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KMRC011 is a novel Toll‐like receptor 5 agonist under development as a treatment for acute radiation syndrome (ARS). The aim of this first‐in‐human study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of a single intramuscular dose of KMRC011 in healthy subjects. A randomized, single‐blind, placebo‐controlled, single dose‐escalation study was conducted with the starting dose of 5 μg. Eight (4 only for 5 μg cohort) subjects per cohort were randomly assigned to KMRC011 or placebo in a 3:1 ratio. Dose‐limiting toxicity (DLT) was assessed throughout the study. Serum concentrations of KMRC011, granulocyte colony‐stimulating factor (G‐CSF), and interleukin‐6 (IL‐6) were measured up to 48 h postdose. Based on safety review, the dose of KMRC011 escalated up to 20 μg, and consequently, a total of 4 dose levels (5, 10, 15, and 20 μg) were explored. The most common adverse event was injection site reaction, showing no dose‐related trend. Three DLTs (2 cases of hepatic enzyme increased and 1 of pyrexia) were observed; 1 in the 15 μg cohort and 2 in the 20 μg cohort. A developed method could not detect any KMRC011 in serum. KMRC011 15 μg and 20 μg showed significant increases of G‐CSF, IL‐6, and absolute neutrophil counts, compared with the placebo. A single intramuscular administration of KMRC011 ranging from 5 to 15 μg was tolerated in healthy subjects. Doses of KMRC011 equal to or greater than 15 μg exerted TLR5 agonist‐like activities by increasing serum G‐CSF and IL‐6. It suggests that KMRC011 has the potential for a treatment for ARS.

We evaluated the tolerability, pharmacokinetics (PK) and preliminary efficacy of KML001, an oral trivalent arsenical, as a monotherapy in patients with advanced solid tumors.With a standard 3 + 3 design for dose-escalation stage, the planned dose levels of KML001 were 5, 7.5, 10, 12.5, and 15 mg/day for 28 days. Once the maximum tolerated dose was determined, 22 subjects were additionally enrolled for dose-expansion stage. PK analysis was performed in the 5, 10, and 15 mg/day cohort at the dose-escalation stage and also at the dose-expansion stage. Moreover, response was assessed using the standard RECIST 1.1.A total of 45 Korean subjects were enrolled. No DLT was reported at the dose-escalation stage. Three DLTs, two cases of prolonged QTc interval and one of neutropenia, were reported in the 12.5 mg/day cohort at the dose-expansion stage. Higher total daily doses up to 12.5 mg/day of KML001 resulted in higher trough plasma concentrations. Among the 18 subjects who completed 2 cycles of therapy, 15 had progressive disease and 3 had stable disease.Doses equal to or greater than 10 mg/day KML001 alone were tolerable and produced plasma concentrations higher than biologically relevant targets.

Background The purpose of this study was to evaluate clinical and radiological outcomes at skeletal maturity after a calcaneo-cuboid-cuneiform osteotomy (triple C osteotomy) for symptomatic flatfoot deformity compared with healthy young adult controls. Methods Nineteen patients (30 feet) who undergone a triple C osteotomy for idiopathic symptomatic flatfeet from July 2006 to April 2013 were compared with 19 controls (38 feet). Radiographic measurements at preoperative examination, 1-year postoperative follow-up, and follow-up at skeletal maturity were evaluated. Functional outcomes were assessed by using the validated visual analog scale foot and ankle (VAS-FA) and the modified American Orthopaedic Foot and Ankle Surgery (AOFAS) score. Results In the triple C osteotomy group, 11 of 12 radiographic measurements were significantly improved at 1 year postoperatively and the last follow-up (p < 0.001). There was no recurrence at skeletal maturity (p > 0.05). There were no significant differences in nine of 12 radiographic measurements between the triple C osteotomy group at maturity and the control group (p > 0.05). Average VAS-FA and AOFAS scores were significantly improved at the time of skeletal maturity (p < 0.001). Conclusions Surgical correction of symptomatic flatfoot deformity in childhood resulted in favorable outcomes after the triple C osteotomy. Deformity correction was also maintained during follow-up at skeletal maturity.

BackgroundCK2α/CSNK2A1 is involved in cancer progression by phosphorylating various signaling molecules. Considering the role of CSNK2A1 in cancer progression and phosphorylation of SIRT6 and the role of SIRT6 in chemoresistance through the DNA damage repair pathway, CSNK2A1 and SIRT6 might be involved in resistance to the conventional anti-cancer therapies.MethodsWe evaluated the expression of CSNK2A1 in the 37 osteosarcoma patients and investigated the effects of CSNK2A1 and phosphorylation of SIRT6 on Ser338 on the resistance to the anti-cancer effects of doxorubicin. Results Higher expression of CSNK2A1 predicted shorter overall survival and relapse-free survival in both general osteosarcoma patients and sub-population of patients who received postoperative chemotherapies. U2OS and KHOS/NP osteosarcoma cells with induced overexpression of CSNK2A1 were resistant to cytotoxic effects of doxorubicin, and knock-down of CSNK2A1 potentiated the cytotoxic effects of doxorubicin. CSNK2A1 overexpression-mediated resistance to doxorubicin was associated with SIRT6 phosphorylation and induction of the DNA damage repair pathway molecules ATM and Chk2. CSNK2A1 and SIRT6 mediated resistance to doxorubicin in vivo was attenuated via mutation of SIRT6 at the Ser338 phosphorylation site. Emodin, a CSNK2A1 inhibitor, potentiated the cytotoxic effects of doxorubicin in osteosarcoma cells in vitro. ConclusionsThis study demonstrates that the expression of CSNK2A1 might be used as a prognostic indicator of osteosarcoma. In addition, it suggests that CSNK2A1 induces resistance to doxorubicin through phosphorylation of SIRT6-mediated activation of the DNA damage repair pathway. Therefore, blocking the CSNK2A1-SIRT6-DNA damage repair pathway might be a new therapeutic stratagem for the poor prognostic subgroup of osteosarcomas with high expression of CSNK2A1.

Celecoxib is a selective cyclooxygenase-2 inhibitor widely used in patients with osteoarthritis and rheumatoid arthritis. Recently, nonclinical data on the inhibition of human ether-à-go-go-related gene potassium channels by celecoxib were reported, but there is no compelling evidence for this finding in humans. The aim of this study was to assess the potential effects of celecoxib on cardiac repolarization by conducting a thorough QT study, which was designed in compliance with the related guidelines.This randomized, open-label, positive- and negative-controlled, crossover clinical study was conducted in healthy male and female subjects. Each subject received, in 1 of 4 randomly assigned sequences, all of the following 3 interventions: celecoxib 400 mg once daily for 6 days; a single dose of moxifloxacin 400 mg, which served as a positive control to assess the assay sensitivity; and water without any drug, which served as a negative control. Serial 12-lead ECG and blood samples for pharmacokinetic analysis were collected periodically over 24 h. Individually RR-corrected QT intervals (QTcI) and Fridericia method-corrected QT intervals (QTcF) were calculated and evaluated.Twenty-eight subjects were allocated to 1 of the 4 intervention sequences. The largest time-matched mean effects of celecoxib on the QTcI and QTcF were5 ms, and the upper bounds of the 1-sided 95% CIs of those values did not exceed 10 ms. Moreover, none of the subjects had an absolute QTcI value of450 ms or a change from baseline in QTcI of60 ms after multiple administrations of celecoxib. The QTcI did not show a positive correlation with celecoxib concentrations in the range up to ~2700 μg/L. The overall effects of moxifloxacin on the QTcI and QTcF were enough to establish assay sensitivity. No serious adverse events were reported, with a total of 11 AEs reported in 8 subjects.Celecoxib caused no clinically relevant increase in the QT/QTc interval at the maximum dose level used in current practice settings. ClinicalTrials.gov identifier: NCT03822520.

The objective of study was to compare the pharmacokinetic and safety profiles of a fixed‐dose combination (FDC) formulation of 5/160/20 mg amlodipine/valsartan/atorvastatin with those of separate formulations of a 5/160‐mg amlodipine/valsartan tablet and a 20‐mg atorvastatin tablet. This was a randomized, open‐label, single‐dose, 3‐sequence, 3‐period replicate crossover study with 42 subjects. Serial blood samples for pharmacokinetic assessment were collected up to 72 hours postdose. For establishing bioequivalence (BE) for amlodipine, valsartan, and atorvastatin, a reference‐scaled average BE approach was used if applicable, as well as the conventional limit of 0.80‐1.25. The 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) for the maximum plasma concentration (Cmax) and the area under the curve to the last measurable concentration (AUCt) between the FDC and separate formulations were within the 0.80‐1.25 limit for all analytes but atorvastatin. The estimated within‐subject standard deviation of the log‐transformed values of the separate formulations, the reference intervention, was 0.3804 for the Cmax of atorvastatin, being set at 0.7489‐1.3352 for the BE acceptance limit. For both the Cmax and AUCt for atorvastatin, the GMRs lay within 0.80‐1.25, and the 90%CIs for the GMRs were within the BE acceptance limit. This 3‐period replicate crossover study demonstrated the BE of the FDC formulation of amlodipine, valsartan, and atorvastatin and the separate formulations of an amlodipine/valsartan tablet and an atorvastatin tablet. A similar incidence of treatment‐emergent adverse events (TEAEs) was observed in both interventions, and headache was the most common TEAE.

