Bo-Hyung Kim

Safety, tolerability and pharmacokinetics of udenafil, a novel PDE-5 inhibitor, in healthy young Korean subjects

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 C(max) 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 (C(max)) 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 C(max) of udenafil increased supraproportionally with increasing dose upon single administration, but there was no significant drug accumulation upon multiple administrations.

Effect of CYP2C19 Polymorphism on the Pharmacokinetics of Voriconazole After Single and Multiple Doses in Healthy Volunteers

The current study assessed the influence of the CYP2C19 genotype on the pharmacokinetics and tolerability of voriconazole after single and multiple oral doses in healthy volunteers. Six subjects for the CYP2C19 homozygous extensive metabolizer (EMs), 6 for heterozygous extensive metabolizer (HEMs), and 6 for poor metabolizer (PMs) were enrolled, and their CYP2C9, CYP3A5, and MDR1 genotypes were analyzed. After a single intravenous infusion or single and multiple oral doses of 200 mg of voriconazole, plasma concentrations of voriconazole were measured. Bioavailability was not significantly different among the CYP2C19 genotypes. Voriconazole exposure in PMs was approximately 3 times higher compared with EMs after a single intravenous or oral dose. At steady state, the plasma concentration just before the next dosing and area under the concentration‐time curve from dosing to the time point of the next dosing for PMs were about 5 times and 3 times higher than EMs, respectively. These results suggest that the CYP2C19 genotype is the major determinant of the wide PK variability of voriconazole.

Pharmacokinetic interaction of flecainide and paroxetine in relation to the CYP2D6*10 allele in healthy Korean subjects

AIMS The objectives were to evaluate the effect of CYP2D6 genetic polymorphism on the pharmacokinetics of flecainide, and also on the extent of drug interaction with paroxetine as a CYP2D6 inhibitor after a single oral administration in healthy subjects. METHODS An open-label, two-period, single-sequence, cross-over study was performed in 21 healthy Korean male volunteers (seven for CYP2D6*1/*1 or *1/*2, group 1; seven for CYP2D6*1/*10, group 2; seven for CYP2D6*10/*10 or *10/*36, group 3). Subjects were administered 200 mg of flecainide on day 1. After a 7-day wash-out period, subjects were administered 20 mg of paroxetine from day 8 to 14, and 200 mg of flecainide on day 15. Blood sampling was performed up to 72 h after flecainide administration. RESULTS Terminal elimination half-life and mean residence time (MRT) were significantly different among three genotype groups after a single oral administration of flecainide (P = 0.021, 0.011, respectively). Area under the concentration-time curve, terminal elimination half-life and MRT increased significantly after paroxetine co-administration only in groups 1 and 2. CONCLUSIONS This study reports that the extent of drug interaction between flecainide and paroxetine is influenced by the CYP2D6*10 allele in healthy subjects, which is frequent in Asians.

Influence of Ginkgo biloba extract on the pharmacodynamic effects and pharmacokinetic properties of ticlopidine: An open-label, randomized, two-period, two-treatment, two-sequence, single-dose crossover study in healthy Korean male volunteers

BACKGROUND Ginkgo biloba extract is an herbal medicine used in the treatment of vascular disorders that may be coadministered with antiplatelet agents such as ticlopidine. Regulatory authorities requested evaluation of the pharmacodynamic and pharmacokinetic interactions between these entities, according to the drug-development guidance for fixed-dose combination formulations in Korea. OBJECTIVE This study was performed to evaluate the potential pharmacodynamic and pharmacokinetic interactions between ticlopidine and Ginkgo biloba extract. METHODS An open-label, randomized, 2-period, 2-treatment, 2-sequence, single-dose crossover study was conducted in healthy Korean male volunteers. All volunteers were randomly assigned to a sequence group for the 2 treatments, which consisted of ticlopidine 250 mg alone and ticlopidine 250 mg with Ginkgo biloba extract 80 mg, separated by a 1-week washout period between the treatments. Bleeding time was determined just before dosing and at 5, 12, and 48 hours after dosing. Platelet aggregation was evaluated before dosing and at 4, 8, 26, and 48 hours after dosing. Blood samples (8 mL) from each of the volunteers were collected from an indwelling intravenous cannula inserted into a forearm vein before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours after dosing. Ticlopidine concentrations were determined by a validated method using HPLC and ultraviolet detection. Adverse events were identified using general health-related questions, vital signs, physical examinations, ECGs, and laboratory tests. RESULTS A total of 24 healthy men participated in the study (mean [SD] age, 24.1 [4.3] years; weight, 66.6 [7.4] kg; height, 174.7 [5.0] cm). The baseline corrected bleeding times were not significantly different between the ticlopidine-alone and ticlopidine/ Ginkgo biloba groups, and changes in platelet aggregation were not significantly different between the groups. Likewise, the pharmacokinetic parameters of ticlopidine were not significantly different between the groups; the geometric mean ratios of the ticlopidine/ Ginkgo biloba group to the ticlopidine-alone group were 1.03 (90% CI, 0.92-1.16) for C(max), 1.08 (90% CI, 0.98-1.19) for AUC(0-last), and 1.10 (90% CI, 1.00-1.20) for AUC(0-infinity). A total of 28 adverse events were reported: 11 in the ticlopidine-alone group and 17 in the ticlopidine/Ginkgo biloba group. The adverse events judged to be possibly related to ticlopidine in the ticlopidine-alone group were epigastric discomfort (2 cases), diarrhea (1), skin eruption (1), and a feeling of being cold (1) or hot (1). The adverse events judged to be related to ticlopidine or Ginkgo biloba in the ticlopidine/Ginkgo biloba group were epigastric discomfort (2), diarrhea (2), nausea (2), and headache (1). CONCLUSIONS In this small group of healthy Korean men, the addition of a single dose of Ginkgo biloba extract did not prolong the bleeding time and was not associated with additional antiplatelet effects compared with the administration of ticlopidine alone. The coadministration of Ginkgo biloba extract with ticlopidine was not associated with any significant changes in the pharmacokinetic profile of ticlopidine compared with ticlopidine administered alone.

