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Prolongation of the QT interval on an ECG is a surrogate marker for predicting the proarrhythmic potential of a drug under development. The aim of this study was to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine immediate release (IR) and escitalopram, in healthy individuals. This was a randomized, open-label, 4×4 Williams crossover study, with four single-dose treatments [placebo, 400 mg moxifloxacin (positive control), 20 mg escitalopram, and 100 mg quetiapine IR], conducted in 40 healthy volunteers. Serial blood samples for pharmacokinetics and ECG were collected. Individually, RR-corrected QTc intervals (QTcI) and placebo-adjusted changes from baseline values of QTcI (ΔΔQTcI) were evaluated. Lower-bound values of the one-sided 95% confidence interval for ΔΔQTcI of moxifloxacin with more than 5 ms confirmed the sensitivity of the assay. The maximum upper bound 95% confidence interval for the ΔΔQTcI of quetiapine IR and escitalopram was 13.7 and 10.5 ms, with mean estimates of 10.2 and 6.9 ms, respectively. Peak effects of moxifloxacin and quetiapine IR on ΔΔQTcI were observed at approximately time to maximum concentration (Tmax), whereas that of escitalopram was observed 3 h after Tmax. The concentration-ΔΔQTcI relationships of quetiapine IR and escitalopram were relatively flat, as compared with that of moxifloxacin. The results demonstrated the validity of trial methodology and that quetiapine IR and escitalopram caused QT prolongation in healthy individuals. In addition, hysteresis of escitalopram-induced QTc prolongation. These results indicate that higher doses of these drugs could lead to greater QT prolongation in a dose-response manner.

Few data are available on whether adjusting the dose of posaconazole syrup is effective in patients receiving anti-cancer chemotherapy. The aim of this prospective study was to analyse the impact of increasing the frequency of posaconazole administration on optimal plasma concentrations in adult patients with haematological malignancy. A total of 133 adult patients receiving chemotherapy for acute myeloid leukaemia or myelodysplastic syndrome who received posaconazole syrup 200 mg three times daily for fungal prophylaxis were enrolled in this study. Drug trough levels were measured by liquid chromatography-tandem mass spectrometry. In 20.2% of patients (23/114) the steady-state concentration of posaconazole was suboptimal (500 ng/mL) on Day 8. In these patients, the frequency of posaconazole administration was increased to 200 mg four times daily. On Day 15, the median posaconazole concentration was significantly increased from 368 ng/mL [interquartile range (IQR), 247-403 ng/mL] to 548 ng/mL (IQR, 424-887 ng/mL) (P = 0.0003). The median increase in posaconazole concentration was 251 ng/mL (IQR, 93-517 ng/mL). Among the patients with initially suboptimal levels, 79% achieved the optimal level unless the steady-state level was200 ng/mL. This study shows that increasing the administration frequency of posaconazole syrup is effective for achieving optimal levels in patients with haematological malignancy undergoing chemotherapy.

Lobeglitazone as a thiazolidinedione antihyperglycemic agent activates peroxisome proliferator-activated receptor (PPAR) γ and may be suitable as monotherapy or in combination with other antihyperglycemic agents. The primary objective of this study was to investigate potential pharmacokinetic interactions between lobeglitazone and metformin in healthy Korean subjects.A randomized, open-label, multiple-dose, three-treatment, three-period, three-sequence, crossover study was conducted in 24 healthy Korean male volunteers. Serial blood samples were collected after lobeglitazone (0.5 mg/day) and metformin (1000 mg/day) were administered alone or concomitantly for 5 days in each period, and drug concentrations were determined by liquid chromatography-tandem mass spectrometry. CLINICAL TRAIL REGISTRATION NUMBER: NCT01005160.The steady-state maximum plasma concentrations (C(max, ss); mean ± standard deviation) of lobeglitazone and metformin alone were 29.38 ± 5.25 ng/mL and 1661.84 ± 471.88 ng/mL, respectively; the C(max, ss) during co-administration were 27.15 ± 5.75 ng/mL and 1779.92 ± 405.20 ng/mL, respectively. The steady-state areas under the concentration-time curves during the dose interval (AUC(τ, ss); mean ± standard deviation) of sole administration of lobeglitazone and metformin were 277.53 ± 65.25 ng*h/mL and 9650.27 ± 2089.81 ng*h/mL, respectively. When lobeglitazone and metformin were administered concomitantly, the AUC(τ, ss) were 257.29 ± 60.61 ng*h/mL and 10600.58 ± 1960.40 ng*h/mL, respectively. The geometric mean ratios (90% confidence interval) of co-medication to lobeglitazone alone were 0.92 (0.87-0.97; C(max, ss)) and 0.93 (0.87-0.99; AUC(τ, ss)), and those for co-medication to metformin monotherapy were 1.09 (0.99-1.19; C(max, ss)) and 1.11 (1.04-1.19; AUC(τ, ss)). Both monotherapies and combination therapy were well tolerated; 52 self-resolving, non-serious adverse events were reported from 17 subjects.Lobeglitazone did not significantly affect the pharmacokinetics of metformin or vice versa when both drugs were co-administered. Lobeglitazone can be co-administered with metformin without dose adjustment for either agent. Therefore further patient studies are needed to corroborate these results.

Fimasartan is an angiotensin II receptor antagonist used to treat hypertension.The aim of this study was to evaluate the effects of fimasartan on the pharmacodynamics and pharmacokinetics of warfarin in healthy volunteers to meet regulatory requirements for drug marketing and labeling in Korea.An open-label, 1-sequence, 2-treatment, 2-period crossover study was conducted in healthy male volunteers. The subjects were administered a single-dose of warfarin 25 mg on day 1. After a 7-day washout period, once-daily fimasartan 240 mg was administered every morning from day 8 to day 16. On day 11, warfarin 25 mg was administered concomitantly with fimasartan. Serial blood samples were collected for 144 hours after each warfarin dose. The plasma concentrations of R- and S-warfarin were analyzed by using HPLC-MS/MS, and the pharmacokinetic parameters were estimated by using noncompartmental analysis. The maximal international normalized ratio (INR) and the AUC-INR curve were evaluated to assess warfarin pharmacodynamics. Tolerability was assessed via vital sign measurements, physical examinations, ECGs, clinical laboratory tests, and adverse events.A total of 15 healthy Korean men aged 20 to 39 years (mean [SD], 26.7 [5.1] years) and weighing 60.2 to 85.7 kg (mean, 71.4 [8.3] kg) participated in the study; 12 completed the study. The geometric mean ratios (GMRs [90% CIs]) of C(max) and AUC(0-last) for R-warfarin were 1.06 (0.97-1.16) and 1.07 (1.03-1.12), respectively. For S-warfarin, the GMRs (90% CIs) of C(max) and AUC(0-last) were 1.02 (0.94-1.11) and 0.99 (0.94-1.04). The INR values reached 1.93 (0.31) and 1.96 (0.37) at 36 hours and decreased to1.2 at 144 hours after warfarin treatment alone and coadministered with fimasartan, respectively. The GMRs (90% CIs) of the maximal INR and AUC-INR curve were 1.01 (0.97-1.05) and 0.98 (0.96-1.01). One (7.7%) of the 13 subjects reported epistaxis during treatment with warfarin alone, and 2 (16.7%) of 12 subjects receiving the combination treatment experienced headache, skin erosion, and an increase in blood creatine phosphokinase. No subjects had an elevated INR4 or reported any symptoms related to hypotension, including fainting or dizziness.Multiple doses of fimasartan did not seem to alter the pharmacodynamics or pharmacokinetics of warfarin in this small, select population of healthy male volunteers.

A simple, rapid and sensitive LC–MS/MS method in positive ion mode was developed and validated to determine CKD-501, lobeglitazone, in human plasma and urine using glipizide as an internal standard (IS). Lobeglitazone is a novel thiazolidinedione (TZDs)-based peroxisome proliferator-activated receptor (PPAR) agonist, used for the management of type-2 diabetes. After mixing the IS, dissolved in acetonitrile, with a plasma or urine sample containing lobeglitazone, 10 μL of supernatant was injected into the LC–MS/MS system. Quantification was performed in the multiple reaction monitoring (MRM) mode using transition of 481.5 → 152.2 (m/z) for lobeglitazone and 446.1 → 321.2 (m/z) for the IS. The method showed good linearity over concentration ranges of 0.5–1,000 ng mL−1 for plasma and 0.2–250 ng mL−1 for urine (r 2 ≥ 0.9996). The mean percent extraction recovery of lobeglitazone was 90.8 % for plasma and 87.3 % for urine, while the recoveries of the IS were greater than 86.4 % for both. The intra-day and inter-day precision of plasma ranged from 1.1 to 3.7 and 2.5 to 3.3 % (RSD), respectively, and the intra- and inter-day precision of urine ranged from 1.5 to 2.7 and 3.2 to 3.5 %, respectively. This method is simple, sensitive, and applicable for the pharmacokinetic study of lobeglitazone in human plasma. Most of the urine concentrations of lobeglitazone were below the LLOQ because the lobeglitazone is extensively metabolized.