Purpose. We evaluated potential drug-drug interactions between cilostazol and simvastatin, both CYP3A substrates, in healthy subjects. Methods. An open-label, two-period, fixed-sequence clinical study was conducted. Seventeen subjects were given a single oral dose of simvastatin 40 mg on day 1 and multiple oral doses of cilostazol 100 mg twice daily on days 2 to 5 followed by a single dose of cilostazol and simvastatin on day 6. Plasma concentrations of simvastatin and its active metabolite, simvastatin acid, were measured using liquid chromatography-tandem mass spectrometry for pharmacokinetic assessment. Moreover, serum lipid profiles under fasting conditions were determined. Results. The geometric mean ratios of the area under the plasma concentration-time curve from time zero to time infinity of simvastatin combined with cilostazol to that of simvastatin alone were 1.64 (90% CI, 1.38-1.95) for simvastatin and 1.31 (1.04-1.66) for simvastatin acid. In addition, coadministration with cilostazol significantly increased the maximum concentration of simvastatin and simvastatin acid, up to 1.8-fold and 1.6-fold, respectively. However, the effects of a single dose of simvastatin on serum lipid profiles were not affected notably when simvastatin was coadministered with cilostazol. Conclusions. Multiple doses of cilostazol increased the systemic exposure of simvastatin and simvastatin acid following a single dose of simvastatin.

Background IL4Rα and IL13Rα1 are constituents of the type II IL4 receptor. Recently, IL4Rα and IL13Rα1 were reported to have roles in cancer progression and suggested as potential prognostic markers. However, studies on IL4Rα and IL13Rα1 in soft-tissue sarcomas have been limited. Methods This study investigated the immunohistochemical expression of IL4Rα and IL13Rα1 in 89 soft-tissue sarcomas of the extremities, superficial trunk, and retroperitoneum. Immunohistochemical staining for IL4Rα and IL13Rα1 were scored according to a combination of staining intensity and staining area in tissue microarray samples. Positivity for the immunohistochemical expression of IL4Rα and IL13Rα1 were determined using receiver operating curve analysis. Statistical analysis was performed using regression analysis and a chi-square test. Results In human soft-tissue sarcomas, immunohistochemical expression of IL4Rα was significantly associated with IL13Rα1 expression. Nuclear and cytoplasmic expression of IL4Rα and IL13Rα1 were significantly associated with shorter survival of soft-tissue sarcoma patients in univariate analysis. Multivariate analysis indicated that nuclear expression of IL4Rα and IL13Rα1 were independent indicators of shorter overall survival (IL4Rα; p = 0.002, IL13Rα1; p = 0.016) and relapse-free survival (IL4Rα; p = 0.022, IL13Rα1; p p p Conclusions This study suggests IL4Rα and IL13Rα1 are associated with the progression of soft-tissue sarcoma, and the expression of IL4Rα and IL13Rα1 might be novel prognostic indicators of soft-tissue sarcoma patients.

Background SIRT6 has diverse roles in cells, and the role of SIRT6 in tumorigenesis is controversial. Considering the role of SIRT6 as an inducer of DNA damage repair, it might be involved in resistance to anti-cancer therapy. Methods We evaluated the prognostic significance of SIRT6 in 37 osteosarcomas and investigated the therapeutic efficacy of SIRT6 on the anticancer effects of doxorubicin, olaparib, and ATM inhibitor. Results Immunohistochemical expression of SIRT6 was significantly associated with shorter overall survival and relapse-free survival of osteosarcoma patients, especially in patients who received adjuvant chemotherapy. In U2OS and KHOS/NP osteosarcoma cells, knock-down of SIRT6 significantly potentiated apoptotic effects of doxorubicin and SIRT6 overexpression induced resistance to doxorubicin. Moreover, SIRT6 induced the DNA damage repair pathway and SIRT6-mediated resistance to doxorubicin was attenuated by blocking the DNA damage repair pathway with olaparib and ATM inhibitor. Conclusions This study suggests that suppression of SIRT6 in combination with doxorubicin might be an effective modality in the treatment of osteosarcoma patients, especially for osteosarcomas with shorter survival with high expression of SIRT6.

BackgroundCubitus varus is a complex three-dimensional deformity. Various osteotomies have been introduced to correct this complex deformity. The objective of the present study was to evaluate clinical and functional outcomes of adult cubitus varus deformity treated with translation step-cut osteotomy.MethodsSeventeen consecutive patients with a mean age of 25 years (range, 19–50 years) who underwent translation step-cut osteotomy were enrolled in this study. Their average follow-up period was 28.2 months. Radiographic measurements preoperatively, 3-month postoperatively, and at the last follow-up were compared. Functional outcomes were assessed using Disabilities of the Arm, Shoulder and Hand (DASH), Mayo Elbow Performance Score (MEPS), and Oppenheim criteria.ResultsThe mean humerus–elbow–wrist angle improved from 14.7° ± 6.4° (range, 6°–23°) varus preoperatively to 12.1° ± 6.6° (range, 5°–20°) valgus postoperatively (p p > 0.05) different from that at the initial presentation. Based on Oppenheim criteria, results were excellent for 7, good for 8, and poor for 2 patients. Mean final DASH value and MEPS were 2.5 ± 3.8 points (range, 0–15 points) and 97.0 ± 5.8 points (range, 85–100 points), respectively. With regard to complications, one case had delayed union and one case had transient radial nerve injury.ConclusionTranslation step-cut osteotomy using Y plate is an efficient procedure to correct varus alignment and flexion-extension deformities so that they are within normal limits of adults with post-traumatic cubitus varus deformity.Trial registrationInstitutional Review Board of Jeonbuk National University Hospital (IRB No.2020–01-020).

Objective: There is limited literature concerning the outcomes and role of THA as a surgical option for amputee patients. The aim of this study is to determine the mid-to long-term survival and complication rates of cementless total hip arthroplasty (THA) in patients with contralateral below knee amputations. Methods: A retrospective review of 54 patients with below knee amputation were perfomed who underwent THA for osteoarthritis of the contralateral hip over a 5-year period between 1999 and 2014. Patients were monitored for at least 5 years and assessed with the Harris Hip Score and activities of daily living scale and by evaluating migration or osteolysis around the acetabular cup and femoral stems (amputee group). The amputee group was compared with a control group (non-amputee group) with the same number of patients. Results: Differences in the Harris Hip Score (p = 0.021) and activities of daily living scale (p = 0.043) between the two groups were statistically significant lower in the amputee group at 3 months after surgery. However, no differences were found between the groups from 6 months postoperatively to the last follow-up (Harris Hip Score p = 0.812, activities of daily living scale p = 0.885). Radiologically, any cups or stems showed no signs of migration or osteolysis. In the amputee group, dislocation was found in 1 patient 2 months after arthroplasty (p = 0.315) and long stem revision surgery were performed on two patients due to periprosthetic fracture (p = 0.153). Conclusions: THA performed on the contralateral side of patients with below knee amputation is considered to be an effective treatment with good clinical and radiological results at mid-to long-term follow-up. Level of evidence: Level IV, therapeutic study. Keywords: Below knee amputation, Lower extremity amputation, Osteoarthritis, Total hip arthroplasty, Functional recovery

Although the proximal humerus is a common site of osteochondroma, osteochondroma arising from the lesser tuberosity of the proximal humerus is rare. Because of the anatomy of the shoulder, mechanical impingement can occur via direct contact of the protruding lesser tuberosity against the glenoid rim or coracoid. In younger patients, this may cause isolated tearing of the subscapularis. In this study, is presented a rare case of osteochondroma on the lesser tuberosity that caused a subscapularis tear after shoulder impingement in a 34-year-old male. This case was managed using an arthroscopic approach. One year after the surgery, the patient had recovered a normal range of motion, with the resolution of impingement symptoms and the tearing of the subscapularis. Level of evidence IV.

Background FAM83H was initially identified as a protein essential for dental enamel formation. Recent reports have shown that FAM83H is also involved in the progression of human cancers in conjunction with tumor-associated molecules, such as MYC and β-catenin. However, the role of FAM83H in sarcoma has not yet been investigated. Methods The expression and roles of FAM83H and β-catenin were evaluated in human osteosarcomas from 34 patients and osteosarcoma cells. Results The expression of nuclear FAM83H, cytoplasmic FAM83H, and β-catenin were significantly associated with each other and significantly associated with shorter survival of osteosarcoma patients by univariate analysis. In multivariate analysis, cytoplasmic expression of FAM83H was an independent indicator of shorter survival of osteosarcoma patients (overall survival; P

Rationale: Myositis ossificans (MO) is a benign condition characterized by heterotopic bone formation in the skeletal muscle of extremities. Marked variation can occur in the incidence and location of the bone formed as well as resulting complications. Femoral vessel obstruction caused by MO is an extremely rare but disabling complication. Arterial occlusion may aggravate ischemic conditions, resulting in necrosis in the lower extremity. Patient concerns: We report a 41-year-old female with progressive pain and swelling of the right thigh region for 1 year. Diagnoses: We diagnosed it as obstruction of the superficial femoral artery and vein caused by external compression of the MO between the sartorius and vastus medialis of the thigh. Interventions and outcomes: Adherent tissues and mass were excised with care without damaging the femoral artery or the vein. However, normal morphology did not recover due to loss of elasticity of femoral vessels. Therefore, after resection of the narrowed region of the femoral artery, a femoral-to-femoral graft interposition using the greater saphenous vein was performed. At 12 months after the surgery, vessel reconstruction computed tomography images confirmed normal continuous flow of the femoral artery. Lessons: Vascular compression and peripheral inflammatory response due to MO can cause loss of normal vascular morphology. Surgical excision of the mass and the involved femoral artery segment followed by femoral arterial reconstruction should be considered for lesions that do not spontaneously regress to prevent functional impairment and secondary complications in extremities.

