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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 Fesoterodine is a pro-drug of the active metabolite 5-hydroxymethyl tolterodine (5-HMT), a muscarinic receptor antagonist. This study aimed to evaluate the safety profile and pharmacokinetic characteristics of multiple oral doses of sustained-release fesoterodine (fesoterodine SR) in healthy Korean males. METHODS A randomized, double-blind, placebo-controlled, multiple-dose study with two oral doses (4 mg and 8 mg) was conducted in healthy Korean male participants. The study drug was administered once daily for 5 days. The plasma concentration of 5-HMT was measured up to 72 hours after the last drug administration. The CYP2D6 genotype was analyzed using polymerase chain reaction (PCR) methods to assess the effect of genetic polymorphisms on the pharmacokinetic parameters. RESULTS 20 participants completed the study. The mean (SD) areas under the plasma concentration-time curves during the dosing interval (AUCτ) of the 4 mg and 8 mg dose groups were 26.1 (8.0) and 64.2 (30.5) μg·h/ml and the mean peak concentrations (Cmax) were 2.6 (0.7) and 6.0 (2.0) μg/ml, respectively, at steady-state. The mean AUCτ and Cmax of 5-HMT increased in approximately the same proportion as the dose increased. Fesoterodine SR was well tolerated without any serious adverse events or abnormal clinical laboratory findings. CONCLUSION Systemic 5-HMT exposure showed dose-proportional characteristics in the 4 mg to 8 mg dose range in healthy Korean males. Thus, 4 mg or 8 mg doses of fesoterodine SR taken once-daily were tolerable in healthy Korean males.

The plasma concentrations of valproic acid (VPA) are known to decrease during the concomitant administration of carbapenem antibiotics, such as meropenem, imipenem, and ertapenem. This study summarizes 6 cases of drug-drug interactions between VPA and carbapenem antibiotics.To investigate the onset and severity of the reductions in the concentration of VPA in patients with or without the coadministration of carbapenem antibiotics, the authors performed a retrospective evaluation of therapeutic drug monitoring (TDM) reports that described a decrease in the serum concentrations of VPA during the concomitant use of carbapenem antibiotics from January 2008 to December 2010 in the Seoul National University Hospital. The evaluated TDM reports included 6 cases. The decrement ratio of the VPA serum concentration was calculated from the TDM reports, and the change in the half-life of the VPA was also estimated.Six cases presented with changes in the VPA serum concentration before and after the administration of carbapenem antibiotics. (Three cases were treated with meropenem, 2 were treated with ertapenem, and 1 was treated with imipenem.) The VPA concentrations reduced by (mean ± SD) 88.7 ± 5.3% (3 cases of meropenem), 74.0 ± 9.8% (2 cases of ertapenem), and 73.3% (1 case of imipenem), respectively, and the half-life of VPA reduced by 80.1 ± 9.0%, 64.4 ± 24.2%, and 50.6%, respectively.The interaction between VPA and carbapenem antibiotics caused decreases in the VPA serum concentrations; the extent of this decrease was greater in the meropenem-treated patients than in the imipenem-treated or ertapenem-treated cases. Because the therapeutic effect of VPA depends on its serum concentration, it should be recognized that there may be a loss of seizure control in patients using VPA with carbapenem antibiotics.

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.

Background Cinacalcet (KRN1493) was developed to manage secondary hyperparathyroidism in patients with chronic kidney disease. The characteristics of cinacalcet have not been studied in the Korean population. Objective The aim of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties and tolerability of single-dose cinacalcet 50 to 100 mg in healthy male Korean subjects for the purposes of a New Drug Application package for the Korean Food and Drug Administration. Methods A randomized, open-label, single ascending–dose, parallel-group study was conducted in healthy male Korean subjects. Subjects were randomly assigned to receive a single oral dose of cinacalcet 50, 75, or 100 mg. Serial blood samples for PK/PD analysis were taken for up to 96 hours after administration. Plasma cinacalcet concentrations were analyzed by HPLC-MS/MS. PK parameters were determined using noncompartmental methods. Plasma intact parathyroid hormone (iPTH) concentrations, albumin-corrected serum calcium concentrations, and serum phosphorus concentrations were measured for PD evaluation. For the evaluation of tolerability, adverse events (AEs) were collected using investigators' questionnaires, subjects' spontaneous reports, clinical laboratory tests, ECG, and physical examinations including vital sign measurements. Results Sixteen subjects in the 50-mg group, 16 in the 75-mg group, and 6 in the 100-mg group completed the study and were included in the PK/PD analysis. The mean (SD) age, height, and weight of the study population were 4.3 (3.0) years, 174.8 (4.9) cm, and 68.2 (7.5) kg, respectively. The median T max value in each of the 3 dose groups was 6.0 hours. Mean C max values in the 50-, 75-, and 100-mg dose groups were 12.0 (5.5), 17.2 (14.9), and 43.1 (15.5) μg/L; mean AUC 0–∞ values were 126.6 (56.4), 184.3 (87.9), and 417.4 (169.9) μg · h/L. Characteristics were not linear, based on the data over the dose range of 50 to 100 mg. Mean plasma iPTH concentrations in the 50-, 75-, and 100-mg dose groups were decreased from baseline by 64.0% (11.7%), 63.1% (14.6%), and 70.6% (6.3%). Albumin-corrected serum calcium concentrations displayed patterns similar to those of the plasma iPTH concentrations. Sixteen AEs were reported in 11 subjects. No clinically significant abnormalities were observed in the tolerability assessments. Conclusions A single oral dose of cinacalcet was well-tolerated up to 100 mg in this small, selected population of healthy male Korean subjects. In addition, the PK characteristics of cinacalcet and its accompanying PD changes—the decreases in the concentrations of plasma iPTH and albumin corrected serum calcium—were demonstrated in the same population. ClinicalTrials.gov identifier: NCT00942773.

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.

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.