OBJECTIVE This study explored microdosing methods for evaluating the distribution and pharmacokinetics (PK) of a central nervous system (CNS) drug candidate. METHODS We used sertraline as a model drug. In this open-label, one-arm, three-period, multiple-dosing study, 10 healthy male volunteers received 6-day administrations of sertraline at doses of 5, 25 or 50 mg/d in three different periods. Before the first dose of Period 1, and 24 h after the last dose of each period, an intravenous bolus of [11C]sertraline was injected for positron emission tomography (PET) scanning. After the sixth dose in each period, serial blood samples were collected at scheduled intervals over 48 h; then serum sertraline concentrations were determined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS Sertraline was distributed in the brain within 20 min, and it was highly distributed in the putamen, cingulate, and thalamus. Linearity in steady-state Cmax and AUClast were observed in the 5 - 50 mg dose range. The results suggested that microdosing with PET was a useful method for exploring the bloodbrain- barrier penetration and distribution of a candidate CNS drug. CONCLUSIONS This study described a microdosing method that combined PET with LC-MS/MS for determining the brain distribution and PK characteristics of a CNS drug candidate.

HM30181 is an oral P-glycoprotein (P-gp) inhibitor developed to enhance the oral bioavailability of P-gp substrate drugs.The objective of this study was to investigate the tolerability and pharmacokinetic properties of HM30181 after single and multiple oral administrations to healthy Korean male volunteers. The study was performed to meet regulatory criteria for marketing the test product in South Korea.A dose-block-randomized, double-blind, placebo-controlled, dose-escalation study was performed in 180-, 360-, 600-, and 900-mg single-dose groups and 60-, 180-, and 360-mg multiple-dose groups with 10 subjects (8 active; 2 placebo) per group. In the single-dose study, blood and urine samples were collected for up to 120 hours after drug administration. In the multiple-dose study, subjects received the study drug or placebo orally once daily for 5 days. Blood samples were collected up to 624 hours after the last dose, and up to 24 hours after the first dose to evaluate the accumulation index. Urine samples were collected up to 120 hours after the last dose. Pharmacokinetic analysis was performed using noncompartmental methods. Adverse events were collected by the spontaneous reporting of the subjects or when subjects were asked general health-related questions.Thirty and 70 healthy male volunteers completed the single- and multiple-dose studies, respectively. Mean (SD) age and body weight of subjects in the single administration group were 24.0 (1.8) years and 68.8 (7.4) kg, respectively, and those of the multiple administration group were 24.5 (2.6) years and 67.6 (7.7) kg, respectively. The plasma concentrations peaked at 14 to 42 hours and declined with t(½) of 75.7 to 169.3 hours after single administration, and peaked at 5.5 to 8.0 hours and declined with t(½) of 153.5 to 215.2 hours after multiple administrations. C(max) and area under the concentration curve within dosing intervals (AUC(τ)) increased dose dependently after single administration; however, dose-dependent increases in C(max) and AUC(τ) were not observed after multiple administrations. The fraction of drug excreted unchanged in urine was minimal, with values0.01% in all dose groups. HM30181 accumulated after multiple administrations with an accumulation index of 4.0 to 7.4. All adverse events reported were mild in intensity; there were no serious adverse events reported. The most frequently reported adverse event was gastrointestinal disorder.HM30181 was well tolerated after oral administration within the dose range evaluated, with the exception of the repeated administration of 360 mg, for which gastrointestinal disorders were frequently reported. The systemic exposure of HM30181 was relatively low, and dose proportional properties of HM30181 were not observed.

Fimasartan is a selective angiotensin II receptor blocker. Hydrochlorothiazide (HCTZ), which is used to treat hypertension and edematous conditions, is coadministered with many antihypertensive agents.An open-label, randomized, multiple-dosing, 2-arm, 1-sequence, 2-period study was conducted to assess the effects of fimasartan (240 mg) on HCTZ (25 mg) or vice versa in 18 and 14 healthy male volunteers, respectively. During each drug administration period, drugs were given once daily for 7 days, with a 7-day washout period between the 2 administration periods.The respective geometric mean ratios of fimasartan for AUC τ,ss and C max,ss with HCTZ were 1.30 [90% confidence interval (CI), 0.84-2.01] and 1.17 (90% CI, 0.93-1.47) compared with fimasartan alone. The respective geometric mean ratios of HCTZ for AUC τ,ss and C max,ss with fimasartan were 0.94 (90% CI, 0.84-1.04) and 0.88 (90% CI, 0.80-0.97) compared with HCTZ alone. Plasma renin activity indicated no significant differences between fimasartan monotherapy and coadministered treatment.Fimasartan administered alone or in combination with HCTZ was well tolerated at the described dosages. Coadministration of fimasartan increased the urinary excretion of HCTZ and urine volume, but these observations are unlikely to have any clinical relevance.

The rapid achievement of effective levels of antiepileptic drugs (AEDs) is required in patients with epilepsy who have a higher risk of seizures, and oral loading of AEDs may be an important consideration in these patients. We performed the present study to investigate the efficacy and tolerability of oral loading of oxcarbazepine in patients with recurrent seizures, or after temporary discontinuation of AEDs for diagnostic or presurgical evaluation of epilepsy. Forty adult patients were studied and oxcarbazepine was administered orally at a single loading dosage of 30 mg/kg. The plasma levels of oxcarbazepine and its active metabolite, 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD), were measured, and clinical assessment of adverse events was performed at 2, 4, 6, 8, 10, 12, 16, and 24 h after oral loading of oxcarbazepine. Approximately two-thirds of patients reached effective levels of MHD 2 h after receiving the oral loading, and all patients reached effective levels 4 h after oxcarbazepine administration. Most patients maintained therapeutic MHD levels for at least 16 h. Almost half of the patients experienced adverse events, but all were mild to moderate in severity and resolved spontaneously within 24 h. Our study shows that oral loading of oxcarbazepine is an effective and well-tolerated method for rapidly achieving therapeutic levels of MHD in patients with epilepsy, and is a useful option in selected patients with recurrent seizures, or after temporary discontinuation of AEDs.

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.

Background The combination of glimepiride and metformin is used for glycemic control in patients with diabetes mellitus. A fixed-dose combination of glimepiride/metformin 2/500 mg slow-release (SR) formulation was developed to improve compliance in polymedicated patients. To accommodate the various dosing regimens of glimepiride, a glimepiride/metformin 1/500 mg SR tablet was also developed. Objective The goal of this study was to compare the pharmacokinetic properties of SR fixed-dose combinations of glimepiride/metformin 2/500 mg and the newly developed glimepiride/metformin 1/500 mg formulation to meet the regulatory requirements for marketing in Korea. Methods An open-label, randomized, 2-treatment, 2-period, 2-sequence crossover study was conducted with healthy male volunteers. Eligible subjects were randomly assigned to receive a single dose of glimepiride/metformin 1/500 mg SR (test) or glimepiride/metformin 2/500 mg SR (reference) followed by a 1-week washout period and then administration of the alternate treatment. Serial blood samples were collected immediately before and after dosing for 30 hours, and plasma concentrations were determined by using LC-MS/MS with validated methods. Adverse events were assessed by subjects' self-report and interviews addressing general health-related issues. Safety profiles were evaluated throughout the study. Results Thirty-three subjects were enrolled (mean [SD] age: 27.9 [4.95] years [range, 21–40 years]). Safety profiles were assessed for all 32 subjects who were administered the study drugs, and pharmacokinetic characteristics were evaluated in the 30 subjects who completed the study. The geometric mean ratios (90% CIs) of test to reference for the dose-normalized C max and AUC 0–last of glimepiride were 0.98 (0.90–1.07) and 1.06 (0.98–1.14), respectively. In the case of metformin, the geometric mean ratios (90% CIs) of test to reference for C max and AUC 0–last were 1.06 (0.98–1.15) and 1.04 (0.97–1.12), respectively. Nine adverse events were reported. Among them, loose stool, abdominal pain, and headache were considered to be likely related to the study drug. All reported adverse events were mild in intensity. Conclusions Dose-proportional characteristics of glimepiride and comparable pharmacokinetic properties of metformin were observed between the SR fixed-dose combinations of glimepiride/metformin 1/500 mg and 2/500 mg. A single dose of either treatment was well tolerated, and the safety profiles of the 2 treatments were comparable in this small, selected all-male group of healthy Korean volunteers. ClinicalTrials.gov identifier: NCT00934323.