Background and Purpose ASPECTS (Alberta Stroke Program Early CT Score) is a 10-point topographic CT scan score that has been shown to be a strong prognostic factor in acute ischemic stroke. We investigated whether all ASPECTS regions have the same prognostic value. Methods Clinical characteristics, ASPECTS, and 3-month modified Rankin Scale (mRS) data were retrospectively collected in 350 patients who were diagnosed with middle cerebral artery (MCA) territory stroke. To describe the 3-month mRS data, an ordered categorical approach was applied using a proportional odds model. Furthermore, external validation was performed using additional data from 30 patients. Results As expected, ASPECTS was an independently important predictor. However, when 10 regions were analyzed separately, the M1, M2, and M3 regions, related to MCA cortex, were not found to predict 3-month mRS scores in the final model. The odds ratios for ischemic change in other regions (except M1, M2, and M3) ranged from 2.6 to 3.8. Moreover, among clinical characteristics, only age was identified as a significant predictor. The sensitivity and specificity of the final model in the external validation were 91% and 88%, respectively. Conclusions All ASPECTS regions did not have the same predictive power for functional outcomes, defined as the 3-month mRS. The implementation of a proportional odds model allowed a proper description of the ordered categorical nature of the mRS and the identification of relevant predictors.

Objective A novel fixed-dose combination (FDC) capsule of 10/5 mg of montelukast/levocetirizine may lead to better compliance than two separate tablets taken together. The aim of this study was to evaluate the pharmacokinetics (PK) and tolerability of an FDC of montelukast and levocetirizine compared to separate tablets. Materials and methods A randomized, open-label, single-dose, two-sequence, two-period, crossover study was conducted with healthy male subjects. In each period, either an FDC or separate tablets were administered orally, and serial blood samples were collected for PK analysis for up to 34 hours after dosing. PK parameters were calculated using noncompartmental methods. The 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of the maximum plasma concentration (Cmax) and the area under the curve to the last measurable concentration (AUClast) for the two interventions were estimated. Tolerability assessments were performed for all the subjects who received the drug at least once. Results The PK profiles of the two interventions were comparable. For montelukast, the GMRs and 90% CIs for the Cmax and AUClast were 0.9800 (0.8903 - 1.0787) and 1.0706 (0.9968 - 1.1498), respectively. The corresponding values for levocetirizine were 0.9195 (0.8660 - 0.9763) and 1.0375 (1.0123 - 1.0634), respectively. Both interventions were well tolerated. Conclusion The PK and tolerability profiles of montelukast and levocetirizine after a single oral administration were comparable between the FDC and separate tablets. For patients with allergic rhinitis who require a combination treatment, the FDC of montelukast and levocetirizine will be a convenient therapeutic option. .

Background PARP1 facilitates the recovery of DNA-damaged cells by recruiting DNA damage response molecules such as γH2AX and BRCA1/2, and plays a role in resistance to antitumor therapies. Therefore, PARP inhibition being evaluated as an anti-cancer therapy. However, there are limited studies regrading PARP inhibition in osteosarcoma. Methods We evaluated the expression of DNA damage response molecules in 35 human osteosarcomas and investigated the effects of co-treatment of the PARP inhibitor, olaparib, and doxorubicin in osteosarcoma cells. Results The expression patterns of PARP1, γH2AX, BRCA1, and BRCA2 were significantly associated with shorter survival of osteosarcoma patients. In osteosarcoma cells, knock-down of PARP1 and treatment of olaparib significantly inhibited proliferation of cells and induced apoptosis. Moreover, the anti-tumor effect was more significant with co-treatment of olaparib and doxorubicin in vitro and in vivo. Conclusions This study suggests that combined use of a PARP inhibitor with doxorubicin, a DNA damaging agent, might be effective in the treatment of osteosarcoma patients, especially in the poor-prognostic subgroups of osteosarcoma expressing PARP1, γH2AX, or BRCA1/2.

Jung-Ryul Kim,1 Hye In Woo,2 Mi-Ryung Chun,3 Shinn-Won Lim,4 Hae Deun Kim,5 Han Sung Na,5 Myeon Woo Chung,5 Woojae Myung,6 Soo-Youn Lee,1,3 Doh Kwan Kim6 1Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, 2Department of Laboratory Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, 3Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 4Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, 5Clinical Research Division, Toxicological Evaluation and Research Department, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Chungcheongbuk-do, 6Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Purpose: This study investigated population pharmacokinetics of paroxetine, and then performed an integrated analysis of exposure and clinical outcome using population pharmacokinetic parameter estimates in depressed patients treated with paroxetine. Patients and methods: A total of 271 therapeutic drug monitoring (TDM) data were retrospectively collected from 127 psychiatric outpatients. A population nonlinear mixed-effects modeling approach was used to describe serum concentrations of paroxetine. For 83 patients with major depressive disorder, the treatment response rate and the incidence of adverse drug reaction (ADR) were characterized by logistic regression using daily dose or area under the concentration–time curve (AUC) estimated from the final model as a potential exposure predictor. Results: One compartment model was developed. The apparent clearance of paroxetine was affected by age as well as daily dose administered at steady-state. Overall treatment response rate was 72%, and the incidence of ADR was 30%. The logistic regression showed that exposure predictors were not associated with treatment response or ADR in the range of dose commonly used in routine practice. However, the incidence of ADR increased with the increase of daily dose or AUC for the patients with multiple concentrations. Conclusion: In depressed patients treated with paroxetine, TDM may be of limited value for individualization of treatment. Keywords: exposure–outcome relationship, paroxetine, therapeutic drug monitoring, population pharmacokinetics, NONMEM

Purpose Rotigotine, a nonergolinic dopamine receptor agonist, is a once-daily transdermal patch developed for the treatment of Parkinson's disease and restless legs syndrome. The objective of the present study was to determine the pharmacokinetic characteristics and tolerability of rotigotine transdermal patch after repeated-dose application in healthy male and female Korean subjects. Methods In this randomized, double-blind, placebo-controlled, repeated-dose study, subjects were randomly assigned to receive either rotigotine or placebo (ratio, 20 rotigotine to 4 placebo, per sex). Rotigotine patches were applied once daily at a dose of 2 mg/24 h on days 1 to 3, followed by 4 mg/24 h on days 4 to 6. Serial blood and urine samples were collected on days 1 to 9 for the determination of the concentrations of rotigotine and its metabolites. Tolerability was evaluated by adverse events determined using physical examination, including vital signs with orthostatic measurements; ECG; and clinical laboratory testing. Findings A total of 48 healthy Korean subjects were enrolled (24 men, 24 women; mean age, 24 years). Approximately 50% of the total drug content was delivered within 24 hours. The mean plasma concentration of unconjugated rotigotine increased proportionally with dose. At the 2 mg/24 h dose at steady state, the geometric mean AUC 0–24h and C max values of unconjugated rotigotine were 5.88 ng·h/mL and 0.347 ng/mL, respectively; at the 4 mg/24 h dose, the corresponding values were 13.74 ng·h/mL and 0.838 ng/mL. The mean t ½ of rotigotine was 4.96 hours. At the 2 mg/24 h dose at steady state, the geometric mean AUC 0–24h and C max values of total rotigotine were 14.02 ng·h/mL and 0.776 ng/mL; at the 4-mg/24 h dose, 32.38 ng·h/mL and 1.867 ng/mL. Common adverse events reported in the rotigotine-treated subjects included nausea (17 subjects, 42.5%), headache (11, 27.5%), and dizziness (9, 22.5%). No clinically significant changes in blood pressure, ECG, or laboratory values were observed. Implications The mean plasma exposures of unconjugated rotigotine increased proportionally with dose. Repeated daily application of the rotigotine patch was well tolerated in these healthy Korean volunteers. ClinicalTrials.gov identifier: NCT01964573.

Jin Ah Jung,1 Soo-Yun Lee,2 Jung-Ryul Kim,1 Jae-Wook Ko,1,2 Seong Bok Jang,3 Su Youn Nam,3 Wooseong Huh1,41Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, 2Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, 3Yuhan Research Institute, Yuhan Corporation, 4Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, KoreaPurpose: Valsartan, an angiotensin-receptor blocker, and rosuvastatin, a competitive inhibitor of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, are frequently coadministered to treat patients with hypertension and dyslipidemia. The study reported here sought to evaluate the pharmacokinetic and pharmacodynamic interactions between rosuvastatin and valsartan in healthy Korean subjects. Subjects and methods: Thirty healthy male Korean subjects were administered with rosuvastatin (20 mg/day), valsartan (160 mg/day), and both drugs concomitantly for 4 days in a randomized, open-label, multiple-dose, three-treatment, three-period crossover study. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and valsartan were determined using validated high-performance liquid chromatography with tandem mass spectrometry. Lipid profiles and vital signs (systolic and diastolic blood pressure and pulse rate) were measured for the pharmacodynamic assessment.Results: For rosuvastatin, the geometric mean ratios (90% confidence intervals [CIs]) of coadministration to mono-administration were 0.8809 (0.7873-0.9857) for maximum plasma concentration at steady state and 0.9151 (0.8632-0.9701) for area under the concentration–time curve (AUC) over a dosing interval at steady state. For valsartan, the geometric mean ratios (90% CIs) of those were 0.9300 (0.7946-1.0884) and 1.0072 (0.8893-1.1406), respectively. There were no significant differences in the metabolic ratio of N-desmethyl rosuvastatin AUC to rosuvastatin AUC between coadministration and rosuvastatin alone. No interaction was found in terms of systolic or diastolic blood pressure or lipid profiles. Combined treatment with valsartan and rosuvastatin was generally well tolerated without serious adverse events.Conclusion: The pharmacokinetic profiles of rosuvastatin and valsartan in combination were comparable with those of rosuvastatin and valsartan administered individually, suggesting that their individual pharmacokinetics were not affected by their coadministration. No dose adjustment was required and the results are supportive of a study in a larger patient population.Keywords: pharmacokinetics, pharmacodynamics, hypertension, dyslipidemia&nbsp