The pharmacokinetics (PK) of ceftazidime after intravenous (i.v.) administration during automated peritoneal dialysis (APD) and their dependence on peritoneal membrane transport are the targets of the present study. Eleven patients receiving a single i.v. dose of ceftazidime (15 mg/kg of body weight) (seven males, median [interquatile] age, 59 [36 to 62]) were recruited. Serum and dialysate samples were collected at the beginning, middle, and end of each of the five dwells during a 24-h period, with dwells 1, 2, and 3 using an automated cycler (designated on-cycler) and dwells 4 and 5 being manual exchanges (designated off-cycler), together with urine collection during the same period. Population PK analysis was employed to estimate the PK parameters. Peritoneal equilibration tests were performed for all patients, and correlations between peritoneal clearance (CL PD ) for ceftazidime and dialysate-to-plasma ratios for creatinine (D/P cr ) were obtained using the Spearman's product correlation coefficient (ρ). Ceftazidime renal clearance (CL renal ) was 0.052 ml/min/kg, and CL PD was 0.063 ± 0.050 ml/min/kg. CL PD for on- and off-cycler were 0.071 and 0.058 ml/min/kg ( P = 0.164), respectively. A significant correlation between CL PD and D/P cr was observed, with one outlier excluded, suggesting that CL PD for ceftazidime during APD is dependent upon the peritoneal small-solute transport rate. A model prediction yielded adequate serum and dialysate concentrations of ceftazidime throughout a 24-h period for sensitive organisms (MIC, 8 μg/ml) by either i.v. (at 15 mg/kg) or intraperitoneal (i.p.; at 20 mg/kg) administration during off-cycler dwells. The present study suggests that the i.v. administration of ceftazidime at 15 mg/kg or i.p. administration of ceftazidime at 20 mg/kg during a long dwell every 24 h can be recommended for treating systemic or intraperitoneal infections of APD patients.

Dopamine D2 receptor occupancy of antipsychotic drugs is calculated relative to the subject's D2 receptor binding potential (BP) in the drug-free state (baseline BP). Because baseline BP is seldom known in patients with schizophrenia, population means from unrelated control samples are often used to estimate it. However, this is likely to introduce bias and error into the occupancy measure. There is thus a need for a method to reliably estimate baseline BP for patient populations in whom it may be impractical or unethical to get baseline measurements. It has been previously found that the relationship between plasma concentration and dopamine receptor occupancy by antipsychotic drugs follows a sigmoid Emax model. Based on this, we developed a method for calculating dopamine D2 receptor occupancy by antipsychotic drugs using an inhibitory Emax model ( Imax method) that estimates individual baseline BPs. To validate this, we compared the result from the Imax method with actual occupancy and estimated occupancy calculated from the average baseline BP (substitution method). The data for validation were obtained from two different receptor occupancy studies with the antipsychotic medications YKP1358 and aripiprazole. We estimated the reliability between the true measured occupancy and the predicted occupancy using the intraclass correlation coefficient (ICC), and the variability of occupancy was also compared between the Imax and substitution methods. In YKP1358 study, all the ICCs of the Imax method were above 0.8, but those of the substitution method showed values lower than 0.8. In aripiprazole study, the ICCs of the Imax method were higher than those of the substitution method, but all the ICCs showed higher values than 0.8. The variability of Imax method was significantly smaller than that of substitution method in both studies. The Imax method shows better reliability and less variability than the substitution method. The Imax method can be applied for receptor occupancy study, and bring more reliability and accuracy to the occupancy study in patients with schizophrenia.

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.

Background: Recombinant human erythropoietin is indicated for the treatment of anemia resulting from chronic renal failure or chemotherapy. It is also used for patients at high risk for transfusions because of significant blood loss during surgery. A new recombinant human erythropoietin (epoetin alfa) that excludes fetal bovine serum and human serum albumin from among its ingredients was developed in Korea. This study was planned as part of a product development project at the request of the Korean regulatory agency. Objective: The aim of this study was to compare the pharmacokinetic and pharmacodynamic characteristics of a new recombinant human erythropoietin (test) formulation with an existing branded (reference) for- mulation after a single subcutaneous administration. Methods: An open-label, sequence-randomized, 2-period, 2-sequence, 2-treatment crossover study was conducted. Healthy male subjects were randomly assigned with a random number table into 1 of 2 sequence groups, and each subject was given recombinant human erythropoietin 4000 IU SC in the upper arm as the test formulation in one period and the reference formulation in the other period, according to the sequence group. Each period was separated by a 4-week washout period. Serial blood samples were taken up to 120 hours after drug administration for the pharmacokinetic assessments and up to 240 hours for reticulocyte counts as the pharmacodynamic end point. Pharmacokinetic analysis was performed without baseline correction. Adverse events (AEs) were collected by spontaneous reporting of the subjects or solicited by asking general health-related questions. Results: Twenty healthy men (mean [range] age, 25.6 [21–36] years; height, 175 [167–187] cm; weight, 70 [57.6–85.5] kg) were enrolled in and completed the study. The mean (SD) baseline erythropoietin plasma concentrations were 10.4 (2.4) mIU/mL for the test formulation and 10.8 (3.5) mIU/mL for the reference formulation. After the injection of 4000 IU SC per subject, the erythropoietin plasma concentrations reached a maximum at a median Tmax of 10 hours for both formulations (range: test formulation, 7.00–95.95 hours; reference formulation, 6.98–24.13 hours). The mean (SD) Cmax values for the test and reference formulations were 74.34 (30.63) and 80.46 (30.56) mIU/mL, respectively; the mean AUC0–last values were 3664 (731.5) and 3553 (723.2) mIU·h/mL. The ratios of the geometric mean (test/reference) for Cmax and AUC0–last were 0.92 (90% CI, 0.81–1.05) and 1.03 (90% CI, 0.98–1.09). The mean baseline hemoglobin, hematocrit, and reticulocyte counts were 15.4 g/dL, 45.5%, and 49.6 · 103/μL, respectively, for the test formulation and 15.5 g/dL, 45.3%, and 47.5 · 103/μL for the reference formulation. The mean reticulocyte counts slowly reached Tmax for both formulations at a median of 120 hours after administration (test formulation, 120.0 hours [range, 95.5–240.8 hours]; reference formulation, 120.1 hours [range, 72.0–240.5 hours]). The mean (SD) maximum reticulocyte counts for the test and reference formulations were 77.7 (12.2) · 103/μL and 80.7 (15.2) · 103/μL, respectively; values for area under the effect curve to the last observation (AUEC0–last) were 14,781.5 (2439.2) · 103/μL · h and 14,783.8 (2415.4) · 103/μL · h. The 2 agents did not exhibit any significant differences in maximum reticulocyte counts or AUEC0–last. During the study, a total of 6 AEs were reported, which were mild in severity. After the administration of test formulation, 1 case each of rhinorrhea, epigastric discomfort, and joint sprain (left ankle) were reported. After the administration of reference formulation, 2 cases of rhinorrhea and 1 case of cough were reported. Conclusion: In this small, selected group of healthy male volunteers, there were no significant differences in pharmacokinetic parameters or effects on reticulocytes between a test formulation and a reference formulation of recombinant human erythropoietin.