A simultaneous simple, rapid, and sensitive LC–MS–MS method was developed and validated for the determination of HM30181A, [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl]-4,5-dimethoxy-phenyl]amide, as a P-glycoprotein inhibitor and its two metabolites, M1 and M2, in human plasma using docetaxel as an internal standard (IS). The analytes were extracted from 200 μL of biological sample by liquid–liquid extraction using 1 mL of methyl-t-butyl ether. Chromatographic separation was carried on a Luna C8 column at 30 °C with mobile phase consisting of distilled water with 0.1% formic acid and acetonitrile (75:25, v/v) at a flow rate of 0.7 mL min−1 for human plasma samples. The method was linear over concentration ranges of 0.5–50, 0.1–10, and 0.1–10 ng mL−1 for HM30181A, M1, and M2, respectively, in human plasma. The values of coefficient variation for the assay precision were

Background Bicalutamide is an oral nonsteroidal antiandrogenic drug used in the treatment of prostate cancer. A new generic 50-mg tablet formulation of bicalutamide has recently been developed. Objective This study evaluated the relative bioavailability and tolerability of the new generic formulation of bicalutamide 50-mg tablets (test) and the currently marketed formulation (reference) in healthy Korean male subjects. The study was conducted to meet Korean regulatory requirements for authorization to market the generic formulation. Methods This was a randomized-sequence, open-label study in which healthy Korean male subjects (aged 20–55 years) received single doses of the test and reference formulations in a 2-period crossover fashion, with a 6-week washout period between doses. Blood samples for the determination of plasma bicalutamide concentrations were obtained at regular intervals over 672 hours after dose administration. Pharmacokinetic parameters were determined using noncompartmental methods. Relative bioavailability was evaluated by comparing the log-transformed C max and AUC 0–672 of the 2 formulations; Korean regulatory requirements for the assumption of bioequivalence were met if the 90% CIs fell within the range of 0.80 to 1.25. Tolerability was assessed based on physical examinations, vital signs, clinical laboratory tests, electrocardiograms (ECGs), and adverse events (AEs) (spontaneously reported or observed by investigators). Results Of 47 volunteers screened for inclusion, 38 were enrolled and 32 completed the study (mean [SD] age, 24.9 [3.7] years; mean height, 173.8 [6.2] cm; mean weight, 66.1 [7.1] kg). Median T max was 24 hours for both formulations. The C max of the test and reference formulations was 1176.2 (191.6) and 1118.9 (209.5) μg/L, respectively. The corresponding values for AUC 0–672 were 277,503 (66,865) and 271,961 (75,597) μg · h/L. The 90% CIs for the geometric mean ratios of log-transformed C max and AUC 0–672 were 1.00 to 1.11 and 0.99 to 1.07, respectively. Thirty-three AEs were reported, including 17 events in 9 subjects who received the test formulation and 16 events in 12 subjects who received the reference formulation. All AEs were mild, and no subjects discontinued the study because of AEs. Conclusions In this single-dose study in healthy Korean male subjects, the pharmacokinetic parameters of the new generic formulation of bicalutamide 50-mg tablets did not differ significantly from those of the reference formulation. The new generic formulation met Korean regulatory criteria for the assumption of bioequivalence to the currently marketed formulation. Both formulations were well tolerated. Korea Food and Drug Administration registration number: PSPD 3057.

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.

Background The aim of this study was to explore the pharmacokinetic-pharmacodynamic (PK-PD) relationship of metformin on glucose levels after the administration of 250 mg and 1000 mg of metformin in healthy volunteers. Methods A total of 20 healthy male volunteers were randomized to receive two doses of either a low dose (375 mg followed by 250 mg) or a high dose (1000 mg followed by 1000 mg) of metformin at 12-h intervals. The pharmacodynamics of metformin was assessed using oral glucose tolerance tests before and after metformin administration. The PK parameters after the second dose were evaluated through noncompartmental analyses. Four single nucleotide polymorphisms in MATE1, MATE2-K, and OCT2 were genotyped, and their effects on PK characteristics were additionally evaluated. Results The plasma exposure of metformin increased as the metformin dose increased. The mean values for the area under the concentration-time curve from dosing to 12 hours post-dose (AUC0-12h) were 3160.4 and 8808.2 h·μg/L for the low- and high-dose groups, respectively. Non-linear relationships were found between the glucose-lowering effect and PK parameters with a significant inverse trend at high metformin exposure. The PK parameters were comparable among subjects with the genetic polymorphisms. Conclusions This study showed a non-linear PK-PD relationship on plasma glucose levels after the administration of metformin. The inverse relationship between systemic exposure and the glucose-lowering effect at a high exposure indicates a possible role for the intestines as an action site for metformin. Trial registration ClinicalTrials.gov NCT02712619.

Vitiligo is an acquired pigmentary disorder of the skin involving melanocyte dysfunction. It has been reported that melanocyte impairment could be related to increased oxidative stress. The glutathione S-transferases (GSTs) are group of polymorphic enzymes that are important in protection against oxidative stress. To find the relationship between GSTM1 and GSTT1 polymorphisms with vitiligo susceptibility, GSTM1 and GSTT1 (homozygous deletion vs. non-deleted) polymorphisms between vitiligo patients (n=310) and healthy controls (n=549) were analyzed. We observed significant association in null alleles of the GSTM1 (P

To investigate the possible association between polymorphisms [the -2510A/G promoter polymorphism (rs1024611) and the Cys35Cys coding polymorphism (rs4586) in exon 2] of the chemokine (C-C motif) ligand 2 (CCL2) gene and knee osteoarthritis (OA) in a Korean population.DNA was obtained from 153 Korean primary knee OA patients and 270 healthy controls. CCL2 genomic variants (-2510A/G and Cys35Cys polymorphisms) were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In additional, the effect of -2510A/G on CCL2 transcription was examined, using a luciferase reporter gene construct transfected into HMC-1 cells.The -2510A/G promoter polymorphism was associated with OA [genotype frequency, p = 0.041; allele frequency, p = 0.017, odds ratio (OR) = 1.45, 95% confidence interval (CI) = 1.07-1.96]. Significant association was observed between the G carrier of the -2510A/G promoter polymorphism and primary knee OA patients (p = 0.021, OR = 2.25, 95% CI = 1.12-4.52). The G carrier of the -2510A/G promoter polymorphism was also associated with both clinically subtyped OA patients (OA patients with functionally poor index and radiographically severe OA patients). However, no significant difference was found in the Cys35Cys polymorphism. Haplotype frequency analysis revealed a significant difference (chi(2) = 8.98, p = 0.030). The CCL2 serum level of subjects with the G carrier (290.0+/-87.5 pg/mL) of the -2510A/G promoter polymorphism was statistically higher than that of subjects with the non-G carrier (161.5+/-48.3 pg/mL). The luciferase activity was significantly greater from interleukin (IL)-1beta-induced cells transfected with constructs containing G at position -2510.The G carrier of the -2510A/G promoter polymorphism was found to be associated with primary knee OA, and could be a susceptibility factor in the development of primary knee OA in the Korean population.

Age-related physiological changes are known to alter the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs. Metformin is commonly used as first-line medication for management of diabetes in elderly patients. However, the PK and PD of metformin have not been sufficiently studied in elderly subjects. Here, 12 elderly subjects, aged 65 to 85 years, and 20 younger healthy volunteers were orally administered 750 mg of metformin 2 hours after dinner, followed by administration of a second dose (500 mg) 12 hours later. An oral glucose tolerance test (OGTT) was performed 2 hours after the second dose, with 75 g of glucose administered. Blood samples were collected at specific time points after the second metformin dose for the assessment of PK and the glucose-lowering effect of metformin. Elderly subjects exhibited 1.7 and 2.0 times higher average Cmax and AUC∞ than the younger subjects, respectively (P = .007 and .001, respectively), and t1/2 was comparable between the elderly and younger subjects. However, relative glucose level changes from baseline after metformin administration tended to be lower in elderly subjects. Systemic exposure to metformin was elevated by 50% or more in elderly subjects, whereas the glucose-lowering effect was similar compared to younger subjects after 2 doses of metformin.