Jin Ah Jung,1 Soo-Yun Lee,2 Tae-Eun Kim,3 Jung-Ryul Kim,1 Chin Kim,4 Wooseong Huh,1,5 Jae-Wook Ko1,2 1Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, 2Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, 3Department of Clinical Pharmacology, Konkuk University Medical Center, 4Clinical Research Team, CKD Pharmaceuticals, 5Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Aims: Lobeglitazone has been developed for the treatment of type 2 diabetes mellitus. This study was conducted to evaluate potential drug–drug interactions between lobeglitazone and warfarin, an anticoagulant with a narrow therapeutic index.Methods: In this open-label, three-treatment, crossover study, 24 healthy male subjects were administered lobeglitazone (0.5mg) for 1–12days with warfarin (25mg) on day 5 in one period. After a washout interval, subjects were administered warfarin (25mg) alone in the other period. Pharmacokinetics of R- and S-warfarin and lobeglitazone, as well as pharmacodynamics of warfarin, as measured by international normalized ratio (INR) and factor VII activity, were assessed. Results: The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for area under the curve from time zero to the time of the last quantifiable concentration (AUClast) for warfarin + lobeglitazone: warfarin alone were 1.0076 (90% CI: 0.9771, 1.0391) for R-warfarin and 0.9880 (90% CI: 0.9537, 1.0235) for S-warfarin. The maximum observed plasma concentration (Cmax) values were 1.0167 (90% CI: 0.9507, 1.0872) for R-warfarin and 1.0028 (90% CI: 0.9518, 1.0992) for S-warfarin, both of which were contained in the interval 0.80–1.25. Lobeglitazone had no effect on the area under the effect–time curve from time 0 to 168hours (AUEC) of INR and factor VII activity, as demonstrated by the GMRs of 1.0091 (90% CI: 0.9872, 1.0314) and 0.9355 (90% CI: 0.9028, 0.9695), respectively. In addition, the pharmacokinetics of lobeglitazone was also unaffected by warfarin.Conclusion: Concomitant administration of lobeglitazone and warfarin was well tolerated. Lobeglitazone had no meaningful effect on the pharmacokinetics or pharmacodynamics of warfarin. These findings indicate that lobeglitazone and warfarin can be coadministered without dosage adjustments for either drug. Keywords: lobeglitazone, thiazolidinedione, warfarin, pharmacokinetics, pharma­codynamics

Summary What is known and objective Sarpogrelate is a selective 5-hydroxytryptamine receptor subtype 2A antagonist that inhibits platelet aggregation and vasoconstriction. The aim of this study was to compare the pharmacokinetics of a sarpogrelate controlled-release formulation (CR) with those of the immediate-release formulation (IR). The effect of food on the pharmacokinetics of CR sarpogrelate was also evaluated. Methods A randomized, open-label, 3-period, 3-treatment crossover study was conducted in 50 healthy male subjects. Subjects were allocated into one of six sequence groups. In one period, a 100-mg IR formulation was administered three times at 6-h intervals, and in the other two periods, a 300-mg CR formulation was administered once to fasting and once to fed subjects. Each period was separated by a 7-day washout period. Serial blood samples were collected up to 24 h after the first drug administration in each period. The plasma concentrations of sarpogrelate were analysed by liquid chromatography–tandem mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental methods. Results and discussion After the administration of the IR formulation, the plasma concentration reached a peak at 0·48 h and the drug was eliminated with a half-life (t1/2) of 0·7 h. After administration of the CR formulation, the plasma concentration reached a peak at 0·5 h and the drug was eliminated with a t1/2 of 3·23 h. The geometric mean ratios (CR/IR) for sarpogrelate area under the plasma concentration–time curve (AUC) and the maximum plasma drug concentration (Cmax) were 1·2040 (90% confidence interval (CI): 1·0992–1·3188) and 0·9462 (90% CI: 0·8504–1·0529). When CR was administered to fed subjects, the time to peak concentration was prolonged to 3·97 h and t1/2 was shortened to 1·45 h. The geometric mean ratios (fasting/fed) for sarpogrelate AUC and Cmax were 0·8573 (90% CI: 0·7687–0·9561) and 0·6452 (90% CI: 0·5671–0·7341). What is new and conclusion After the administration of CR and IR formulations of the same daily dose of sarpogrelate hydrochloride, the overall systemic exposure was slightly higher for the CR than for the IR formulation, whereas peak concentration was comparable between the two formulations. Food reduced the bioavailability of sarpogrelate CR.

Background context There is no comparative study of the in vitro and in vivo osteogenic potential of iliac bone chips (autogenous iliac cancellous bone chips) compared with bone dusts generated during the decortication process with a high-speed burr in spine fracture or fusion surgery. Purpose To compare the osteogenic potential of three sizes of bone dusts with iliac bone chips and to determine whether bone dusts can be used as a bone graft substitute. Study design In vitro and in vivo study. Methods Bone chips were harvested from the posterior superior iliac spine and bone dusts from the vertebrae of 15 patients who underwent spinal fracture surgery. Bone dust was divided into three groups: small (3 mm), middle (4 mm), and large (5 mm) according to the size of the burr tip. A comparison was made using a cell proliferation assay, alkaline phosphatase (ALP) activity, the degree of mineralization in an in vitro model, and radiographic and histologic studies (the change of absorbable area and tissue density) after implantation of the various materials into back muscles of nude mice. Results Although all three bone dust groups were less active with regard to cell proliferation, ALP activity, and the degree of mineralization, than were bone chips, they still exhibited osteogenic potential. Furthermore, there was no significant difference among the three bone dust groups. The three bone dust groups did show greater absorbable area and change of the tissue density than did the iliac bone chip group. Again, there was no significant difference among the three bone dust groups in this regard. Histologically, specimens from the bone dust groups had a higher osteoclast cell number than specimens from the iliac bone chip group. Conclusions The osteogenic potential of bone dusts is lower than that of iliac bone chips, and the absorption speed of bone dusts in vivo is faster than that of iliac bone chips. The increased resorption speed appeared to result from an increase in osteoclast cell number. Therefore, caution needs to be used when surgeons employ bone dust as a bone graft substitute.

The aim of this research was to compare the pharmacodynamics of the combination of mitiglinide and sitagliptin to that of each agent alone in Korean patients with type 2 diabetes mellitus (T2DM). Patients with T2DM received mitiglinide alone, sitagliptin alone, or both drugs together in randomized sequence. A meal tolerance test (MTT) was conducted for each group, and plasma concentrations of glucose, insulin, C-peptide, glucagon, and intact glucagon-like peptide-1, and dipeptidyl peptidase-4 activity were measured from 2 h before breakfast through 4 h after breakfast on day 0 (pretreatment) and day 1 (posttreatment) of each treatment period. Integrated values of these pharmacodynamic variables were analyzed for changes from pretreatment to posttreatment and for differences between the three treatment groups. Twenty-six patients with glycated hemoglobin A1c level of 7.4% ± 0.6%, fasting plasma glucose concentration of 141 ± 22 mg/dL, postprandial plasma glucose (PPG) concentration of 264 ± 48 mg/dL 1 h after the MTT, and diabetes duration of 3.0 ± 3.1 years (mean ± SD) were included in the study. Compared with mitiglinide or sitagliptin alone, the combination treatment lowered PPG additively (P

Background Dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid (ASA) is used for the treatment of acute coronary syndrome. A combined formulation of ASA and clopidogrel has been developed to provide dosing convenience and improve adherence. Objective This study was designed to compare the pharmacokinetic properties and safety profile of a fixed-dose combination formulation of ASA and clopidogrel with concurrent administration of each agent in healthy male Korean volunteers. Methods This single-dose, randomized, open-label, 2-period crossover study was conducted in 64 healthy Korean volunteers. Equal numbers of eligible participants were randomly assigned to receive either the fixed-dose combination of ASA 100 mg and clopidogrel 75 mg or the free combination of each agent followed by a 7-day washout period and then administration of the alternate formulation. Serial blood samples were collected immediately before and after dosing for 24 hours. The safety profile was evaluated by using adverse events (AEs), which were assessed by physical examination, vital signs, ECGs, clinical laboratory tests, and interviews. The 2 formulations were considered to be bioequivalent if the 90% CIs for the log-transformed C max and AUC 0–last values were within the predetermined range of 0.8 to 1.25. Results Sixty-four volunteers (mean [SD] age, 27.51 [8.15] years; weight, 68.55 [7.86] kg; height, 173.80 [5.94] cm) were enrolled, and 63 completed the study. For ASA, the 90% CIs for the geometric mean ratios of C max and AUC 0–last were 0.9483 to 1.1717 and 0.9946 to 1.1020, respectively. For salicylic acid, the 90% CIs were 0.9614 to 1.0396 for C max and 0.9778 to 1.0163 for AUC 0–last . For clopidogrel, the 90% CIs were 0.9809 to 1.2562 for C max and 0.9674 to 1.2073 for AUC 0–last . Six of the 20 AEs reported were drug related: decreased hemoglobin levels (n = 2), fever (n = 1), and headache (n = 1) with the test formulation and increased alanine aminotransferase levels (n = 1) and dyspepsia (n = 1) with the reference formulation. All of the drug-related AEs were transient and mild in severity. Conclusions The fixed-dose combination of ASA and clopidogrel 100 mg/75 mg did not meet the regulatory criteria for bioequivalence as defined by the Korea Food and Drug Administration. Both formulations were well tolerated in these healthy male Korean subjects. ClinicalTrials.gov Identifier: NCT01448330

Pharmacokinetic/pharmacodynamic (PK/PD) models can be useful tools in new drug development and also optimal drug therapy in patients. This study was designed to develop a PK/PD model of sitagliptin based on the physiology of incretin. The PK/PD data included information derived from two different studies. Study 1 was conducted as a one-sequence, three-period, repeated-dose, dose escalation (sitagliptin 25, 50 and 100 mg q.d.) design in twelve healthy volunteers. Study 2 was a first-in-man study for the newly developed dipeptidyl peptidase-4 (DPP-4) inhibitor in healthy volunteers. In study 1, blood samples were collected to measure sitagliptin concentrations, DPP-4 activity and active glucagon-like peptide-1 (GLP-1) concentrations. In study 2, only data from the 'placebo group' were used, and blood samples were collected to measure DPP-4 activity, active GLP-1 concentrations and glucose concentrations. A PK/PD analysis was conducted using a non-linear mixed effects modelling approach. Sitagliptin pharmacokinetics was modelled using a two-compartment model with first-order absorption. Changes in DPP-4 inhibition were linked to the PK model using a sigmoid Emax model, whereas the active GLP-1 changes were explained using an indirect response model; this model incorporated the glucose and DPP-4 inhibition models. The PK/PD model developed adequately described the changes in sitagliptin concentration, DPP-4 inhibition and active GLP-1 concentration in healthy volunteers.