We investigated genetic polymorphisms in the pregnane X receptor (NR1I2) in Korean individuals (n = 83) and the effects of NR1I2 genotypes on rifampin-mediated induction of bupropion hydroxylation. The pharmacokinetics of bupropion and hydroxybupropion were evaluated after an oral dose of bupropion (150 mg) administered before and after rifampin treatment for 7 days in 35 healthy subjects. The area under the time-concentration curve (AUC) ratio of hydroxybupropion to bupropion in CYP2B6*6 carriers was significantly lower than that in CYP2B6*6 noncarriers in both the basal and rifampin-induced states (p = 0.012). Among the CYP2B6*6 carriers (n = 13), the NR1I2 TGT (-25385T + g.7635G + g.8055T) carriers exhibited a significantly lower AUC ratio, representing the CYP2B6 hydroxylation activity, compared with the TGT noncarriers, in the induced state (11.9 versus 20.3, p = 0.045). The percent difference in the AUC ratio between the basal and induced states was also significantly different (212% versus 58.8%, p = 0.006). However, no significant difference was observed among the NR1I2 TGT genotypes for the CYP2B6*6 noncarriers (n = 22). In conclusion, it is suggested the NR1I2 TGT genotype decreases the bupropion hydroxylation induced by treatment with rifampin, particularly in CYP2B6*6 carriers.

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.

Three kinds of herbal medicines, commonly used in Korea, Angelicae tenuissima radix, Angelicae dahuricae radix and Scutellariae radix were studied to evaluate their effect on cytochrome P450 (CYP) activities in healthy volunteers. A total of 24 healthy male volunteers were assigned to one of three parallel herbal treatment groups, each consisting of eight volunteers. A cocktail of probe drugs for CYP enzymes was orally administered before and after multiple administrations of herbal medicines, three times a day for 13 days. Probe drugs used to measure CYP activities were caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4). The probe drugs and their metabolites were quantified in plasma or urine using HPLC or LC-MS/MS. Changes in each CYP activity was evaluated by metabolic ratio of the probe drug (concentration ratio of metabolite to parent form at reference time point) following the herbal medication period, compared to the baseline values. A. dahuricae radix significantly decreased CYP1A2 activity to 10% of baseline activity (95% CI: 0.05-0.21). S. radix also showed significant changes in CYP2C9 and CYP2E1 activities. Compared to baseline values, the metabolic activities of losartan were decreased to 71% (0.54-0.94). In addition, S. radix showed a 1.42-fold (1.03-1.97) increase in chlorzoxazone metabolic activity. However, CYP activities were not meaningfully influenced by A. tenuissima radix. Changes in certain CYP activities were observed after the administration of S. radix and A. dahuricae radix in healthy volunteers. Therefore, herbal medicines containing S. radix or A. dahuricae radix are candidates for further evaluation of clinically significant CYP-mediated herb-drug interactions in human beings.

Background: Ticlopidine is an antiplatelet agent used for the prevention of vascular accidents. In clinical practice in Korea, ginkgo extract may be administered along with ticlopidine to enhance the inhibition of platelet aggregation. Objective: To meet the requirements for marketing a combined fixed-dose formulation in Korea, the investigators compared the pharmacokinetic characteristics of ticlopidine in a combined fixed-dose tablet of ticlopidine/ginkgo extract with the concomitant administration of ticlopidine and ginkgo extract tablets. Methods: An open-label, 2-period, 2-treatment, single-dose, randomized-sequence crossover study was conducted in healthy Korean male volunteers. Subjects were randomly allocated to 2 sequence groups. In one period, a combined ticlopidine 250 mg/ ginkgo extract 80-mg fixed-dose tablet was administered and, in the other period, ticlopidine 250-mg and ginkgo extract 80-mg tablets were concomitantly administered. A 7-day washout separated the 2 periods. For analysis of pharmacokinetic properties, including C max , T max , t ½ , AUC 0−∞ , and AUC 0−last , serial blood sampling was performed up to 48 hours after study drug administration during each period. Ticlopidine concentrations in plasma were determined by a validated method using LC-MS/MS. In order for the 2 treatments to be considered bioequivalent, the 90% CI of the geometric means ratios for C max and AUC needed to be between 80% and 125%. Bleeding time was determined before dosing (0 hour) and at 5 and 24 hours after dosing. Adverse events (AEs) were identified through patient interview, recording of blood pressure, heart rate, and body temperature, physical examination, 12-lead ECG, and laboratory assessments. Results: Twenty-four healthy Korean male subjects (mean [range] age, 23.9 [22–38] years; height, 174.0 [162–184] cm; weight, 67.4 [56–80] kg) completed the study. Median (range) T max of ticlopidine was 1.5 (0.5–2.0) hours in both groups. The mean (SD) t ½ of ticlopidine in the combined fixed-dose formulation and the concomitant administration groups was 19.5 (3.4) and 19.0 (3.3) hours after study drug administration, respectively. The geometric means ratios of ticlopidine AUC 0−last , AUC 0–∞ , and C max between the combined fixed-dose formulation and concomitant administration were 1.04 (90% CI, 0.96–1.13), 1.04 (90% CI, 0.96–1.13), and 1.09 (90% CI, 0.96–1.23), respectively. The mean (SD) bleeding time at predose (0), and 5 and 24 hours after dose administration was 4.5 (1.6) to 5.4 (1.7) minutes in the combined fixed-dose formulation group and 4.4 (1.6) to 5.1 (1.1) minutes in the concomitant administration group. Five subjects (3 in the combined fixed-dose formulation group and 2 in the concomitant administration group) had bleeding times >8 minutes, but this was not considered to be clinically significant. A total of 24 AEs were reported in 13 of 24 subjects: nausea (3 cases), diarrhea (3), dizziness (3), epigastric discomfort (2), headache (2), rhinorrhea (2), purulent sputum (2), dyspepsia (1), upper abdominal pain (1), cough (1), pharyngolaryngeal pain (1), oropharyngeal swelling (1), dysphonia (1), and dysphagia (1). All were considered mild or moderate in nature. There was no statistically significant difference between the 2 treatments in the number of AEs or in the number of subjects who reported an AE. Conclusion: Administration of a single dose of a combined fixed-dose formulation of ticlopidine 250 mg/ ginkgo extract 80-mg tablets and concomitant administration of ticlopidine and ginkgo extract tablets did not result in statistically significant differences in the pharmacokinetics of ticlopidine in these healthy Korean male volunteers