Hyewon Chung,1,* Howard Lee,1,2,* HyeKyung Han,1 Hyungmi An,1 Kyoung Soo Lim,1,3 YongJin Lee,4 Joo-Youn Cho,1 Seo Hyun Yoon,1 In-Jin Jang,1 Kyung-Sang Yu1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 2Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea; 3Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and CHA Bundang Medical Center, Seongnam, Republic of Korea; 4Medical and Regulatory Affairs Team, Samyang Biopharmaceuticals Corporation, Seoul, Republic of Korea *These authors contributed equally tothis work Purpose: SYP-1018 is a lyophilized polymeric nanoparticle formulation of voriconazole that is under development for intravenous dosing. This study compared the pharmacokinetic and tolerability profiles of SYP-1018 with those of Vfend®, the marketed formulation of voriconazole. The effect of CYP2C19 polymorphism on the voriconazole pharmacokinetics was also evaluated. Methods: An open-label, two-treatment, two-period, two-sequence crossover study was conducted in 52 healthy male volunteers, who randomly received a single intravenous infusion of either of the two voriconazole formulations at 200 mg. Blood samples were collected up to 24 hours after drug administration for pharmacokinetic analysis. The plasma concentrations of voriconazole were determined using liquid chromatography with tandem mass spectrometry, and the pharmacokinetic parameters were estimated using a noncompartmental method. CYP2C19 genotype was identified in 51 subjects. Results: The geometric mean ratio (90% confidence interval) of SYP-1018 to Vfend® was 0.99 (0.93–1.04) for the maximum plasma concentrations (Cmax) and 0.97 (0.92–1.01) for the area under the concentration–time curve (AUC) from dosing to the last quantifiable concentration (AUClast). Nineteen homozygous extensive metabolizers (EMs, *1/*1), 19 intermediate metabolizers (IMs, *1/*2 or *1/*3), and ten poor metabolizers (PMs, *2/*2, *2/*3, or *3/*3) were identified, and the pharmacokinetic comparability between SYP-1018 and Vfend® was also noted when analyzed separately by genotype. The systemic exposure to voriconazole was greatest in the PM group, followed by the IM, and then the EM groups. Furthermore, the intrasubject variability for Cmax and AUClast was greater in IMs and PMs than in EMs. No serious adverse event occurred, and both treatments were well tolerated. Conclusion: SYP-1018 had comparable pharmacokinetic and tolerability profiles to Vfend® after a single intravenous infusion. CYP2C19 genotype affected not only the pharmacokinetics of voriconazole, but its intrasubject variability. SYP-1018 can be further developed as a clinically effective alternative to Vfend®. Keywords: voriconazole, pharmacokinetics, pharmacogenetics, CYP2C19

A bioequivalence study of Ranitidine HCI tablet (Sudo Pharma. Ind. Co., Ltd.) to tablet (Il Dong Pharma. Ind. Co., Ltd.) was conducted according to the guidelines of Korea Food and Drug Administration (KFDA). Twenty four healthy male Korean volunteers received each medicine at the ranitidine hydrochloride dose of 150 mg in a 2x2 crossover study. There was a one week wash-out period between the doses. Plasma concentrations of ranitidine were monitored by a high-turbulent liquid chromatography (HTLC) for over a period of 12 hours after drug administration. (the area under the plasma concentration-time curve from time zero to 12 hr) was calculated by the linear trapezoidal rule method. (maximum plasma drug concentration) and (time to reach ) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed and . No significant sequence effect was found far all of the bioavailability parameters indicating that the crossover design was properly performed. The 90% confidence intervals of the ratio and the ratio for Ranitidine were 0.92-1.00 and 0.90-1.03, respectively. These values were within the acceptable bioequivalence intervals of 0.80-1.25. Thus, our study demonstrated the bioequivalence of Ranitidine HCI and with respect to the rate and extent of absorption.

The use of topiramate (TPM) in the treatment of binge-eating disorder, bulimia nervosa, and antipsychotic-induced weight gain has recently increased, however, the exact molecular basis for its effects on body weight reduction and improved glucose homeostasis, is yet to be elucidated. Here we investigated the effect and signaling pathway of TPM on glucose uptake in L6 rat skeletal muscle cells, which account for70% of glucose disposal in the body. Intriguingly, we found that TPM (10 microM) stimulated the rate of glucose uptake up to twofold increase. And TPM-stimulated glucose transport was inhibited with the overexpression of dominant-negative form of AMP-activated protein kinase (AMPK), an important mediator in glucose transport, implicating that AMPK-mediated pathway is involved. The TPM-stimulated glucose transport was blocked by SB203580, a specific inhibitor of AMPK downstream mediator, p38 mitogen-activated protein kinase (MAPK) protein. LY294002, an inhibitor of phosphatidylinositol (PI) 3-kinase, which is another crucial mediator in independent glucose transport pathway, did not inhibit TPM-stimulated glucose transport. We also found that TPM increased the phosphorylation level of AMPK and p38 MAPK, whereas no effect on the activity of PI 3-kinase of TPM, when assessed by PI 3-kinase assay, was observed. These results together suggest that TPM stimulates glucose transport, not via PI 3-kinase mediated, but via AMPK-mediated pathway in skeletal muscle cells, thereby contributing to the body weight regulation and glucose homeostasis.

The interleukin 4 receptor (IL4R) polymorphism Q576R (rs 180275) has been well known to be associated with atopy and other inflammatory diseases. A single nucleotide polymorphism (SNP) A > G transition potentiates the binding specificity of the adjacent tyrosine residue. In this study we investigated the possible relationship between sudden deafness (SD) and IL4R polymorphism Q576R in 97 Korean SD patients and 613 controls using pyrosequencing method. The odds ratio (OR) for SD associated with the G vs. A allele was 2.58 [P < 0.0001, 95% confidence interval (CI) = 1.84-3.60]. We then sub-grouped SD into Tinnitus positive (+) and Tinnitus negative (-). G allele in Tinnitus (+) is significantly associated with the development of Tinnitus (+) [X(2) = 32.02, P < 0.0001, OR (95% CI) = 2.74 (1.91-3.93)] but not with Tinnitus (-). Taken together these results suggest that G allele could be a risk factor for SD.

Melatonin is reported to be an anti-inflammatory agent. No genetic study concerning the association between melatonin and inflammatory disease has yet been reported. Here we performed a polymorphism study on the melatonin receptor type 1B (MTNR1B) in Korean rheumatoid arthritis (RA) patients and controls. The polymorphism of MTNR1B located in 3¢- untranslated region (rs 1562444) was selected for its higher rate of heterozygosity among other single nucleotide polymorphisms (SNPs) in both MTNR1A and MTNR1B genes and investigated in RA patients (n ¼ 173) and healthy controls (n ¼ 195) by polymerase chain reaction-restriction fragment length polymorphism assay using NlaIII restriction enzyme. No statistically significant difference in either genotype distribution or allele frequency was observed between RA patients and controls. The genotype distributions and allele frequencies of rheumatoid factor negative (RF())) patients were similar to those of controls. However, statistical analysis of genotype revealed a significant association (v 2 ¼ 6.42, P ¼ 0.04) is present between RF(+) and MTNR1B SNP (rs 1562444). Although no statistically significant difference in allele frequency between RF(+) and controls was observed (v 2 ¼ 2.75, P ¼ 0.10), the results might suggest that MTNR1B SNP

Low incidence of cancer in schizophrenia is one of the interesting puzzles in psychiatric field over decades. Analysis of genetic difference between schizophrenia and lung cancer might provide us with possible clues to understand molecular mechanisms of pathophysiology of schizophrenia. Epidermal growth factor (EGF), one of the potent growth promoting factors, has been studied for its roles in cancer development. EGF is also known to be involved in cognitive function. In order to analyze the genetic difference between schizophrenia and lung cancer, polymorphism of EGF gene was studied from 174 schizophrenia patients, 122 lung cancer patients and 132 controls in Korean population. Genotype frequency analysis of EGF gene (AluI restriction site, 5'-UTR, rs4444903) in the EGF gene was studied. The genotype and allele frequencies of the AluI polymorphism showed significant differences between schizophrenia and lung cancer patients [p0.0001; p0.0001, odds ratio (95% CI), 0.3690 (0.2600-0.5236)]. When compared with controls, schizophrenia patients showed no significant differences from controls in genotype and allele frequencies [p=0.5151; p=0.3516, odds ratio (95% CI), 0.8589 (0.6235-1.1830)]. However, lung cancer patients showed significant differences from controls in genotype and allele frequencies [p0.0001; p0.0001, odds ratio (95% CI), 2.3275 (1.6082-3.3687)]. These results indicate that schizophrenia is not associated with AluI polymorphism of EGF gene and EGF gene polymorphism is different between schizophrenia and lung cancer patients.