Objective Sarpogrelate hydrochloride is a selective 5-hydroxytryptamine receptor subtype 2A (5HT(2A)) antagonist that blocks serotonin-induced platelet aggregation. The aim of this study was to compare the pharmacokinetics of sarpogrelate and its metabolite after dosing with a controlledrelease (CR) formulation or an immediaterelease (IR) formulation. Methods In this open-label, 2-period, 2-treatment crossover study, 36 healthy male subjects were evenly allocated to two groups in a sequence-randomized manner. In the first period, the first group received 100-mg sarpogrelate IR 3 times at a 6-h interval, and the second group received 300-mg sarpogrelate CR once. After a 7-day washout, the two groups switched their dosing schedule. Serial blood sampling was performed up to 24 hours after the first drug administration during each period. Plasma concentrations of sarpogrelate and its metabolite (M-1) were measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental methods. Results There were no significant differences between two formulations in the pharmacokinetic properties in the time to reach maximum plasma concentration (C(max)) of sarpogrelate and its metabolite. The CR-to-IR geometric mean ratios, as measured by area under the plasma concentration-time curve (AUC) were 1.31 (90% confidence interval, 1.22 - 1.41) for sarpogrelate and 1.21 (1.14 - 1.29) for M-1. The C(max) was 0.98 (0.85 - 1.12) for sarpogrelate and 1.07 (0.96 - 1.19) for M-1. Conclusions After the administration of sarpogrelate hydrochloride CR and IR formulations using the same daily dose, AUCs were slightly higher for the CR formulation than for the IR formulation for both sarpogrelate and its metabolite M-1, but the C(max) values were similar.

The aim of this study is to analyze the characteristics of isolated horizontal meniscal tears in young patients and compared traumatic and non-traumatic isolated horizontal meniscal tear without other type of meniscal tear.Forty patients who underwent partial meniscectomy with isolated horizontal meniscal tears and followed up for more than 2 years were divided into two groups according to the presence of distinct previous traumatic events (defined as contusion or sprain) to the knees. Analyzed variables included in this descriptive statistics were involved side of knee and location of meniscus, physical examinations (joint line tenderness and McMurray's testing), subjective International Knee Documentation Committee (IKDC) criteria, and Lysholm functional questionnaires.Twenty-two of the forty patients (55 %) had distinct previous traumatic events. Fourteen cases (63.6 %) in traumatic group and 14 cases (77.8 %) in non-traumatic group are involved non-dominant knees during locomotion or playing sports. Twenty patients (90.9 %) in traumatic group and eight patients (44.4 %) in non-traumatic group presented with tear in the midportion of the medial meniscus on arthroscopic findings (p0.01). Six patients (60.0 %) in traumatic group and twelve patients (85.7 %) in non-traumatic group had meniscal cysts on arthroscopic findings at the time of surgery (p0.01). There was no statistic difference between the two groups with respect to physical examinations, subjective IKDC scores, and Lysholm functional scores.Isolated horizontal meniscal tears in young patients predominantly involved non-dominant knees and medial meniscus. Anterior aspect of medial meniscus was more frequently involved in traumatic group. Meniscal cysts were more frequently showed in non-traumatic group.

Background Lobeglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist with partial PPAR-α affinity, was developed to treat type 2 diabetes mellitus. Objective This study's aim was to evaluate the tolerability and pharmacokinetic (PK) properties of lobeglitazone to satisfy regulatory requirements for marketing approval in Korea. Methods A block-randomized, double-blind, placebo-controlled, single- and multiple-dose study was conducted in healthy subjects. In the pilot study, 4 subjects were administered 0.5 mg, including 1 receiving a placebo. Then, the single-dose study was conducted with 1, 2, 4, and 8 mg doses (8 subjects in each group, including 2 receiving placebos), followed by the multiple-dose study with 1, 2, and 4 mg doses (once daily for 7 days; 8 subjects in each group, including 2 receiving placebos). Serial samples of blood and urine were collected and drug concentrations were determined by high turbulence liquid chromatography-LC/MS/MS. Tolerability assessments were performed throughout the study. Adverse events (AEs) were determined from general health-related questions and self-reports. Results Thirty-six (mean [SD]; age, 23.6 [2.7] years; weight, 70.0 [6.9] kg) and 25 Korean male subjects (age, 23.5 [3.1] years; weight 69.4 [9.4] kg) were enrolled in the single- and multiple-dose studies, respectively. The data from subjects administered lobeglitazone who completed the study (27, single; 18, multiple) was included in the PK analyses. In the single-dose study, the AUC and C max of lobeglitazone increased with the dose. After repeated dosing for 7 days, the accumulation ratio ranged from 1.1 to 1.4. A total of 25 AEs were reported by 11 (30.6%) and 8 subjects (33.3%) in the single- and multiple-dose studies, respectively. All AEs were mild in intensity and not serious. Conclusions Lobeglitazone was well tolerated in this small, selected group of healthy male Korean volunteers. The AUC and C max of lobeglitazone increased in a dose-proportional manner from 1 to 4 mg.

This study was conducted to evaluate the preliminary outcome of palliative minimally invasive surgery for humeral metastasis in patients who have multiple advanced cancers with short life expectancy. Percutaneous Ender nailing and direct transcortical intramedullary cementing were performed on a total of 15 patients with metastatic disease of the humerus. The origins of the cancers were the lung (n=9), breast (n=3), colon (n=2) and liver (n=1). Each patient had multiple unresectable organic metastases and proved to be at high risk for anesthesia and bloody surgery. All procedures were performed under regional anesthesia and fluoroscopic guidance. The mean amount of intramedullary cement injection after Ender nailing was 13.4ml. The mean of the numeric rating scale (NRS) score for pain decreased from 9.6 points before surgery to 3.6 points after surgery (P

Objective: This study compared the bioavailability and tolerability of a fixed-dose combination (FDC) tablet of glimepiride/metformin 2/500 mg and glimepiride 2-mg + metformin 500-mg tablets administered separately in healthy Korean subjects. Methods: In this single-dose, open-label, 2-period crossover study, healthy Korean volunteers were randomly assigned to receive, in 1 of 2 randomized sequences, an FDC tablet of glimepiride/metformin 2/500 mg (test) and glimepiride 2-mg + metformin 500-mg tablets administered separately (reference), with a 1-week washout period between treatments. Plasma concentrations of glimepiride and metformin were measured using LC/MS-MS. Pharmacokinetic parameters were analyzed using noncompartmental methods. Bioequivalence was concluded if the 90% CIs of the geometric mean test/reference ratios (GMRs) of the logarithm-transformed C max , AUC from 0 to 30 hours (AUC 0–30 ), and AUC 0−∞ values were within the predetermined regulatory range of 80% to 125%. Tolerability was assessed using physical examination and laboratory analysis. Results: A total of 32 subjects were enrolled (16 men [mean (SD) age, 21.8 (2.7) years (range, 18–26 years); weight, 68.9 (8.3) kg (range, 55.5–85.0 kg)]; 16 women [age, 23.5 (4.5) years (range, 20–38 years); weight, 51.7 (3.5) kg (range, 46.8–58.0 kg)]). The GMRs (90% CI) of glimepiride C max , AUC 0–30 , and AUC 0−∞ were 1.01 (0.91–1.11), 0.98 (0.92–1.03), and 0.97 (0.93–1.04), respectively. For metformin, these values were 0.96 (0.87–1.06), 0.96 (0.90–1.03), and 0.96 (0.90–1.03). A total of 49 adverse events (AEs) were reported in 10 subjects (31.3%) with the FDC and in 13 subjects (40.6%) with the separate tablets. The most commonly reported AEs with the test and reference treatments were dizziness (6 [19%] and 7 [22%]) and sweating (4 [13%] and 7 [22%]), respectively. The severity of all of the AEs was considered to be mild, and there were no significant differences in the prevalences of AEs between the 2 formulations. Conclusions: In this study in healthy Korean subjects, the requirements for bioequivalence of the glimepiride/metformin 2/500-mg FDC and coadministration of separate tablets of each drug were met. Both formulations were generally well tolerated.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The importance of efficient drug development using biomarkers has been increasingly emphasized, from preclinical studies to clinical trials. • However, as yet few ‘validated’ or ‘qualified’ biomarkers are used in early-stage drug development in terms of clinical pharmacology and disease pathophysiology. WHAT THIS STUDY ADDS • This first-time-in-human study provides evidence of the pharmacological activity of LC15-0444 in humans, by using dipeptidyl peptidase IV activity and active glucagon-like peptide-1 concentrations. • LC15-0444 possesses pharmacokinetic and pharmacodynamic characteristics that support a once-daily dosing regimen. AIMS LC15-0444 is a selective and competitive inhibitor of dipeptidyl peptidase (DPP) IV with potential for the treatment of Type 2 diabetes. The aim was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles after multiple oral ascending doses of LC15-0444 in healthy male subjects. METHODS A dose block-randomized, double-blind, placebo-controlled, parallel group study was performed in three groups with 10 subjects (eight for active drug; two for placebo) per group; each group received 200, 400 or 600 mg of LC15-0444 once daily for 10 days. Blood and urine samples were collected up to 24 h after the first dosing and up to 72 h after the last dosing. RESULTS The LC15-0444 concentration–time profiles exhibited characteristics of multicompartment disposition. No dose- or time-dependent change in PK parameters was observed. Mean elimination half-life was in a range 16.6–20.1 h in the dose groups. Mean renal clearance and fraction of unchanged drug excreted in urine was 18.6–21.9 and 0.40–0.48 l h−1, respectively. In the steady state, mean accumulation ratios by dose groups were between 1.22 and 1.31. More than 80% inhibition of DPP IV activity from baseline was sustained for >24 h in all dose groups. CONCLUSIONS This study provides evidence of the pharmacological activity of LC15-0444 in humans. LC15-0444 possesses PK and PD characteristics that support a once-daily dosing regimen.