Background: Mirodenafil is a phosphodiesterase type 5 (PDE-5) inhibitor developed for the treatment of erectile dysfunction. Mirodenafil has the possibility of being administered with alcohol. Objective: This study assessed the hemodynamic effects and pharmacokinetic properties of mirodenafil administered with alcohol. Methods: This single-dose, randomized-sequence, open-label, crossover study was conducted in healthy male volunteers at the Clinical Trials Center, Seoul National University Hospital, Seoul, Korea. Volunteers were randomly allocated to 1 of 3 randomized-sequence groups, each of which consisted of 3 administration phases, each separated by a 1-week washout period: oral mirodenafil 100 mg, alcohol 0.5 g/kg, and both. Vital signs (systolic blood pressure [SBP], dia-stolic BP [DBP], and pulse rate) were measured before (baseline) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours after administration. Because volunteers were given a standardized meal at 4 hours after mirodenafil and/or alcohol administration, hemody-namic results were assessed using the maximum decrease from baseline during a period of up to 4 hours after administration. For pharmacokinetic assessment, serial blood samples were collected before (baseline) and at 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after administration. Tolerability was assessed using monitoring of adverse events (AEs), clinical laboratory parameters, and results of 12-lead electrocardiography. Results: A total of 20 subjects participated in the study (mean [range] age, 25.5 years [20–41 years]; weight, 69.8 kg [57.4–87.2 kg]; and height, 174.7 cm [168–186 cm]). Up to 4 hours after the administration of mirodenafil, alcohol, and mirodenafil + alcohol, the mean (SD) maximum decreases in SBP were 8.5 (3.5), 13.5 (7.8), and 15.1 (6.7) mm Hg, respectively, and the maximum decreases in DBP were 6.4 (4.8), 13.3 (7.4), and 13.8 (5.2) mm Hg. Simultaneous administration of mirodenafil + alcohol was associated with additional mean (95% CI) decreases in SBP and DBP of 1.7 mm Hg (−6.0 to 2.6 mm Hg) and 0.6 mm Hg (−4.7 to 3.6 mm Hg) compared with alcohol alone. Pharmacokinetic parameters of mirodenafil were not significantly different when the drug was administered with or without alcohol. The mean (SD) AUC 0−t values were 842.0 (434.7) ng/mL/h with mirodenafil and 833.4 (398.2) ng/mL/h with mirodenafil + alcohol. The most common AEs considered at least possibly related to study drug were nasal congestion (7 subjects [35%]), headache (3 [15%]), nausea (1 [5%]), and hiccups (1 [5%]). Conclusions: The concurrent administration of mirodenafil with alcohol was not associated with clinically significant hemodynamic changes in these healthy male volunteers in Korea. The pharmacoki-netics of mirodenafil were not significantly altered by this concurrent administration. Mirodenafil administered with alcohol had a tolerability profile comparable to that of mirodenafil alone.

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.

Background We developed a method for detecting important SLCO1B1 polymorphisms and compared the haplotype frequencies in 3 Asian populations. Methods We designed a duplex pyrosequencing assay to detect simultaneously the 388A > G and 521T > C variants of SLCO1B1 ; this method can identify SLCO1B1⁎1b , SLCO1B1⁎5 , and SLCO1B1⁎15 . The method was validated by direct sequencing of 96 Korean subjects. In addition, duplex genotyping and the monoplex method were compared and validated with 469 Korean subjects. To characterize the haplotype frequencies based on the 2 polymorphisms, we genotyped 106 Chinese and 104 Vietnamese subjects, as well as Korean subjects, using the new method. Results The results showed 100% concordance among the monoplex and duplex pyrosequencing assays and direct sequencing method. The allele frequencies were similar in the 3 Asian populations: the most common allele was SLCO1B1⁎1b , while SLCO1B1⁎5 was rare or absent. The frequencies of functional SLCO1B1⁎15 alleles differed statistically between Chinese (8.2%) and Korean (14.0%) and Vietnamese (16.3%) ( p χ 2 -test). Conclusions The duplex pyrosequencing assay appears to be an accurate, rapid, and cost-effective genotyping method to detect major SLCO1B1 important alleles in Asian populations.

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

The aim of the present study was to evaluate the effects of polymorphisms in dopamine D2 receptor (DRD2) and cytochrome P450 (CYP) 2D6 genes on delta EEG power response to aripiprazole in healthy male volunteers. Seventeen volunteers were recruited according to the DRD2 Taq1A genotype, and separated into the following groups: homozygous wild-type (A2/A2, n = 7), heterozygous (A2/A1, n = 5) and homozygous variant-type (A1/A1, n = 5) groups. After enrollment in this study, they were genotyped for CYP2D6. The volunteers received single 10 mg oral doses of aripiprazole, in accordance with an open-label parallel group study design. Plasma levels of aripiprazole and its metabolite were determined and EEGs were obtained simultaneously. The pharmacodynamic parameter was absolute delta power in the Cz channel. The changes of delta power were not different according to DRD2 Taq1A genotypes. As to the CYP2D6 allele, the subjects had the following CYP2D6 genotypes: *10/*10 (n = 4), *1/*10 (n = 5), *1/*5 (n = 2), *1/*1 (n = 3), *2/*41 (n = 1), *2/*2 (n = 1), *2N/*10 (n = 1). Subjects exhibiting the *1/*5 and *1/*10 genotypes showed a trend toward high area under the plasma aripiprazole concentration-time curve (AUC), which was linearly related to area under the EEG response-time curve (AUEC). Our results demonstrate a need for further evaluation of the CYP2D6 genotypic effect on the pharmacodynamics of aripiprazole.

We examined whether common single nucleotide polymorphisms (SNP) in SULT1A1 (c.779G>A, *14A>G, and *85C>T) and SULT1E1 (IVS1-447C>A, IVS4-1653T>C, and *959G>A) genes influenced the risk and survival of breast cancer. Our study population consisted of 989 histologically confirmed sporadic breast cancer patients and 1,054 controls without history of cancer recruited from three teaching hospitals in Seoul. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by logistic regression model. In the survival analysis for 529 breast cancer patients with completed treatments, the hazard ratios (HR) were calculated with Cox proportional hazard model. Women with the SULT1E1 *959 GA/AA genotype had a moderately decreased breast cancer risk compared with those with the GG genotypes (OR, 0.8; 95% CI, 0.70-1.00). When the haplotypes were considered, the homozygous *959 AA genotype together with the IVS4-1653 T>C base change (CTA-CCA haplotype) was associated with halved breast cancer risk (OR, 0.5; 95% CI, 0.24-0.88) compared with the wild type CTG-CTG haplotype. No other significant overall association was observed between the SULT1A1 and SULT1E1 SNPs nor haplotypes and breast cancer risk. When stratified by survival, patients with the SULT1E1 IVS4-1653 TC/CC genotypes showed a >3-fold risk of recurrence (HR, 3.2; 95% CI, 1.39-7.48) compared with those with the TT genotype. Moreover, when the haplotypes were considered, the SULT1E1 *959 G>A base change together with the IVS4-1653 T>C base change (CTG-CCA haplotype) was associated with a >4-fold risk of breast cancer (OR, 4.2; 95% CI, 1.15-15.15). These findings suggest that genetic polymorphisms of SULT1E1 are associated with increased risk and a disease free survival of breast cancer in Korean women.