The posaconazole tablet formulation was developed to have improved bioavailability compared to the oral suspension. Here, we compared posaconazole plasma concentration (PPC) with the posaconazole oral suspension versus the tablet in Korean patients undergoing remission induction chemotherapy for hematologic malignancies. PPC was measured at 3, 8, and 15 days of treatment with the oral suspension (174 patients) or the tablet (40 patients). At all time-points, mean PPC was significantly higher with the tablet compared to the oral suspension. Our findings suggest that posaconazole tablets generate an optimal PPC earlier and in more patients than the oral suspension among Korean patients.

Yu-Jung Cha,1,* Kyoung Soo Lim,2,* Min-Kyu Park,1 Stephen Schneider,3 Brian Bray,3 Myung-Chol Kang,3 Jae-Yong Chung,1 Seo Hyun Yoon,1 Joo-Youn Cho,1 Kyung-Sang Yu11Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea; 2Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and CHA Bundang Medical Center, Seongnam, South Korea; 3Kainos Medicine USA Inc., Morrisville, NC, USA *These authors contributed equally to this workBackground: KM-023 is a new second-generation nonnucleoside reverse-transcriptase inhibitor that is under development for the treatment of human immunodeficiency virus (HIV) type 1 infection. Objective: This study determined KM-023 tolerability and pharmacokinetic characteristics in healthy subjects. Materials and methods: A randomized, double-blinded, placebo-controlled, dose-escalation study was conducted in 80 healthy South Korean male volunteers. The subjects were allocated to single- or multiple-dose (once daily for 7 days) groups that received 75, 150, 300, or 600 mg drug or placebo in a 4:1 ratio. Safety and pharmacokinetic assessments were performed during the study. Plasma and urine concentrations were quantified using liquid chromatography–tandem mass spectrometry. Results: The average maximum concentration (Cmax) and area under the concentration–time curve from time 0 to infinity (AUC∞) values of KM-023 for the 75–600 mg doses in the single-dose study ranged from 440.2 ng/mL to 1,245.4 ng/mL and 11,142.4 ng • h/mL to 33,705.6 ng • h/mL, respectively. Values of the mean Cmax at a steady state and AUC within the dosing interval ranged from 385.1 ng/mL to 1,096.7 ng/mL and 3,698.9 ng • h/mL to 10,232.6 ng • h/mL, respectively, following 75–600 mg doses in the multiple-dose study. Dose proportionality was not observed for KM-023. KM-023 showed a 0.6-fold accumulation after multiple doses in the 600 mg dose group. The mean half-life values ranged between 20.7 and 31.2 hours. KM-023 was generally well tolerated without serious adverse events. Conclusion: KM-023 demonstrated dose- and time-dependent nonlinear pharmacokinetic characteristics after single or multiple doses over a dose range (75–600 mg) in healthy subjects. KM-023 showed favorable tolerability in this study. This Phase I clinical trial information can be used to design further clinical studies appropriately to evaluate KM-023 in patients with HIV-1 infection. Keywords: KM-023, HIV-1, nonnucleoside reverse-transcriptase inhibitor, pharmacokinetics, tolerability, healthy subjects

Kyungho Jang, Seonghae Yoon, Sung-Eun Kim, Joo-Youn Cho, Seo Hyun Yoon, Kyoung Soo Lim, Kyung-Sang Yu, In-Jin Jang, Howard LeeDepartment of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of KoreaBackground: Megestrol acetate is an effective treatment for improving appetite and increasing body weight in patients with cancer-associated anorexia. However, Megace® oral suspension (OS), a micronized formulation of megestrol acetate, has low bioavailability in the fasting state. To overcome this limitation, a nanocrystal formulation has been developed. This study was performed to evaluate the pharmacokinetics and tolerability of the nanocrystal formulation and to compare them with those of Megace® OS in the fed and fasting states.Methods: A randomized, open-label, two-treatment, two-period, two-sequence, crossover study was performed in three parts in 93 healthy subjects. A single 625 mg/5 mL oral dose of a nanocrystal formulation was administered in the fasting and fed states (part I). In parts II and III, a single 625 mg/5 mL oral dose of the nanocrystal formulation or Megace® OS 800 mg/20 mL was given in the fed and fasting states, respectively. Blood samples were collected for up to 120 hours post dose for pharmacokinetic analysis. Tolerability was evaluated throughout the entire study period.Results: The nanocrystal formulation of megestrol acetate was rapidly absorbed in both the fed and fasting states. In the fed state, systemic exposure was comparable between the nanocrystal formulation of megestrol acetate and Megace® OS. In the fasting state, however, the peak plasma concentration and area under the plasma concentration-time curve to the last measurable concentration of megestrol acetate was 6.7-fold and 1.9-fold higher, respectively, for the nanocrystal formulation than for Megace® OS. No serious adverse events were reported.Conclusion: Systemic exposure to megestrol acetate is less affected by lack of concomitant food intake when it is administered using the nanocrystal formulation. The nanocrystal formulation of megestrol acetate could be more effective in treating patients with cachexia or anorexia.Keywords: megestrol acetate, nanocrystal formulation, food, anorexia

A simple, rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of a newly developed antihypertensive agent fimasartan (BR-A657, Kanarb(®)) in human plasma was developed and validated. Fimasartan and internal standard (IS, BR-A563) were extracted by simple protein precipitation using acetonitrile and separated on a Phenyl-Hexyl column (Luna(®), 5 µm, 50 mm × 2.0 mm, Phenomenex) under the gradient conditions of mobile phase A (distilled water with 0.1% formic acid) and mobile phase B (100% acetonitrile with 0.1% formic acid) at a flow rate of 0.25 mL/min. Detection and quantification were performed by the mass spectrometer using multiple reaction monitoring mode at m/z 500.2 → 221.2 for fimasartan and m/z 524.3 → 204.9 for the IS. The assay was linear over a calibration range of 0.5-500 ng/mL with a lower limit of quantification of 0.5 ng/mL. The coefficient of variation of this assay precision was

As inhibitors of organic cation transporters (OCTs), proton pump inhibitors (PPIs) may affect the plasma levels of metformin, an OCT substrate. We investigated the effects of two PPIs, pantoprazole and rabeprazole, on metformin pharmacokinetics and glucose levels in healthy subjects. In this open, randomized, six-sequence, three-period crossover study, 24 participants were administered metformin, either alone or in combination with pantoprazole or rabeprazole. The plasma concentrations of metformin and serum concentrations of glucose after a 75-g oral glucose tolerance test (OGTT) were determined. The area under the concentration-time curve (AUC) for metformin was 15% and 16% greater following coadministration with pantoprazole and rabeprazole, respectively. The maximum plasma metformin concentrations (Cmax) also increased by 15% and 22%, respectively, compared with when it was administered without the PPIs. The percentage change in the AUC for glucose concentration versus time for metformin plus rabeprazole was significantly lower than that for metformin plus pantoprazole [geometric mean ratio: 0.96 (90% confidence interval: 0.92-0.99) and 0.77 (0.63-0.93), respectively]. There was no significant difference in the maximum glucose concentration. In conclusion, concomitant administration of PPIs with metformin significantly increased plasma metformin exposure, but the effects on glucose disposition were minor and varied depending on the PPI administered.