Background: Coadministration of glimepiride and metformin has been used to achieve glucose control. Because compliance with a multiple medication regimen can be difficult for some patients, combination tablets of glimepiride + metformin might be a suitable alternative for these patients. Objective: This study was conducted to compare the pharmacokinetics of test and reference formulations of glimepiride + metformin fixed-dose combination tablets under fasting conditions to meet the regulatory requirements for marketing approval of a new drug in Korea. Methods: This was a single-dose, randomized, open-label, 2-period, 2-way crossover study conducted between March 2007 and May 2007. Healthy fasting Korean men were randomized to 1 of 2 dosing sequences: a single oral administration of a fixed-dose glimepiride 1-mg + metformin 500-mg combination tablet (test) followed by single oral administration of a fixed-dose glimepiride 2 mg + metformin 500 mg combination tablet (reference), separated by a 1-week washout period between doses; or a single oral administration of a fixed-dose glimepiride 2-mg + metformin 500-mg combination tablet followed by single oral administration of a fixed-dose glimepiride 1 mg + metformin 500-mg combination tablet, separated by a 1-week washout period between doses. Serial samples of blood were collected up to 24 hours after oral administration, and drug concentrations in plasma were determined by HPLC-MS/MS. Tolerability was assessed based on adverse events and changes in clinical parameters. Serious adverse events included those that resulted in death, a life-threatening condition, congenital anomaly or birth defect, or required hospitalization or prolongation of existing hospitalization. Results: A total of 30 healthy male subjects (mean age, 25.6 years [range, 20–36 years]; weight, 69.5 kg [range, 58.2–90.7 kg]) participated in the study. After administration of the test and reference formulations, glimepiride was rapidly absorbed, reaching C max with a median T max of 1.75 and 2.0 hours, respectively, and then declined exponentially with an average t½ of 8.2 and 8.5 hours. The individual C max and AUC last of glimepiride were observed to be proportionally increased according to the administered glimepiride dose. The mean (SD) dose-normalized Cmax values of glimepiride 1 and 2 mg were 168.2 (54.9) and 149.9 (47.4) ng/mL/mg, respectively; the mean dose-normalized AUC last values of glimepiride 1 and 2 mg were 681.5 (190.3) and 635.8 (194.1) ng · h/mL/mg. Individual plots of dose-normalized C max and AUC last values identified a similarity between the 2 groups but no significant between-group differences. A total of 25 adverse events (12 after the test dose and 13 after the reference dose) were reported by 13 of the 30 subjects. All adverse events were considered mild. Twenty-one adverse events were considered related to the study drug (8 after the test dose and 13 after the reference dose). Adverse events believed to be related to the test formulation were diarrhea (4 cases), dizziness (1), headache (1), tingling sensation (1), and weakness (1). Adverse events believed to be related to the reference formulation were diarrhea (6 cases), headache (3), cold sweats (1), dyspepsia (1), epigastric discomfort (1), and lethargy (1). There were no clinically significant findings in the laboratory test results or vital sign monitoring during the study. There were no serious adverse events reported. Conclusions: The C max and AUC last of glimepiride increased proportionally according to the administered glimepiride dose in this study of healthy, fasting Korean men. The safety profiles of the 2 combination tablets were comparable.

Background : LC15-0444 is a selective inhibitor of dipeptidyl peptidase (DPP) IV under investigation in Korea for the treatment of type 2 diabetes. Objective : The aim of this study was to investigate the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles of a single dose of LC15-0444 in healthy male subjects. Methods : A dose—block-randomized, double-blind, placebo-controlled, ascending single-dose, Phase I study was performed in healthy Korean male subjects assigned to receive 25, 50, 100, 200, 400, or 600 mg of LC15-0444 capsules. Blood and urine samples were collected up to 72 hours after administration. Plasma and urine drug concentrations were determined by tandem mass spectrometry coupled with high-performance liquid chromatography. DPP IV activity was measured by continuous spectrophotometric assay. An additional food effect study was performed in the 100-mg dose group; changes in PK and PD parameters after highfat diet were evaluated. Adverse events (AEs) were detected through investigator inquiries, spontaneous reports, and clinical evaluations such as physical examinations, vital sign measurements, 12-lead electrocardiography, clinical laboratory tests (eg, hematology, blood chemistry, coagulation, urinalysis), and computerized impedance cardiography. Results : Sixty Korean men (mean age, 25.3 years [range, 19-39 years]; weight, 68.3 kg [range, 53.6-84.9 kg]) were enrolled, providing 10 subjects for each dose group. After administration, LC15-0444 reached T max at 0.5 to 5.1 hours, and was eliminated with a t ½ of 16.7 to 21.3 hours. The mean fraction of unchanged drug excreted in urine ranged from 0.21 to 0.34 and mean renal clearance was 15.5 to 23.6 L/h. The dose-normalized AUC exhibited dose-linearity over the range of 50 to 400 mg. All doses of LC15-0444 =200 mg were found to inhibit 80% of DPP IV activity for 24 hours. High-fat diet did not significantly influence the AUC of LC15-0444. LC15-0444 was generally well tolerated. None of the subjects developed any serious clinical or laboratory AEs or discontinued the study due to an AE. All AEs were mild or moderate, and no dose-related trends were observed. Fortysix AEs were reported in 18 subjects (30.0%). AEs considered to be related to the study drug were headache (6 cases), dizziness (2), nausea (1), epistaxis (1), and increased heart rate (1). All AEs resolved spontaneously. Conclusions : A single dose of LC15-0444 exhibited linear PK properties over the range of 50 to 400 mg in these healthy Korean male subjects. PK characteristics were not significantly influenced by food. In addition, doses ≥200 mg of LC15-0444 inhibited plasma DPP IV activity by >80% over a 24-hour dosing interval, and a 600-mg dose increased active glucagon-like peptide-1 levels after a standardized meal. LC15-0444 was generally well tolerated.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The phosphodiesterase (PDE) type 5 inhibitor is a widely used agent that facilitates penile erection. • Udenafil is newly developed as a PDE-5 inhibitor. WHAT THIS STUDY ADDS • This is the first study to determine the safety, tolerability and pharmacokinetics of udenafil in healthy subjects. • Udenafil was safe and well tolerated in healthy Korean subjects. • The AUC and Cmax of udenafil increased supraproportionally with increasing dose upon single administration, but there was no significant drug accumulation upon multiple administrations. AIM To evaluate the safety, tolerability and pharmacokinetics (PK) of udenafil, a novel phosphodiesterase type 5 inhibitor. METHODS A double-blind, randomized, placebo-controlled, dose-rising, parallel-group, single- and multiple-dose study was conducted in healthy Korean subjects. The subjects were allocated to single-dose groups of 25, 50, 100, 200 or 300 mg (eight subjects in each dose group, including two placebos), or to multiple-dose groups of 100 or 200 mg (once-daily dosing for 7 days; nine subjects in each dose group, including three placebos). Serial samples of blood and urine were collected after oral administration and the drug concentrations in plasma and urine were determined by high-performance liquid chromatography. Safety and tolerability were evaluated by monitoring clinical laboratory parameters and adverse events. RESULTS Udenafil reached peak plasma concentrations at 0.8–1.3 h, and then declined mono-exponentially with a terminal half-life of 7.3–12.1 h in the single-dose study. The area under the time–concentration curves (AUC) and maximum plasma concentrations (Cmax) increased supraproportionally with increasing dose in the single-dose study. During multiple dosing, a steady state was reached at 5 days and little accumulation occurred after repeated dosing for 7 days. Udenafil was generally well tolerated in these healthy subjects, and no serious adverse events occurred. CONCLUSIONS Udenafil was safe and well tolerated in healthy volunteers. The AUC and Cmax of udenafil increased supraproportionally with increasing dose upon single administration, but there was no significant drug accumulation upon multiple administrations.

Objectives. To determine the frequency and chemokine receptor-related migratory capacity of CD4 + CD25 + regulatory T cells (Tregs) and their association with clinical parameters in patients with SLE. Methods. The expression of CD4, CD25, FoxP3 and CCR4 was examined with flow cytometry after staining with fluorescence-conjugated antibodies in 20 patients with SLE, 20 patients with RA and 21 age- and sex-matched healthy controls. For analysis of migration capacity in 24-well chemotaxis chambers, sorted cells were stimulated with ligands of CCR4, CCL17 and CCL22 and analysed with FACScan. Correlations between the number of Tregs and CCR4 + Treg cells and clinical parameters were analysed. Results. The numbers of Tregs bright and CCR4 + Tregs bright were significantly decreased in the patients with SLE compared with healthy controls. The number of Tregs bright was negatively correlated with the levels of anti-dsDNA antibody and the number of CCR4 + Tregs bright had a positive correlation with the levels of C 3 . Percentage of migrated Tregs bright by CCL17 or CCL22 was significantly decreased in the patients with SLE compared with healthy controls. Conclusions. These results suggest that altered frequency of Tregs and CCR4 + Tregs bright and decreased migratory capacity of Tregs might be involved in the pathogenesis of SLE and indicate that targeting the Tregs can be a new therapeutic strategy in SLE.