Purpose: The rationale for developing an alternative paclitaxel formulation concerns Cremophor EL-related side effects, and a novel paclitaxel delivery system might augment its therapeutic efficacy. Genexol-PM is a polymeric micelle formulated paclitaxel free of Cremophor EL. A phase I study was performed to determine the maximum tolerated dosage, dose-limiting toxicities, and the pharmacokinetic profile of Genexol-PM in patients with advanced, refractory malignancies. Experimental Design: Twenty-one patients were entered into the study. Genexol-PM was i.v. administered over 3 h every 3 weeks without premedication. The Genexol-PM dose was escalated from 135 mg/m2 to 390 mg/m2. Results: All of the patients were evaluable for toxicity and response. Acute hypersensitivity reactions were not observed. Neuropathy and myalgia were the most common toxicities. During cycle 1, grade 3 myalgia occurred in 1 patient at 230 and 300 mg/m2, respectively. At 390 mg/m2, 2 of 3 patients developed grade 4 neutropenia or grade 3 polyneuropathy. Therefore, the maximum tolerated dosage was determined to be 390 mg/m2. There were 3 partial responses (14%) among the 21 patients. Of the 3 responders, 2 were refractory to prior taxane therapy. The paclitaxel area under the curve from time 0 to infinity and peak or maximum paclitaxel concentration seemed to increase with escalating dose, except at 230 mg/m2, which suggests that Genexol-PM has linear pharmacokinetics. Conclusion: The main dose-limiting toxicities were neuropathy, myalgia, and neutropenia, and the recommended dosage for a phase II study is 300 mg/m2. Genexol-PM is believed to be superior to conventional paclitaxel in terms of the obviation of premedication and the delivery of higher paclitaxel doses without additional toxicity.

A sensitive high-performance liquid chromatographic (HPLC) method with ultraviolet absorption detection (292 nm) was developed and validated for the determination of the new phosphodiesterase V inhibitor, DA-8159 (DA), in human plasma and urine. A single step liquid–liquid extraction procedure using ethyl ether was performed to recover DA and the internal standard (sildenafil citrate) from 1.0 ml of biological matrices combined with 200 μl of 0.1 M sodium carbonate buffer. A Capcell Pak C18 UG120 column ( 150 mm ×4.6 mm I.D., 5 μm) was used as a stationary phase and the mobile phase consisted of 30% acetonitrile and 70% 20 mM potassium phosphate buffer (pH 4.5) at a flow rate of 1.0 ml/min. The lower limit for quantification was 5 ng/ml for plasma and 10 ng/ml for urine samples. Within- and between-run accuracy and precision were ≤15 and ≤10%, respectively, in both plasma and urine samples. The recovery of DA from human plasma and urine was greater than 70%. Separate stability studies showed that DA is stable under the conditions of analysis. This validated assay was used for the pharmacokinetic analysis of DA during a phase I, rising dose study.

♦ Objective This study was performed to elucidate the pharmacokinetic profiles of antimycobacterial regimens for peritoneal dialysis patients. ♦ Patients Nine patients on maintenance continuous ambulatory peritoneal dialysis (CAPD) were included in this study. ♦ Methods After administering a conventional oral dose of antituberculosis medications, we measured plasma and peritoneal fluid concentrations of isoniazid by fluorometry, and rifampin and pyrazinamide by high performance liquid chromatography. The assay data were subjected to pharmacokinetic analysis. ♦ Results Average peak plasma concentrations of isoniazid, rifampin, and pyrazinamide were 3.3 mg/L, 6.5 mg/L, and 30.9 mg/L, respectively, all of which much exceed the minimum inhibitory concentration (MIC) for Mycobacterium tuberculosis. Peritoneal fluid concentrations of isoniazid and pyrazinamide were maintained well above the MICs for M. tuberculosis; however, peritoneal fluid concentration of rifampin was below the therapeutic range most of the time. ♦ Conclusion For the treatment of systemic or pulmonary tuberculosis in CAPD patients, no dose adjustments are required for isoniazid, rifampin, or pyrazinamide. On the contrary, for the treatment of tuberculous peritonitis, oral rifampin therapy is not expected to be effective because of its low peritoneal fluid concentration.

To evaluate the effect of the CYP2D6 genotype on the pharmacokinetics of tropisetron in healthy Korean subjects. A single 5-mg capsule of tropisetron was administered orally to 13 healthy subjects. Plasma concentrations were determined by validated HPLC procedures and data were analyzed by using noncompartmental linear PK methods. Four alleles, CYP2D6*1, CYP2D6*2 ×2, CYP2D6*5, and CYP2D6*10, were identified by PCR. Thirteen subjects, consisting of two homozygous carriers of the wild type allele (*1/*1), four heterozygous carriers of poor metabolizer (PM)-associated allele (*1/*10), six homozygous carriers of PM-associated alleles (four with *10/*10 and two with *5/*10), and one carrier of a duplicated allele *1/*2 ×2. All tested pharmacokinetic parameters (AUCinf, AUCinf NL70, Cmax, CmaxNL70, T1/2, and Tec) were significantly different among four different genotypic groups. The mean AUCs of carriers with the heterozygous PM-associated allele and the homozygous PM-associated allele were 1.9- and 6.8-higher than those of carriers with the wild type allele, respectively. In contrast, the mean AUC of carriers with a duplicated allele was 0.5-fold lower than that of those carriers with the wild type allele. The presence of CYP2D6*5, CYP2D6*10, and CYP2D6*2 ×2 has an important impact on the pharmacokinetics of tropisetron, which may influence clinical response to tropisetron therapy.