GC1113, a hybrid Fc-fused erythropoietin, is a novel erythropoiesis-stimulating agent that is expected to have an extended duration of action. The preclinical data showed that the hemoglobin increase lasted longer following GC1113 administration than it did following the administration of darbepoetin alfa (NESP®). This study aimed to investigate the pharmacodynamic and pharmacokinetic characteristics and tolerability profiles of GC1113 in humans after single intravenous or subcutaneous administration and to compare the results with those for darbepoetin alfa. A dose-block randomized, placebo- and active-controlled, dose-escalation phase I clinical trial was conducted in 96 healthy volunteers. Blood samples were collected before and up to 672 h after drug administration and the serum erythropoietin concentration following the GC1113 or darbepoetin alfa administration was measured by an ELISA. The reticulocyte counts were measured for pharmacodynamic assessments. Pharmacokinetic and pharmacodynamic parameters were determined using non-compartmental methods. The reticulocyte count–time profiles in the intravenous GC1113 3–5 μg/kg groups were comparable with those of the darbepoetin alfa 30 μg group. After subcutaneous administration of GC1113, reticulocyte count peaked later and decreased more slowly than it did following darbepoetin alfa administration. GC1113 (0.3–5 μg/kg intravenous, 1–8 μg/kg subcutaneous) was well-tolerated in the volunteers, and no immunogenicity was observed. GC1113 was tolerated and effective in the studied dose range; these findings could be applied to further clinical studies with patients.

SummaryWhat is known and objective Both metformin and acarbose are recommended monotherapy and add-on therapy in type 2 diabetes mellitus (T2DM). A fixed-dose combination (FDC) of acarbose and metformin has been developed to reduce pill burden and potentially improve compliance. The current study investigated the bioequivalence of the acarbose/metformin FDC compared with the individual agents administered simultaneously (loose combination). Secondary endpoints were the safety and tolerability of the FDC and the potential for drug–drug interactions between acarbose and metformin. Methods A single-centre, randomized, open-label, four-period crossover study was conducted in healthy male Korean subjects aged 18–45 years. Following one-period balanced Williams design, participants were randomized to receive four single oral treatments on different study days separated by ≥7 days' washout. Treatments were as follows: (i) acarbose/metformin 50/500 mg FDC (test); (ii) acarbose 50 mg and metformin 500 mg as loose combination (reference); (iii) acarbose 50 mg; and (iv) metformin 500 mg. Serial blood samples were taken for glucose and insulin levels for 4 h after a sucrose load on the day before and day of study drug administration. Additionally, serial blood samples were taken for analysis of metformin levels for 24 h after each drug containing metformin. The area under the curve for 4 h post-test (AUC0–4 h) and the maximal serum concentration (Cmax) of plasma glucose and serum insulin were primary pharmacodynamic (PD) parameters, and Cmax, AUC0–last and AUC for metformin levels were primary pharmacokinetic (PK) parameters. The bioequivalence of the FDC to the loose combination was considered established if the 90% confidence intervals (CIs) of the baseline-adjusted PD parameter ratios (test vs. reference) for plasma glucose and the PK parameter ratios for metformin fell completely within current acceptance limits (0·8–1·25). Results and discussion Thirty-three of 40 randomized subjects completed the study; five withdrew consent and two discontinued because of adverse events (AEs). The 24-h plasma concentration–time curves of metformin and the 4-h plasma glucose–time curves after acarbose/metformin FDC (test) and acarbose + metformin loose combination (reference) were almost superimposable. The geometric least squares (LS) mean of the RatioAUC and RatioCmax for plasma glucose after the FDC vs. loose combination, and the LS mean of the ratios in metformin AUC, AUC0–last and Cmax were close to unity, and the 90% CI of all these parameters fell within the predefined equivalence range of 0·8–1·25, confirming bioequivalence. The metformin AUC was reduced by 26% and Cmax by 34% after acarbose + metformin compared with metformin alone. Eight subjects (20·0%) reported AEs, but all were mild, and most were gastrointestinal, as expected for these agents. The incidence of AEs was not higher with the combinations vs. monotherapy. What is new and conclusion These data demonstrate that the acarbose/metformin FDC is bioequivalent to the loose combination of these agents. Although acarbose slightly reduced the bioavailability of metformin, the accumulated evidence of the efficacy of this combination implies that this is clinically irrelevant. The observed AE profile was consistent with the established knowledge on the safety of the two drugs.

DA-3031 is a newly developed pegylated filgrastim, a recombinant human granulocyte colony-stimulating factor, that is expected to have an extended duration of action compared with non-modified filgrastim.This study evaluated the tolerability, pharmacokinetics, and pharmacodynamics of DA-3031 in humans, and compared them with filgrastim.The study was conducted in 48 healthy male Korean subjects. Forty subjects received subcutaneous single doses of 1.8, 3.6, 6, or 18 mg of DA-3031 or placebo in a dose block-randomized, double-blind, dose-escalation design. The remaining eight subjects were given subcutaneous doses of 100 μg/m² of filgrastim daily for 5 days. Serial blood samples were collected for pharmacokinetic and pharmacodynamic analyses up to 312 h after the administration of DA-3031 and up to 264 h following the first administration of filgrastim.DA-3031 reached its peak plasma concentration at 6.0-48.0 h and was eliminated mono-exponentially. The pharmacokinetic parameters of DA-3031 increased with dose in a non-linear fashion. Absolute neutrophil count (ANC) levels increased with the dose of DA-3031, although the extent of the increase in ANC decreased at higher dose levels. DA-3031 resulted in similar ANC changes in the 3.6 to 6 mg dose range as 100 μg/m² of filgrastim. The most frequent adverse event was back pain, which was observed after both DA-3031 and filgrastim administration.DA-3031 showed non-linear pharmacodynamic and pharmacokinetic profiles and an extended duration of action compared with non-modified filgrastim, without unexpected toxicities in healthy subjects.

OBJECTIVES Oral loading of oxcarbazepine tablet is effective and well tolerated to adequately achieve the therapeutic levels of its active metabolite, 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD) in epilepsy patients. The present study was performed to investigate the safety, tolerability, and pharmacokinetic profiles of oral loading of oxcarbazepine suspension in epilepsy patients with a high risk of recurrent seizures. METHODS Oxcarbazepine suspension was administered orally at a single loading dose of 30 mg/kg to 38 adult patients with recurrent seizures, who required rapid seizure control or temporarily discontinued antiepileptic drugs for diagnostic or pre-surgical evaluation. Plasma concentrations of oxcarbazepine and MHD were determined, and adverse events were assessed at 2, 4, 6, 8, 10, 12, 14, 16, and 24 hours after oral loading of oxcarbazepine suspension. RESULTS 30 patients experienced ≥ 1 adverse event during the first 24 hours after oral loading of oxcarbazepine (e.g., dizziness, transient diplopia, nausea or vomiting), most of which occurred within 4 hours after loading, suggesting no temporal association with MHD plasma levels. 35 (92.1%) patients were still compliant with a maintenance dose of oxcarbazepine after discharge from hospital. 34 (89.4%) patients reached the lower therapeutic level of MHD (12 mg/l) at 4 hours after oral loading of oxcarbazepine suspension, which lasted up to 24 hours in most patients. No patient reached the supratherapeutic levels of MHD (> 35 mg/l) during the study. The mean plasma concentration-time curves and pharmacokinetic profiles of oral loading of oxcarbazepine suspension were similar to those of oral loading of oxcarbazepine tablet. CONCLUSIONS Oral loading of oxcarbazepine suspension followed by maintenance dosing is well tolerated and effective in steadily achieving the therapeutic level of MHD in selected patients with epilepsy.

The aim of this study was to investigate the population pharmacokinetics of theophylline in premature Korean infants and to assess the influence of clinical covariates.Blood samples were first obtained after 1 week of maintenance dosing and then acquired approximately 4 weeks after continuous dosing. The time points were just before dosing and 2, 4, or 6 hours (at randomly assigned time points) after dosing. Two single-nucleotide polymorphism markers, -3860 GA (CYP1A2*1C) and -163CA (CYP1A2*1F), were genotyped. Gestational age (GA), postnatal age (PNA), postconceptional age (PCA = GA + PNA), body weight (BW), height, serum AST, serum ALT, serum BUN, serum creatinine, oxygen support, sex, delivery mode, and CYP1A2 genotypes were used for covariate model building. External validation was analyzed using data from an additional 27 patients.A total of 334 serum concentration measurements were made in 100 patients. A one-compartment absorptive model with first-order elimination was fitted to the data in NONMEM (version 7.1.2). The final model included the following parameters: Clearance (L/h) = 0.00492 × (BW)(3.53) + 0.00646 × (PNA), and volume of distribution (L) = 1.53 × (BW). The addition of the CYP1A2*1C or CYP1A2*1F genotypes to the model did not improve the model. The external validation results confirmed the predictive performance without bias in the final model.The selected covariates were generally consistent with previous studies. However, the mean volume of distribution was higher than the values reported in other population pharmacokinetic studies, which may have been due to the use of 2 sampling time points. The predictive performance was reasonably acceptable. Therefore, the present model may permit more accurate selection of doses to achieve target theophylline concentrations in premature infants.