YKP1358 is a novel serotonin (5-HT2A) and dopamine (D2) antagonist that, in preclinical studies, fits the general profile of an atypical antipsychotic. We conducted a D2 receptor occupancy study with YKP1358 in healthy volunteers using positron emission tomography (PET) to measure the D2 receptor occupancy of YKP1358 and to characterize its relationship to plasma drug concentrations. A single oral dose, parallel group, dose-escalation (100, 200, and 250 mg) study was performed in 10 healthy male volunteers with the PET radiotracer [11C]raclopride. The D2 receptor occupancy of striatum was measured pre-dose, and at 2, 5, and 10 h after YKP1358 administration. Serial blood samples were taken for measurement of plasma YKP1358 concentrations. D2 receptor occupancy by YKP1358 increased to 53–83% at 2 h, and then decreased afterwards, ranging from 40–64% at 5 h to 20–51% at 10 h. The YKP1358 dose-plasma concentration relationship exhibited extensive variability, but there was a good relationship between plasma concentrations and D2 receptor occupancy that was well predicted by a sigmoid Emax model using nonlinear mixed effects modeling. To our knowledge, this is the first study in which the relationship between plasma concentration and the biomarker of D2 receptor occupancy was modeled using nonlinear mixed effects modeling. It is anticipated that these results will be useful in estimating for subsequent studies the initial doses of YKP1358 required to achieve a therapeutically effective range of D2 receptor occupancy. Clinical Pharmacology & Therapeutics (2007) 81, 252–258. doi:10.1038/sj.clpt.6100049

Soo-Yun Lee,1 Wooseong Huh,2 Jin Ah Jung,3 Hye Min Yoo,2 Jae-Wook Ko,1,2 Jung-Ryul Kim2,4 1Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, 2Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center,Seoul, 3Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Busan, 4Department of Clinical Research and Evaluation, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea Abstract: Valproic acid (VPA) is mainly metabolized via glucuronide, which is hydrolyzed by β-glucuronidase and undergoes enterohepatic circulation. Amoxicillin/clavulanic acid (AMC) administration leads to decreased levels of β-glucuronidase-producing bacteria, suggesting that these antibiotics could interrupt enterohepatic circulation and thereby alter the pharmacokinetics of VPA. This study aimed to evaluate the effects of AMC on the pharmacokinetics of VPA. This was an open-label, two-treatment, one-sequence study in 16 healthy volunteers. Two treatments were evaluated; treatment VPA, in which a single dose of VPA 500mg was administered, and treatment AMC + VPA, in which multiple doses of AMC 500/125mg were administered three times daily for 7days and then a single dose of VPA was administered. Blood samples were collected up to 48hours. Pharmacokinetic parameters were calculated using noncompartmental methods. Fifteen subjects completed the study. Systemic exposures and peak concentrations of VPA were slightly lower with treatment AMC + VPA than with treatment VPA (AUClast, 851.0h·mg/L vs 889.6h·mg/L; Cmax, 52.1mg/L vs 53.0mg/L). There were no significant between-treatment effects on pharmacokinetics (95% confidence interval [CI]) of AUClast and Cmax (95.7 [85.9–106.5] and 98.3 [91.6–105.6], respectively). Multiple doses of AMC had no significant effects on the pharmacokinetics of VPA; thus, no dose adjustment is necessary. Keywords: drug–drug interaction, pharmacokinetics, enterohepatic circulation

Deleted in breast cancer 1 (DBC1/CCAR2) is a protein of interest because of its diverse roles in tumorigenesis and its possible role as an androgen receptor (AR) co-activator. However, there are limited studies on the role of DBC1 in osteosarcoma. Therefore, we investigated the role of DBC1 and AR and their relationship in osteosarcoma. Immunohistochemical expression of DBC1 and AR was significantly associated with higher clinical stage and higher histologic grade and predicted shorter survival. Especially, DBC1 expression was an independent prognostic indicator of overall survival (p = 0.005) and relapse-free survival (p = 0.004) by multivariate analysis. In osteosarcoma cell lines, U2OS and SaOS2, the knock down of DBC1 and AR with siRNA significantly reduced cellular proliferation and inhibited proliferation-related signaling. In addition, the knock down of DBC1 and AR decreased the invasion activity and inhibited invasion-related signaling of osteosarcoma cells. Interestingly, DBC1 affects the stabilization of AR protein via a mechanism involving the ubiquitination of AR. Proteosome-mediated degradation and poly-ubiquitination of AR were increased with the knock-down of DBC1. In conclusion, this study has shown that DBC1 is involved in the stabilization of AR protein and DBC1-AR pathways might be involved in the progression of osteosarcoma.

Aims: To compare the pharmacokinetics, pharmacodynamics, and safety of sarpogrelate between controlled-release (CR) and immediate-release (IR) formulations after multiple-dose administration. Methods: This study was a randomized, open-label, 2-period, 2-treatment, crossover study in healthy subjects. All subjects received CR sarpogrelate 300 mg once daily and IR sarpogrelate 100 mg three times daily by random order each for 3 days with a 7-day washout period. Serial blood sampling was performed over 24 h. Pharmacokinetic parameters were determined by noncompartmental methods. Platelet aggregation to collagen, measured by light transmission aggregometry, was reported as maximal platelet aggregation. Results: Thirty-two subjects completed the study. CR sarpogrelate increased rapidly, reaching Cmax in 1.25 h (vs. 1.00 h in IR sarpogrelate) and declined with a t1/2 of 3.59 h (vs. 1.12 h in IR sarpogrelate). The 90% CIs for the geometric mean ratio of AUCτ and Cmax,ss between IR and CR formulations were 1.18 to 1.40 and 0.99 to 1.29, respectively. The degree of inhibition of platelet aggregation was similar between two formulations. Conclusions: CR sarpogrelate showed slightly higher systemic exposure and similar peak concentration compared with IR sarpogrelate. The profiles of pharmacodynamics and safety were comparable between two formulations.

There are many modalities of treatment for complex lower extremity deformity in hypophosphatemic rickets. We evaluated the outcomes of deformity correction using an external fixation and/or intramedullary nailing in hypophosphatemic rickets.55 segmental deformities (20 femora, 35 tibiae) from 20 patients were examined retrospectively. There were 9 children and 11 adults. Distraction osteogenesis was used in 28 segments and acute deformity correction in 27. External fixation was applied in 24 segments, intramedullary nailing in 6, and external fixation and intramedullary nailing in 25.There were 18 major and 13 minor complications in 26 of 28 segments with distraction osteogenesis, and 13 major and 10 minor complications in 19 of 27 segments with acute correction. Recurrent deformity or refracture occurred in 10 of 21 segments with distraction osteogenesis by external fixation only, 4 of 6 with acute correction by intramedullary nailing, and 1 of 25 with distraction osteogenesis or acute correction by external fixation and intramedullary nailing. Nail-related complications occurred in 3 of 6 with intramedullary nailing and 2 of 25 with external fixation and intramedullary nailing.External fixation and intramedullary nailing can be recommended to prevent complications during or after deformity correction in hypophosphatemic rickets.

A bone island represents a focus of mature compact bone within the cancellous bone, and it can be diagnosed based on characteristic clinical and radiologic features. The lesion is typically asymptomatic with a preference for the pelvis, femur, and other long bones. On radiographs, the lesion appears as an ovoid, round or oblong homogeneously dense and sclerotic focus in the cancellous bone. The characteristic features of this lesion are radiating bony streaks, known as thorny radiations or pseudopodia. Most bone islands are small, and the majority of these lesions measure from 0.1 to 2.0 cm. A giant bone island, defined as having a diameter greater than 2 cm, has been rarely reported in the English-language literature. We report here on a case of a giant bone island that measured 10 x 1.7 x 1 cm in the diaphysis of the right tibia in a 31-year-old man who complained of right lower leg pain for 3 weeks.