To evaluate the association between genetic polymorphism of GSTM1, GSTT1 and development of bladder cancer, a hospital-based case-control study was conducted in South Korea. The study population consisted of 232 histologically confirmed male bladder cancer cases and 165 male controls enrolled from urology departments with no previous history of cancer or systemic diseases in Seoul during 1997-1999. The GSTM1 null genotype was significantly associated with bladder cancer (OR: 1.6, 95% CI: 1.0-2.4), whereas the association observed for GSTT1 null genotype did not reach statistical significance (OR: 1.3, 95% CI: 0.9-2.0). There was a statistically significant multiple interaction between GSTM1 and GSTT1 genotype for risk of bladder cancer (P=0.04); the risk associated with the concurrent lack of both of the genes (OR: 2.2, 95% CI: 1.2-4.3) was greater than the product of risk in men with GSTM1 null/GSTT1 present (OR: 1.3, 95% CI: 0.7-2.5) or GSTM1 present/GSTT1 null (OR: 1.1, 95% CI: 0.6-2.2) genotype combinations.

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.

Objective Our objective was to investigate ethnic differences in the oral pharmacokinetics of nifedipine and erythromycin, both typical cytochrome P4503A (CYP3A) substrates, in Koreans and Caucasians and to identify the nature of any correlations between the pharmacokinetic parameters of the two drugs. Methods Twenty healthy male volunteers (10 Koreans and 10 Caucasians) received single oral doses of nifedipine (10 mg) or erythromycin (500 mg) in a randomized 2-way crossover study. Pharmacokinetic evaluations were performed, and parameters were compared for the two ethnic groups. During the nifedipine study period, hemodynamic measurements were conducted to determine the pharmacodynamic relevance of the pharmacokinetic differences. Results Koreans showed area under the concentration-time curves (AUCs) for both drugs that were 1.6 to 1.7 times higher than those of Caucasians. This difference decreased to 1.3 when normalized for body weight. Significant correlation between the AUCs of the two drugs was not evident. Hemodynamic changes after nifedipine administration paralleled those of the pharmacokinetic differences, with significantly greater decreases in blood pressure and total peripheral resistance noted in Koreans. Conclusions Koreans showed significantly lower oral clearances of nifedipine and erythromycin, probably because of genetic differences attributed to the CYP3A enzymes. Clinical Pharmacology & Therapeutics (2001) 70, 228–236; doi: 10.1067/mcp.2001.117703

Background Moclobemide, an antidepressant with selective monoamine oxidase-A inhibitory action, is known to be metabolized by CYP2C19 and is also reported to be an inhibitor of CYP2C19, CYP2D6, and CYP1A2. To confirm the involvement of CYP2C19, we performed a pharmacokinetic interaction study. Methods The effect of omeprazole on the pharmacokinetics of moclobemide was studied in 16 healthy volunteers. The volunteer group comprised 8 extensive metabolizers and 8 poor metabolizers of CYP2C19, which was confirmed by genotyping. Subjects were randomly allocated into two sequence groups, and a single-blind, placebo-controlled, two-period crossover study was performed. In study I, a placebo was orally administered for 7 days. On the eighth morning, 300 mg of moclobemide and 40 mg of placebo were coadministered with 200 mL of water, and a pharmacokinetic study was performed. During study II, 40 mg of omeprazole was given each morning instead of placebo, and pharmacokinetic studies were performed on the first and eighth day with 300 mg of moclobemide coadministration. Results The inhibition of moclobemide metabolism was significant in extensive metabolizers even after a single dose of omeprazole. After daily administration of omeprazole for 1 week, the pharmacokinetic parameters of moclobemide and its metabolites in extensive metabolizers changed to values similar to those in poor metabolizers. In poor metabolizers, no remarkable changes in the pharmacokinetic parameters were observed. Conclusion Our results show that CYP2C19 is an important enzyme in the elimination of moclobemide and that it is extensively inhibited by omeprazole in extensive metabolizers, but not in poor metabolizers. Clinical Pharmacology & Therapeutics (2001) 69, 266–273; doi: 10.1067/mcp.2001.114231

The aim of this cross-over study was to investigate whether albumin infusion before furosemide administration could potentiate the diuretic action of furosemide. Seven patients with nephrotic syndrome were given the following infusions in random order on two separate days: 1) a sham solution followed by 160 mg of furosemide, 2) 100 ml of 20% human albumin followed by 160 mg of furosemide. Urine and serum furosemide concentrations were measured by high-performance liquid chromatography. The increment of urine volume was greater in albumin preinfusion than in furosemide alone. However, the increments of sodium and chloride excretions between furosemide alone and albumin preinfusion were not different. No significant differences in the pharmacokinetic parameters between the two treatments were observed: area under the concentration-time curve (AUC: 12.7+/-2.2 vs 15.1+/-4.4 g/ml hr), total plasma clearance (253+/-41 vs 256+/-54 ml/min), volume of distribution (341+/-34 vs 494+/-153 ml/kg), elimination half life (4.0+/-1.1 vs 4.6+/-0.8 hr), and urine furosemide excretion of the administered amount (16.5+/-7.3 vs 7.5+/-1.6%). In conclusion, these data show that albumin preinfusion potentiated diuresis, but not natriuresis, of furosemide without any change in the pharmacokinetics of the agent in patients with nephrotic syndrome.

Objective To evaluate the relationship between the metabolic ratio (MR) of metoprolol, CYP2D6*10B genotype, and the disposition of paroxetine in Korean subjects. Methods A single 40–mg dose of paroxetine was administered orally to one poor metabolizer and 15 healthy subjects recruited from 223 Korean extensive metabolizers whose phenotypes were predetermined by use of the metoprolol MR. Genotypes were determined by allele-specific polymerase chain reaction and the GeneChip microarray technique. Pharmacokinetic parameters were estimated from plasma concentrations of paroxetine for more than 240 hours after the oral dose. Results The oral clearance and area under the plasma concentration versus time curve (AUC) of paroxetine were best described by a nonlinear relationship with metoprolol MR at correlation coefficients of 0.82 and 0.91, respectively (P < .05). Nine extensive metabolizer who were either homozygous or heterozygous for CYP2D6*10B had significantly lower oral clearance values of paroxetine than six extensive metabolizers with CYP2D6*1/*1. The AUC of paroxetine in subjects who were homozygous for CYP2D6*10B (666.4 ± 169.4 ng/mL · h) was significantly greater than that of subjects who were homozygous for the wild type (194.5 ± 55.9 ng/mL · h). Unexpectedly, the average AUC of subjects who were heterozygous for CYP2D6*10B was greater with wide variation (789.8 ± 816.9 ng/mL · h) than that of subjects who were homozygous CYP2D6*10B/*10B mainly because of two atypical subjects whose metoprolol MR was not associated with the CYP2D6*10B genotype and who showed greater AUC and lower oral clearance than subjects with homozygous CYP2D6*10B. Conclusions The CYP2D6 activity measured by metoprolol MR was a strong predictor of paroxetine disposition in Korean extensive metabolizers. In general, the extensive metabolizers with the CYP2D6*10B allele seemed to have higher plasma concentrations of paroxetine than extensive metabolizers with the wild-type CYP2D6 genotype. However, quantitative prediction of paroxetine disposition from the CYP2D6*10B genotype alone was not perfect because several Korean extensive metabolizers had metoprolol MRs that were not associated with the genotype. Clinical Pharmacology & Therapeutics (2000) 67, 567–576; doi: 10.1067/mcp.2000.106128