HM30181 is a new P-glycoprotein (P-gp) inhibitor. This study was conducted to investigate the effect of HM30181 and its duration of action on P-gp inhibition using loperamide as a probe drug. An open-label, five-period, fixed-sequence, cross-over study was conducted in 25 healthy Korean participants, who received a single oral dose of loperamide at 16 mg in five periods lasting for 17 days. In period II, participants also randomly received a single oral dose of HM30181 at 1, 5, 10, 15 mg simultaneously with loperamide. Serial pharmacokinetic blood samples were obtained up to 72 and 336 hr after loperamide and HM30181 administration, respectively. A mixed-effects analysis was performed to compare the area under the plasma concentration versus time curve from time 0 to 72 hr (AUC0-72 hr ) between periods and HM30181 dose groups. Tolerability was also assessed. The AUC0-72 hr of repeatedly administered loperamide was significantly increased 1.18-1.62 times for up to 14 days after a single oral administration of HM30181, particularly at doses ≥10 mg although the between-group difference failed to reach statistical significance. Plasma HM30181 was not detected in many participants including none at any sampling points beyond 48 hr after administration. Most adverse events (AEs) were mild to moderate and resolved spontaneously. The oral bioavailability of loperamide was significantly enhanced by a single oral administration of HM30181, which was sustained for up to 14 days. HM30181 was well tolerated in this selected population.

HM10460A is a newly developed recombinant human granulocyte colony-stimulating factor with long-lasting characteristics. This factor is expected to be used for chemotherapy-related neutropenic conditions.The aim of the present study was to evaluate the pharmacokinetics and pharmacodynamics of HM10460A following subcutaneous administration to healthy Korean subjects.A randomized, double-blind, placebo-controlled, escalating single-dose study was conducted in 40 healthy Korean subjects. The subjects were allocated to single-dose groups of 5, 15, 45, 135 or 350 μg/kg, or placebo. Serial blood samples for pharmacokinetic/pharmacodynamic analyses were collected up to 22 days, and urine samples for pharmacokinetic analysis were collected up to 3 days after subcutaneous administration of HM10460A. The serum and urine concentrations were analyzed by enzyme-linked immunosorbent assay.Most of the serum concentrations in the 5 and 15 μg/kg dosing groups were below the lower limit of quantification (LLOQ). The median times to the peak concentration (T(max)) of HM10460A in the 45, 135, and 350 μg/kg dosing groups were 8.0, 14.0, and 24.0 h, respectively. The mean ± standard deviation values of the dose-normalized maximum concentration (C(max)) and dose-normalized area under the concentration-time curve (AUC(last)) for the 45, 135, and 350 μg/kg dosing groups were 14.13 ± 6.37, 66.19 ± 38.71, and 34.65 ± 19.69 μg/L/mg, respectively, and 265.0 ± 124.1, 2144 ± 1232, and 1386 ± 701.2 μg h/L/mg, respectively. The concentrations of HM10460A in the urine were below the LLOQ in all of the subjects. In all of the dosing groups, the area under the effect-time curve (AUEC(last)) of both the absolute neutrophil count (ANC) and the CD34(+) cell count increased as the dose increased.HM10460A showed dose-dependent pharmacokinetic characteristics, and the systemic exposure of HM10460A was positively correlated with the ANC and CD34(+) cell counts.

of R(+)-α-lipoic acid 200 mg to thioctic acid 600 mg for the Cmax and AUClast were 0.71 (0.43–1.15) and 0.51 (0.37–0.70), respectively. The corresponding R(+)-α-lipoic acid 300 mg to thioctic acid 600 mg values were 1.11 (0.68-1.80) and 0.97 (0.71-1.34), respectively. In conclusion, R(+)-α-lipoic acid 300 mg showed PK characteristics similar to those of thioctic acid 600 mg and both formulations were well tolerated.

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.

Background. Blood levels of voriconazole, a first line therapy for invasive aspergillosis, may correlate with adverse events and treatment response. However, no randomized controlled studies have been conducted to evaluate the clinical utility of routine therapeutic drug monitoring (TDM) of voriconazole. This study aimed to determine whether routine TDM of voriconazole reduces drug adverse events or improves treatment response in invasive fungal infections. Methods. This was a randomized, assessor-blinded, controlled, single center trial. One hundred ten adult patients were randomly assigned to TDM or non-TDM groups. In the TDM group, voriconazole dosage was adjusted (target range, 1.0–5.5 mg/L) according to the serum trough level measured on the fourth day after initiation of voriconazole. The non-TDM group received a fixed, standard dosage. Voriconazole-related adverse events were monitored, and treatment response was assessed three months after the initiation of therapy. Results. Baseline characteristics including the CYP2C19 genotype were comparable between the two groups. While the incidence of adverse events was not different between the TDM group and the non-TDM group (both 42%; P= .97), the proportion of voriconazole discontinuation due to adverse events was significantly lower in the TDM group than in the non-TDM group (4% vs 17%; P= .02). A complete or partial response was observed in 81% (30 of 37) of patients in the TDM group compared to 57% (20 of 34) in the non-TDM group (P= .04). Conclusions. Routine TDM of voriconazole may reduce drug discontinuation due to adverse events and improve the treatment response in invasive fungal infections. Clinical Trial Registration. NCT00890708.

Background Inhibitors of dipeptidyl peptidase (DPP) IV are a class of oral hypoglycemic agents that increase glucagon-like peptide-1 (GLP-1) levels by inhibiting its degradation. Objective This study evaluated the pharmacokinetics, pharmacodynamics, and tolerability of DA-1229, which is a newly developed DPP IV inhibitor. This study was planned as part of a product development project at the request of the Korean regulatory agency. Methods A 7 parallel arm dose-escalation study was conducted in healthy Korean male volunteers. A single oral dose of DA-1229 or placebo was given to 10 subjects (8 active + 2 placebo) in each dose group of 1.25, 2.5, 5, 10, 20, 40, or 60 mg. To assess the effects of food, the subjects in the 10-mg dose group received a single dose of DA-1229 10 mg after a high-fat meal, crossing over from the administration of DA-1229 under a fasting state, after a 7-day washout period. Serial blood samples were collected up to 120 hours after drug administration for pharmacokinetic analysis and the assessment of DPP IV activity, and blood samples were collected up to 2 hours after each meal until the next morning of drug administration to evaluate active GLP-1, glucose, and insulin levels. Results Seventy-two subjects, aged 20 to 39 years and weighing 52.1 to 79.8 kg, participated in this study. Twenty-one adverse events were reported; all were mild, and all subjects recovered spontaneously. DA-1229 reached a peak at 3.0 to 5.5 hours after a single oral dose and the concentrations declined, with a terminal t½ from 32.5 to 39.8 hours. The %CV of Cmax and AUC0–last ranged from 11.1% to 54.6%. Dose-proportional pharmacokinetics were confirmed within the dose range by using a linear regression analysis, and the 95% CIs of the slope of the log-transformed Cmax and AUC0–last included 1.0. The pharmacokinetics of DA-1229 were unchanged by food. The degree of DPP IV inhibition was dependent on the dose, and groups receiving ≥10 mg exhibited >80% DPP IV inhibition for >24 hours. The %CV of the time of the last quantifiable concentration ranged from 4.6% to 15.2%. Cmax of active GLP-1 was achieved at 30 minutes after meal intake. The active GLP-1 levels were enhanced in groups receiving ≥5 mg. There were no changes in the glucose and insulin levels after DA-1229 administration. Conclusions DA-1229 was well tolerated within the dose range of 1.25 to 60 mg. DA-1229 pharmacokinetics suggested dose proportionality, and dose-dependent DPP IV inhibition was exhibited. ClinicalTrials.gov identifier: NCT00961025 .

