the IR formulations for AUC0−last and AUC0−∞) during either the single- or multiple-dose testing. Both CR and IR formulations were well tolerated in all subjects, and no serious AEs or adverse drug reactions were found. No subjects reported any AEs during part I of the study. During part II, 6 subjects (3 from each formulation group) reported headache, 1 reported lumbago before the dose, and 1 subject had a hordeolum while receiving the CR formulation. Conclusions: The Cmax of the simvastatin CR formulation was found to be significantly smaller while the AUC of the active moiety did not differ significantly from that of the IR formulation in these healthy Korean subjects. The simvastatin CR and IR formulations were well tolerated, with no serious AEs observed. To evaluate the characteristics of the CR formulation, its clinical efficacy must be examined in patient populations. [Copyright &y& Elsevier]

Abstract: Background: A sustained-release (SR) formulation of cilostazol was recently developed in Korea and was expected to yield a lower Cmax and a similar AUC to the immediate-release (IR) formulation. Objective: The goal of the present study was to compare the pharmacokinetic profiles of a newly developed SR formulation and an IR formulation of cilostazol after single- and multiple-dose administration and to evaluate the influence of food in healthy Korean subjects. This study was developed as part of a product development project at the request of the Korean regulatory agency. Methods: This was a randomized, 3-part, sequential, open-label, 2-period crossover study. Each part consisted of different subjects between the ages of 19 and 55 years. In part 1, each subject received a single dose of SR (200 mg × 1 tablet, once daily) and IR (100 mg × 2 tablets, BID) formulations of cilostazol orally 7 days apart in a fasted state. In part 2, each subject received a single dose of the SR (200 mg × 1 tablet, once daily) formulation of cilostazol 7 days apart in a fasted and a fed state. In part 3, each subject received multiple doses of the 2 formulations for 8 consecutive days 21 days apart. Blood samples were taken for 72 hours after the dose. Cilostazol pharmacokinetics were determined for both the parent drug and its metabolites (OPC-13015 and OPC-13213). Adverse events were evaluated through interviews and physical examinations. Results: Among the 92 enrolled subjects (66 men, 26 women; part 1, n = 26; part 2, n = 26; part 3, n = 40), 87 completed the study. In part 1, all the primary pharmacokinetic parameters satisfied the criterion for assumed bioequivalence both in cilostazol and its metabolites, yielding 90% CI ratios of 0.9624 to 1.2323, 0.8873 to 1.1208, and 0.8919 to 1.1283 for Cmax and 0.8370 to 1.0134, 0.8204 to 0.9807, and 0.8134 to 0.9699 for AUC0–last of cilostazol, OPC-13015, and OPC-13213, respectively. In part 2, food intake increased Cmax and AUC significantly (P < 0.0001), yielding geometric mean ratios of 3.2879, 2.9894, and 3.0592 for Cmax and 1.7001, 1.7689, and 1.6976 for AUC0–last of cilostazol, OPC-13015, and OPC-13213. In part 3, only the Cssmax of clilostazol in the reference formulation did not satisfy the criterion for assumed bioequivalence, yielding 90% CI ratios of 1.2693 to 1.4238 and 1.2038 to 1.3441, respectively. When each dose was normalized, the Cmax for the SR formulation was significantly lower (P < 0.005 for cilostazol). Headache was the most frequently noted adverse effect (part 1, a total of 14 subjects with the IR formulation and 14 with the SR formulation; part 2, a total of 10 without food and 23 with a high-fat meal; part 3, a total of 10 with the IR formulation and 24 with the SR formulation), followed by nausea (part 1, none; part 2, only 1 without food and 3 with a high-fat meal; part 3, a total of 3 with the IR formulation and 3 with the SR formulation), and then dizziness (parts 1 and 2, none; part 3, a total of 4 with the IR formulation and 5 with the SR formulation). All other AEs, including fever, cough, vomiting, palpitation, diarrhea, and epigastric pain, occurred in <3 subjects. Conclusions: These findings suggest that in this select group of healthy Korean volunteers, the SR formulation of cilostazol was not significantly different in AUC compared with that of the IR formulation, although it did display a significantly lower Cmax per dose in both the single- and multiple-dose groups. Food significantly increased the bioavailability of the SR formulation. The cilostazol SR and IR formulations were well tolerated in all parts of the study, with no serious adverse events reported. ClinicalTrials.gov identifier: NCT01455558. [Copyright &y& Elsevier]

Background: Tacrolimus is a macrolide immunosuppressant used in transplantation. It has been shown to have a comparable therapeutic effect and a low adverse drug reaction profile relative to cyclosporme., Objective: The present study compared the pharmacokinetics of twice-daily doses of 2 tacrolimus formulations used in clinical practice in Korea: a conventional (reference) formulation and a more recently developed (test) formulation. The bioavailability of the 2 formulations was evaluated based on the requirement of 20% deviation at a power of 80%., Methods: This study had a randomized, open-label, 2-period, crossover, non-inferiority design. There was a 96-hour treatment period for each formulation, with a 3-week washout period between formulations. Each healthy adult subject received two 1-mg capsules of the reference or test formulation of tacrolimus twice daily (morning and evening), for a total daily dose of 4 mg. Blood samples were obtained during the 96-hour period after the first dose in each treatment period, with tolerability assessments performed up to 2 weeks after the first dose in each period. The primary pharmacokinetic parameters were C(max) and AUC from time 0 to the last measured concentration and extrapolated to infinity. Secondary pharmacokinetic parameters were T(max), t(1/2), C(min0-24), AUC(0-24), and C(96)., Results: The study enrolled 29 healthy Korean volunteers (22 men, 7 women; mean [SD] age, 29 [7] years; age range, 20-51 years; mean weight, 66 [10] kg; mean height, [171 17] cm). All volunteers completed both treatment periods. The 90% Cls for the ratios of the pharmacokinetic parameters (test:reference drug) were 119.25-161.29 for C(max), 95.29-129.04 for AUC(0-t), and 95.63-131.42 for AUC(0-infinity). Based on the 80% to 125% bioequivalence criterion, these results indicated that pharmacokinetic exposure to the test drug was not inferior to that of the reference drug. Both formulations were well tolerated, with no serious adverse events reported., Conclusion: In these healthy Korean adults, there were no statistically significant differences between the pharmacokinetic parameters of the more recently developed oral formulation of tacrolimus and the conventional formulation.

Purpose: This study was to describe nurses' research activities, perceptions and performances of evidence-based practice and barriers to the use of research evidence in nursing practice in Korea., Method: A cross-sectional survey design was used. A questionnaire, except for Barriers Scale, was developed for the study. Data was collected from a convenient sample of 437 registered nurses working at research and education oriented university hospitals., Result: Nurses' research-related activities were relatively low compared to previous studies. Also perceptions and performances of evidence based nursing practice were low. Preferred informational resources for clinical decision making were identified as ward manuals/clinical guidelines, manager/senior nurses, and literature/research. The major barriers to research utilization were a lack of implication for practice along with inadequate facilitation to implement research evidence and difficulty understanding research written in English. Priorities of barriers factor were Administrator, Communication, Adopter, and Research., Conclusion: The findings provide directions for future training, education, and managerial policy to achieve successful evidence based nursing practice.