Rationale: CNS-active drugs produce specific electroencephalographic changes and the concentration-effect relationship of antipsychotics may be elucidated by adopting electroencephalography (EEG) as an effect measurement tool. Objective: The purpose of the present study was to determine the concentration-effect relationship of risperidone by assessing the EEG effect after oral administrations of single dose risperidone in healthy young males. Methods: Nine healthy male volunteers received a 1 mg single oral dose of risperidone according to a placebo controlled crossover design. Plasma levels of risperidone and its active metabolite 9-hydroxyrisperidone were measured by radioimmunoassay. Quantitative EEG parameters were obtained for each of four frequency bands through spectral EEG analysis. The difference in the absolute power in the delta frequency band for the F3 lead between risperidone and placebo was used as a drug effect parameter. For pharmacokinetic-pharmacodynamic modeling, the hypothetical effect compartment kinetically linked to plasma by a first-order process was postulated. All curve fittings were done with the non-linear curve-fitting program NONLIN. Results: Our results showed that absolute powers in delta and theta frequency bands were higher for risperidone administration than for placebo at all EEG leads, and the maximum effects were detected at about 3 h after administration of the drug. The hysteresis loop was observed in the plot of plasma concentration of risperidone or sum of risperidone and 9-hydroxyrisperidone (Cp) versus EEG effect for each subject. A linear model adequately described the relationship between the effect compartment concentrations (Ce) and EEG effects, and the two limbs of hysteresis in the Cp-effect plot were collapsed in the Ce-effect plot for risperidone or risperidone plus 9-hydroxyrisperidone. Conclusion: The increases of absolute power for delta and theta frequency bands of EEG were induced by single oral administration of risperidone. The linear PK-PD model fit well with the relationship between effect compartment concentrations (Ce) and EEG effects of risperidone.

A rapid, simple method for the measurement of paroxetine in human plasma by reversed-phase high-performance liquid chromatography (HPLC) with fluorescence detection is described. This method includes only one-step extraction of paroxetine and dibucaine, an internal standard, with chloroform. Their recoveries were around 90%. The mobile phase, 10 m M phosphate buffer–acetonitrile (40:60, v/v) was eluted isocratically. Between- and within-day coefficients of variation were in the range of 1.9–9.4% and 2.3–13.3%, respectively. The detection limit was 0.2 ng/ml. The method we describe can be easily applied to the measurement of plasma paroxetine concentration for pharmacokinetic studies as well as for therapeutic drug monitoring in patients taking paroxetine.

The effect of exposure time on the in vitro cytotoxicity of a new platinum complex, cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolan e]platinum(II) (SKI 2053R) and cisplatin (CDDP) toward two human lung-adenocarcinoma cell lines (PC-9, PC-14) and two human stomach-adenocarcinoma cell lines (KATO III, MKN-45) was investigated by variation of the exposure time (1, 4, 12, and 24 h) and drug concentration to yield a constant product of drug concentration times exposure time (C x T). Exposure of cancer cells to low concentrations of SKI 2053R for 12 or 24 h resulted in a greater killing effect than did 1- or 4-h exposure to 24- or 6-fold higher concentrations; the inhibitory effects of SKI 2053R on the colony formation of all tumor cell lines except for KATO III were significantly increased with increasing exposure time (P < 0.05). However, the inhibitory effects of CDDP against all tumor cell lines tested except for PC-14 were inversely correlated with increasing exposure time (P < 0.05). The intracellular accumulation of SKI 2053R and CDDP was measured under the same conditions used in the cell-survival assay using MKN-45 cells. The amount of platinum accumulated from SKI 2053R into MKN-45 cells was greater for the treatment involving low concentrations and long-term exposures (12 and 24 h) than for that using high concentrations and short-term exposures (1 and 4 h) at the constant C x T values; however, the increased accumulation of CDDP was more prominent as the concentration was increased, even if the exposure time became shorter. The pharmacokinetics studies of SKI 2053R following 1-, 4-, 12-, and 24-h infusions were performed in beagle dogs. A single dose of SKI 2053R (5.0 mg/kg) was successively given over various infusion periods to three beagle dogs at 3-week intervals. The peak levels of ultrafiltrable platinum observed for SKI 2053R at the 1-, 4-, 12-, and 24-h infusions were 3.10+/-0.49 (mean +/- SD), 1.24+/-0.06, 0.43+/-0.07, and 0.25+/-0.04 microg/ml, respectively. The mean binding ratios of platinum from SKI 2053R to plasma protein at the end of 1-, 4-, 12-, and 24-h infusions were approximately 91%, 73%, 53%, and 51%, respectively. The steady-state level of free platinum was maintained during long-term infusions (12 and 24 h) after short periods (1-3 h) from the start of the infusion. This study strongly suggests that the therapeutic efficacy of SKI 2053R given by continuous long-term infusion should be investigated in future clinical studies.

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.

Background PT302 is a sustained-release exenatide under clinical development for the treatment of type 2 diabetes mellitus. Objective The aim of this study was to evaluate the pharmacokinetic properties, pharmacodynamic properties, and tolerability of PT302 after a single subcutaneous injection in healthy individuals. Methods A dose-block randomized, double-blind, placebo-controlled, dose-escalating study (0.5, 1, 2, and 4 mg) was performed in 34 healthy individuals. The plasma concentrations of exenatide in serial blood samples were quantified for 56 days after dosing with an exendin-4 fluorescent immunoassay kit. Noncompartmental analysis was performed to assess the pharmacokinetic characteristics of PT302. Oral glucose tolerance tests were repeated weekly until day 42; the concentrations of serum glucose, serum C-peptide, plasma insulin, and plasma glucagon were measured for 2 hours to evaluate the pharmacodynamic characteristics of PT302. Clinical laboratory tests, vital signs, physical examinations, 12-lead ECGs, and adverse events were monitored to evaluate the safety profile and tolerability. Results PT302 exhibits a biphasic pharmacokinetic profile, with the initial peak occurring 2 hours after administration. PT302 was quantifiable in the plasma until days 23, 30, 32, and 55 (median) in the 0.5-mg, 1-mg, 2-mg, and 4-mg dosage groups of PT302, respectively. Systemic exposure increased proportionally to the dose during the entire dose range investigated. The pharmacodynamic effect of PT302 on the postprandial response of insulin and C-peptide was significant on days 21 to 28 at the 4-mg dose and was positively correlated with plasma exenatide concentrations, whereas the correlations with glucose and glucagon were not significant. The fasting levels of these pharmacodynamic biomarkers were not altered by PT302. The most common adverse events were injection site induration and pruritus related to inflammatory foreign body reaction, which were mild and spontaneously resolved within several weeks. Conclusion The pharmacokinetic characteristics of PT302 were biphasic and dose proportional. A single 4-mg dose of PT302 significantly increased the insulin and C-peptide response to oral glucose loading and was well tolerated in healthy individuals. ClinicalTrials.gov identifier: NCT00964262.