Fruit juice reduces the plasma concentrations of several β-adrenoceptor blockers, likely by inhibiting OATP2B1-mediated intestinal absorption. The aim of this study was to investigate the effects of apple juice on the pharmacokinetics of atenolol.Twelve healthy Korean volunteers with genotypes of SLCO2B1 c.1457CT (*1/*1 (n = 6) and *3/*3 (n = 6)) were enrolled in this study. In a three-phase, one-sequence crossover study, the pharmacokinetics (PK) of atenolol was evaluated after administration of 50 mg atenolol. Subjects received atenolol with either 300 ml water, 1200 ml apple juice or 600 ml apple juice.Apple juice markedly reduced the systemic exposure to atenolol. The geometric mean ratios (95% confidence intervals) of apple juice : water were 0.18 (0.13, 0.25, 1200 ml) and 0.42 (0.30, 0.59, 600 ml) for the AUC(0,t(last)). In this study, the PK parameters of atenolol responded in a dose-dependent manner to apple juice.Apple juice markedly reduced systemic exposure to atenolol. The genetic variation of SLCO2B1 c.1457CT had a minimal effect on the pharmacokinetics of atenolol when the drug was administered with water or apple juice.

HD203 is a biosimilar of etanercept, a fusion protein of the ligand-binding portion of the human tumor necrosis factor receptor II linked to the Fc portion of human immunoglobulin G1. Since HD203 is under clinical development, this study was conducted to compare the pharmacokinetics of HD203 with Enbrel®, the first marketed etanercept.A double-blind, randomized, single-dose, two-period, two-sequence, crossover study was conducted in 37 healthy volunteers. In each period, 25 mg/mL of reconstituted lyophilized reference (Enbrel®) or test product (HD203) was administered subcutaneously, either the reference product followed by the test product, or vice versa. Serial blood samples for pharmacokinetic analysis were taken for 480 hours after dosing, and serum concentrations of the products were determined using a commercial enzyme-linked immunosorbent assay. The geometric mean ratios with 90% confidence intervals for the maximum concentration (C(max)) and the area under the concentration-time curve from time 0 to the last measurable time point (AUC(0-t)) were estimated.A total of 35 subjects completed the study; serious adverse events were not observed. The mean serum concentration-time profiles of the two products were similar. The C(max) and AUC(0-t) values of the reference product (mean ± standard deviation) were 1.25 ± 0.45 mg/L and 283.15 ± 98.57 mg*h/L, respectively, while those of the test drug were 1.35 ± 0.47 mg/L and 315.78 ± 99.38 mg*h/L, respectively. The geometric mean ratios (90% confidence intervals) of the test to the reference for C(max) and AUC(0-t) were 1.08 (1.00, 1.16) and 1.13 (1.05, 1.21), respectively.A single subcutaneous injection of HD203 or Enbrel® into healthy volunteers appeared to be safe and well tolerated. Comparative pharmacokinetics demonstrated that reconstituted lyophilized HD203 has bioavailability similar to that of Enbrel®.

Background Freezing of gait (FOG) is one of the most disabling symptoms in Parkinsonism. Open-label studies have suggested that intravenous (IV) amantadine is effective against FOG resistant to dopaminergic therapy in Parkinson's disease (PD). We evaluated the efficacy of IV amantadine on FOG resistant to dopaminergic therapy. Methodology/Principal Findings This was a randomized, double-blind, placebo-controlled, cross-over study on IV amantadine. The placebo (normal saline) and amantadine (400 mg/day) were injected for 2 days with a 52-hour washout period. The instruments for the outcome measures were the Freezing of Gait Questionnaire (FOGQ), Unified Parkinson's disease rating Scale (UPDRS), and the duration of the 4×10 m walking test. The placebo arm was compared to the amantadine arm. Ten patients were enrolled but two patients withdrew, one from each arm. The FOGQ and UPDRS scores and the duration of the 4×10 m walking test improved in both arms compared to the baseline (P

Tolvaptan is a selective arginine vasopressin V2-receptor antagonist that is used as an aquaretic agent. This trial investigated the pharmacokinetics and pharmacodynamics of 15- to 60-mg single oral doses of tolvaptan in healthy Korean men. A dose block-randomized, placebo-controlled, double-blind, single ascending dose trial was conducted with 46 subjects receiving tolvaptan (15, 30, or 60 mg) or placebo. To determine pharmacokinetics and pharmacodynamics, blood and urine samples were collected at baseline and up to 48 hours after drug administration. Urine volume and fluid intake were measured for 24 hours starting the day before dosing (day -1) as baseline, and on the day of drug administration (day 1). Tolvaptan showed dose-linear pharmacokinetic characteristics regarding area under the concentration-time curve. Changes from baseline in 24-hour urine volume and 24-hour fluid balance correlated significantly with area under the concentration-time curve from time 0 to the last measurable time. Dose-dependent increases were observed in serum osmolality, serum sodium concentration, and free water clearance in the 4- to 8-hour interval after dosing, and these increases were maintained for at least 24 hours. Single 15- to 60-mg doses of tolvaptan exhibited linear pharmacokinetics and resulted in substantial, dose-dependent aquaresis in healthy Korean men.

The rapid achievement of effective levels of antiepileptic drugs (AEDs) is required in patients with epilepsy who have a higher risk of seizures, and oral loading of AEDs may be an important consideration in these patients. We performed the present study to investigate the efficacy and tolerability of oral loading of oxcarbazepine in patients with recurrent seizures, or after temporary discontinuation of AEDs for diagnostic or presurgical evaluation of epilepsy. Forty adult patients were studied and oxcarbazepine was administered orally at a single loading dosage of 30 mg/kg. The plasma levels of oxcarbazepine and its active metabolite, 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD), were measured, and clinical assessment of adverse events was performed at 2, 4, 6, 8, 10, 12, 16, and 24 h after oral loading of oxcarbazepine. Approximately two-thirds of patients reached effective levels of MHD 2 h after receiving the oral loading, and all patients reached effective levels 4 h after oxcarbazepine administration. Most patients maintained therapeutic MHD levels for at least 16 h. Almost half of the patients experienced adverse events, but all were mild to moderate in severity and resolved spontaneously within 24 h. Our study shows that oral loading of oxcarbazepine is an effective and well-tolerated method for rapidly achieving therapeutic levels of MHD in patients with epilepsy, and is a useful option in selected patients with recurrent seizures, or after temporary discontinuation of AEDs.

Clopidogrel therapy to prevent atherothrombosis faces the challenge of reduced responsiveness. The absorption of clopidogrel is regulated by multidrug-resistance protein 1 (MDR1) in the intestinal epithelium. Given that aspirin induces MDR1 in cancer cells and peripheral blood cells, it may induce MDR1 in intestinal epithelial cells as well, thereby affecting the absorption of clopidogrel. In this study, aspirin treatment induced the expression of MDR1 in human epithelial colorectal (Caco-2) cells in vitro and in rat intestine in vivo, as evidenced by dose-dependent increases in gene, protein, and efflux function. Along with the upregulation of MDR1 proteins by aspirin, clopidogrel absorption was significantly decreased in the aspirin-treated Caco-2 cells and in rat intestine. Our data provide evidence that prolonged use of aspirin may reduce the intestinal absorption of clopidogrel. Further human studies would be necessary to clarify whether these data have any relevance to prevention of stroke or myocardial infarction.

Interactions between coadministered drugs may unfavorably affect pharmacokinetics. This study evaluated whether fimasartan, an angiotensin receptor II antagonist, affected the pharmacokinetics of atorvastatin.A randomized, open-label, 2-period, 2-sequence, crossover, multiple-dosing study was conducted with 24 healthy male volunteers. Twelve subjects received 80-mg atorvastatin once daily for 7 days; later, they received 80-mg atorvastatin with 240-mg fimasartan for 7 days. Twelve other subjects received the same drugs in the opposite sequence. Blood samples were collected scheduled intervals for 24 hours after the last dosing to determine plasma concentrations of atorvastatin acid, atorvastatin lactone, 2-hydroxy atorvastatin acid, and 2-hydroxy atorvastatin lactone.Compared with atorvastatin alone, coadministration of fimasartan and atorvastatin increased the atorvastatin acid mean (95% confidence interval) maximum concentration (Cmax,ss) by 1.89-fold (1.49-2.39) and the area under the concentration curve (AUCτ,ss) by 1.19-fold (0.96-1.48). Fimasartan also increased the mean 2-hydroxy atorvastatin acid Cmax,ss and AUCτ,ss by 2.45-fold (1.80-3.35) and 1.42-fold (1.09-1.85), respectively. The Cmax,ss and AUCτ,ss of the lactone forms of atorvastatin showed smaller changes than those observed for the acidic forms.We showed that fimasartan raised plasma atorvastatin concentrations. In vitro tests suggested that this effect may have been mediated by fimasartan inhibition of organic anion-transporting polypeptide 1B1.