Imatinib mesylate is effective for chronic myeloid leukaemia and gastrointestinal tumours. We aimed to evaluate the pharmacokinetics of a 200-mg imatinib tablet compared to 2×100-mg imatinib tablets in order to meet the regulatory requirements for marketing in Korea. An open-label, randomized, single-dose, 2-period, 2-treatment cross-over study was conducted in 28 healthy Korean male volunteers. Subjects were administered a 200-mg imatinib tablet and 2×100-mg imatinib tablets under a fasting state according to a randomly assigned order with a 2-week wash-out period. Serial blood samples were collected up to 72 h post-dose. The pharmacokinetic parameters were calculated using non-compartmental methods. A total of 28 subjects were enrolled and 23 subjects completed the study. There were no serious adverse events during the study. 23 mild to moderate adverse events were reported (11 events with 200-mg imatinib vs. 12 events with 2×100-mg imatinib) and subjects recovered without sequelae. The Cmax value was 922.8±318.8 μg/L at 3.15 h for 200-mg imatinib tablet, and 986.3±266.0 μg/L at 2.91 h for the 2×100-mg imatinib tablet. The AUClast of 200-mg and 2×100-mg tablets were 13 084.3±39.1 and 14 131.7±3 826.2 h · μg/L, respectively. The geometric mean ratios (90% confidence intervals) for Cmax and AUClast were 0.9121 (0.8188, 1.0161) and 0.9558 (0.8685, 1.0519), respectively. A newly developed 200-mg imatinib tablet was bioequivalent to 2×100-mg imatinib tablets in healthy Korean subjects. A single-dose of either of the 2 formulations was generally well tolerated.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract. DA-6034 has been shown to be effective in an IBD model and has demonstrated a good toxicological profile in preclinical studies. This study evaluated the tolerability, safety and pharmacokinetics of DA-6034 in healthy volunteers.A double-blind, randomized, placebo-controlled, ascending-dose study was conducted in 67 healthy volunteers. In the single-ascending-dose study, 10, 20, 50, 100 or 200 mg of DA-6034 was administered orally to 40 subjects; in the multiple-ascending-dose study, 40, 100 or 200 mg/day of DA-6034 was administered orally to 27 subjects for 7 days. Serial blood and urine samples were taken for pharmacokinetic analysis. Plasma drug concentrations were determined by high-performance liquid chromatography. Safety and tolerability were assessed throughout the study.DA-6034 had minimal absorption, and the pharmacokinetic parameters were highly variable among subjects. For both the single- and multiple-dose administrations, the coefficients of variation of the area under the plasma concentration-time curve to the last observation (AUClast) and the area under the plasma concentration-time curve over the dosing interval at steady state (AUCss,τ) ranged from 16.0 to 125.0 %. At doses of up to 200 mg of DA-6034, the mean maximum plasma concentration (C max) was3 ng/mL, and the urine recovery ratio was 0.3 % of the dose, indicating a lack of absorption. Twenty-two mild adverse events were reported in 14 subjects. There were no serious adverse events and no significant changes in the safety assessment.DA-6034 was well tolerated and minimally absorbed in healthy volunteers. The non-systemic, local exposure of the gastrointestinal tract to DA-6034 may be advantageous for IBD treatment.

Recently, the possibility of PD1 pathway-targeted therapy has been extensively studied in various human malignant tumors. However, no previous study has investigated their potential application for soft-tissue sarcomas (STS). In this study, we evaluated the clinical impact of intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression in tumor cells in 105 cases of STS. Intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression were seen in 65% and 58% of STS, respectively. Both PD1-positivity and PD-L1 expression were significantly associated with advanced clinicopathological parameters such as higher clinical stage, presence of distant metastasis, higher histological grade, poor differentiation of tumor, and tumor necrosis. Moreover, both PD1-positivity and PD-L1 positivity were independent prognostic indicators of overall survival (OS) and event-free survival (EFS) of STS by multivariate analysis. In addition, the combined pattern of PD1- and PD-L1-positivity was also an independent prognostic indicator for OS and EFS by multivariate analysis. The patents with a PD1(+)/PD-L1(+) pattern had the shortest survival time. In conclusion, this study is the first to demonstrate that the infiltration of PD1 positive lymphocytes and PD-L1 expression in STS cells could be used as novel prognostic indicators for STS. Moreover, the evaluation of PD1- and PD-L1-positivity in STS is also available as possible criteria for selection of patients suitable for PD1-based immunotherapy.

The purpose of this study is to evaluate the hemodynamic interactions between udenafil and tamsulosin.After a placebo lead-in period, 27 healthy volunteers received 200 mg udenafil + tamsulosin placebo, udenafil placebo +0.4 mg tamsulosin, or 200 mg udenafil +0.4 mg tamsulosin. Blood pressure and pulse rate (PR) were measured at 15 time points from 0 to 24 hours.A single dose of udenafil, when administered with multiple tamsulosin doses, produced statistically significant increases in PR (mean: 10.7; 95% confidence interval: 5.3, 16.2 bpm; p0.001) compared with tamsulosin administered with an udenafil placebo. Systolic and diastolic blood pressure measurements remained unchanged. Two subjects who took udenafil with tamsulosin had a decrease in standing systolic blood pressure (SBP) greater than 30 mmHg in comparison to their baseline SBP; however, compared with the frequency of a decrease in standing SBP greater than 30 mmHg in comparison to the baseline, there was no significant difference in frequency among the four treatments (p = 0.243). There was no difference in the Cmax, AUClast, or AUCinf of udenafil and its active metabolite DA-8164 between the administration of udenafil and udenafil with tamsulosin.The coadministration of udenafil and tamsulosin was not associated with clinically significant hemodynamic changes in healthy volunteers. Although this study was conducted on a small number of healthy young subjects, the use of udenafil for the treatment of erectile dysfunction in patients taking tamsulosin for the treatment of benign prostatic hyperplasia is not expected to cause significant safety problems.

In the treatment of diabetes mellitus, combined drugs with different mechanisms of action can be effective when adequate glycaemic control is difficult with monotherapy. A fixed-dose combination (FDC) tablet of mitiglinide and metformin has been developed as a second-line treatment for type 2 diabetes. The objective of this study was to compare the pharmacokinetics and safety of a FDC and a free combination of mitiglinide and metformin in healthy male subjects. A randomized, open-label, two-period, two-treatment, single-dose, crossover study was conducted in 24 healthy Korean male subjects. In one period, a FDC tablet of mitiglinide and metformin (10 mg/500 mg) was administered, and in the other period, corresponding doses of individual formulations were administered. Twenty-four subjects were enrolled and 19 subjects completed the study. The geometric mean ratios (90 % confidence interval) of the maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from time zero to the time of the last measurable concentration (AUClast) were 0.9694 (0.8120, 1.1573) and 0.8951 (0.8440, 0.9494) for mitiglinide, and 1.0235 (0.9373, 1.1057) and 1.0542 (0.9697, 1.1460) for metformin, which were within the bioequivalence range. Among the 23 subjects who received study drugs, 15 subjects experienced 34 adverse events (AEs). The most frequently reported AEs were feeling hot and compensatory sweating. There were no serious AEs and no significant differences in the incidence of AEs between the two treatments. A FDC tablet of mitiglinide and metformin was generally well tolerated in healthy male subjects. Administration of a FDC tablet and concomitant administration of individual formulations did not show significantly different pharmacokinetic profiles.

Clopidogrel selectively inhibits platelet aggregation. Clopidogrel bisulfate (Plavix(®)) was first developed for atherothrombosis prevention and is commonly prescribed for this indication. A new clopidogrel formulation, clopidogrel besylate (KOVIX(®)), has recently been developed.This study was designed to compare the multiple-dose pharmacokinetics/pharmacodynamics and tolerability of clopidogrel besylate with those of clopidogrel bisulfate in 40 healthy male subjects.This was an open-label, randomized-sequence, multiple-dose, two-period, two-treatment crossover study. The subjects were randomly assigned to a sequence group that received two treatments: clopidogrel besylate 75 mg followed by clopidogrel bisulfate 75 mg, or vice versa. The subjects received a 300-mg loading dose on day 1 followed by 75 mg daily for the next 4 days. Serial blood samples were collected to determine the concentrations of clopidogrel and its carboxylic acid metabolite, SR26334. Platelet aggregation and bleeding times were measured. Tolerability was evaluated throughout the study.The clopidogrel plasma concentration-time profiles of the formulations were similar. The measured pharmacokinetic parameters did not differ significantly between the clopidogrel besylate and clopidogrel bisulfate groups. The geometric mean ratios of the clopidogrel besylate group to the clopidogrel bisulfate group with respect to the maximum plasma concentration (C(max)) and the area under the concentration-time curve (AUC) from time zero to the time of last measurable concentration (AUC(last)) were 0.96 (90 % confidence interval [CI] 0.82, 1.12) and 0.95 (0.81, 1.11), respectively. Moreover, the pharmacokinetic parameters of SR26334 did not differ significantly between the two treatment groups. Furthermore, the areas under the platelet aggregation inhibition-time curves (AUIC) and the maximum inhibitory effects (I(max)) did not differ significantly between the two groups. The geometric mean ratios (clopidogrel besylate to clopidogrel bisulfate) were 1.01 (90 % CI 0.95, 1.08) for the I(max) and 0.98 (0.89, 1.07) for the AUIC. Both formulations were well tolerated and exhibited comparable safety profiles.This study demonstrated that the pharmacokinetic/pharmacodynamic profiles of clopidogrel besylate were not significantly different from those of clopidogrel bisulfate. Both formulations were well tolerated in healthy subjects.

OBJECTIVE: LB80380, a dipivoxil ester prodrug of LB80331, is a novel antiviral agent for the treatment of chronic hepatitis B. The aim of this study was to compare the pharmacokinetic differences after single oral administrations of the free base and maleate formulations of LB80380 in healthy male subjects. METHODS: An open-label, single- dose, randomized-sequence, 2-treatment crossover study was conducted in 32 Korean male volunteers. Subjects received either a combination of 60 and 90 mg tablets of the free base LB80380 formulation or a 183 mg (150 mg as a free base) tablet of the maleate LB80380 formulation. Then, after a 14- day washout period, each subject received the other formulation. Plasma and urine concentrations of LB80331 and LB80317 (active metabolites of LB80380) were measured by validated liquid chromatographytandem mass spectrometry assays. A safety assessment, which included vital signs, adverse events, electrocardiograms and clinical laboratory tests, was performed for each subject. RESULTS: A total of 32 healthy subjects was enrolled, and 26 subjects completed the study. Single oral administrations of LB80380 maleate tablets did not result in clinically significant differences in the safety profile compared to the LB80380 free base tablets. The 90% confidence intervals (CIs) for the geometric mean ratios of Cmax and AUClast for LB80331 of the two treatments (maleate versus free base formulation) were 0.986 - 1.1240 and 0.9848 - 1.0533, respectively. The 90% CIs for the geometric mean ratios of Cmax and AUClast for LB80317 were 0.8379 - 0.9696 and 0.7224 - 0.9196. CONCLUSIONS: In healthy male subjects, the 183 mg LB80380 maleate tablet was pharmacokinetically equivalent to the 60 and 90 mg LB80380 free base tablets.