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.

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.

We assessed the changes of plasma haloperidol concentrations and clinical responses repeatedly up to 4 weeks after coadministration or discontinuation of rifampin in 12 schizophrenic patients taking haloperidol alone (group I) and 5 patients taking haloperidol and antituberculotic drugs (group II). After coadministration of rifampin in group I, daily trough haloperidol concentrations rapidly decreased and reached 63% of baseline level by day 3, 41.3% by day 7, and 30% by day 28. On the other hand, after discontinuation of rifampin in group II, plasma haloperidol concentration increased to 140.7% of baseline level by day 3, 228.7% by day 7, and 329% by day 28. In this study, a 30% or greater change in the clinical rating scale was considered a positive clinical response of the drug interaction. Using this criterion, 50% of the group I subjects responded according to the Brief Psychiatric Rating Scale (BPRS) total score, and 25% responded according to the BPRS subscale for psychiatric symptoms. No positive responses were observed in group II patients. These results strongly suggest that rifampin interacts with the clinical effects as well as the plasma concentrations of coadministered haloperidol, and careful monitoring should be considered when coadministration or discontinuation of rifampin is needed in a schizophrenic patient taking haloperidol.

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.

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.

The effects of aripiprazole on cognitive function are obscure, possibly due to the difficulty in disentangling the specific effects on cognitive function from effects secondary to the improvement of other schizophrenic symptoms. This prompts the necessity of using an intermediate biomarker relating the drug effect on the brain to change in cognitive function.To explore the effect of aripiprazole on cognitive function, we measured changes in frontal metabolism as an intermediate biomarker and sought to determine its relationship with D2 receptor occupancy and changes in working memory.Fifteen healthy male volunteers participated in the study. Serial positron emission tomography (PET) scans with [(11)C]raclopride and [(18) F]FDG were conducted 1 day before and 2 days after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [(18) F]FDG scan.The mean (±SD) D2 receptor occupancies were 22.2 ± 16.0 % in the 2 mg group, 35.5 ± 3.6 % in the 5 mg group, 63.2 ± 9.9 % in the 10 mg group and 72.8 ± 2.1 % in the 30 mg group. The frontal metabolism was significantly decreased after the administration of aripiprazole (t = 2.705, df = 14, p = 0.017). Greater striatal D2 receptor occupancy was related to greater decrease in frontal metabolism (r = -0.659, p = 0.010), and greater reduction in frontal metabolism was associated with longer reaction times (r = -0.597, p = 0.019) under the greatest task load.Aripiprazole can affect cognitive function and alter frontal metabolic function. The changes in these functions are linked to greater D2 receptor occupancy. This suggests that it may be important to find the lowest effective dose of aripiprazole in order to prevent adverse cognitive effects.

Both mirodenafil, a phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction, and tamsulosin, a selective α(1A)-adrenergic receptor antagonist for the treatment of benign prostatic hyperplasia, have mild vasodilational effects.The aim of this study was to investigate the effect of mirodenafil on the hemodynamics of healthy volunteers who were administered tamsulosin.Healthy, Korean normotensive male volunteers were enrolled in a randomized, placebo-controlled, double-blind, 2-sequence, 2-period crossover study. Mirodenafil 100 mg or placebo was administered orally after pretreatment with tamsulosin 0.2 mg once daily for 7 days in each period, with a 1-week washout period. Blood pressure (BP) and pulse rate (PR) in supine and standing positions were measured repeatedly before and until 24 hours after the administration of mirodenafil or placebo. The mean differences from the baseline values of the maximum changes of BP and PR, which were measured at 4 and 24 hours, were analyzed by using a mixed-effects model.Eighteen subjects (mean [SD] age, 26.8 [3.9] years; weight, 65.5 [7.0] kg) were administered any trial medication, and 16 of them completed the study. For 4 hours/24 hours after mirodenafil administration, the mean maximal changes from baseline versus placebo in supine systolic BP, diastolic BP, and PR were -1.0 mm Hg (95% CI, -4.2 to 2.2) (P = 0.53)/-1.2 mm Hg (95% CI, -5.3 to 2.9) (P = 0.56), -2.1 mm Hg (95% CI, -4.6 to 0.4) (P = 0.10)/-1.1 mm Hg (95% CI, -3.9 to 1.6) (P = 0.39), and 7.2 beats/min (95% CI, 4.7 to 9.6) (P0.05)/4.8 beats/min (95% CI, 1.4 to 8.1) (P0.05), respectively. Those changes in a standing position were -4.0 mm Hg (95% CI, -8.9 to 0.9) (P = 0.10)/-4.3 mm Hg (95% CI, -10.0 to 1.5) (P = 0.13), -1.1 mm Hg (95% CI, -4.9 to 2.7) (P = 0.54)/-1.9 mm Hg (95% CI, -5.5 to 1.7) (P = 0.27), and 10.7 beats/min (95% CI, 4.4 to 16.9) (P0.05)/6.0 beats/min (95% CI, 0.7 to 11.3) (P0.05), respectively. A total of 33 adverse events (AEs) were reported in 9 of 18 subjects. The number of subjects with AEs (P = 0.13) and the number of AEs (P = 0.26) were not significantly different between the 2 groups. The most common AEs were vasodilational symptoms, such as nasal congestion, headache, and flushing.The coadministration of mirodenafil 100 mg did not induce a significant decrease in BP when associated with an increase in PR in these healthy male Korean volunteers administered tamsulosin 0.2 mg compared with placebo. (Clinical Trial Registry, http://cris.cdc.go.kr/cris/en/: KCT0000117).

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 .