Pharmacokinetics and pharmacodynamics of LC15-0444, a novel dipeptidyl peptidase IV inhibitor, after multiple dosing in healthy volunteers.

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.

Influence of alcohol on the hemodynamic effects and pharmacokinetic properties of mirodenafil: A single-dose, randomized-sequence, open-label, crossover study in healthy male volunteers in Korea

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.

Predicting brain occupancy from plasma levels using PET: superiority of combining pharmacokinetics with pharmacodynamics while modeling the relationship.

Positron emission tomography (PET) studies of dopamine receptor occupancy can be used to assess dosing of antipsychotics. Typically, studies of antipsychotics have applied pharmacodynamic (PD) modeling alone to characterize the relationship between antipsychotic dose and its effect on the brain. However, a limitation of this approach is that it does not account for the discrepancy between the time courses of plasma concentration and receptor occupancy by antipsychotics. Combined pharmacokinetic—PD (PK—PD) modeling, by incorporating the time dependence of occupancy, is better suited for the reliable analysis of the concentration—occupancy relationship. To determine the effect of time on the concentration—occupancy relationship as a function of analysis approach, we measured dopamine receptor occupancy after the administration of aripiprazole using [11C]raclopride PET and obtained serial measurements of the plasma aripiprazole concentration in 18 volunteers. We then developed a PK—PD model for the relationship, and compared it with conventional approach (PD modeling alone). The hysteresis characteristics were observed in the competitor concentration—occupancy relationship and the value of EC50 was different according to the analysis approach (EC50 derived from PD modeling alone = 11.1 ng/mL (95% confidence interval (CI) = 10.1 to 12.1); while that derived from combined PK—PD modeling = 8.63 ng/mL (95% CI = 7.75 to 9.51)). This finding suggests that PK—PD modeling is required to obtain reliable prediction of brain occupancy by antipsychotics.

Effects of Angelicae tenuissima radix, Angelicae dahuricae radix and Scutellariae radix Extracts on Cytochrome P450 Activities in Healthy Volunteers

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.

The Effects of Ketoconazole and Rifampicin on the Pharmacokinetics of Mirodenafil in Healthy Korean Male Volunteers: An Open-Label, One-Sequence, Three-Period, Three-Treatment Crossover Study

BACKGROUND Mirodenafil, a phosphodiesterase 5 inhibitor reported to be effective in the treatment of erectile dysfunction, is metabolized by cytochrome P450 (CYP) 3A4 to the active metabolite N-dehydroxyethyl mirodenafil. Mirodenafil may have drug-drug interactions with ketoconazole and/or rifampicin. OBJECTIVE The aim of this study was to investigate the effects of a potent inhibitor (ketoconazole) and inducer (rifampicin) of the CYP3A4 isozyme on the pharmacokinetics of mirodenafil to meet the regulatory requirements for the marketing of mirodenafil in Korea. METHODS An open-label, 1-sequence, 3-period, 3-treatment crossover study was conducted over 22 days in healthy Korean male volunteers. Each subject received 100 mg of mirodenafil in each of 3 study periods: mirodenafil alone (period 1); mirodenafil after pretreatment with ketoconazole 400 mg once daily for 3 days (period 2); and mirodenafil after pretreatment with rifampicin 600 mg once daily for 10 days (period 3). Serial blood samples were collected for pharmacokinetic analysis after the administration of mirodenafil in each study period. Plasma concentration-time data for mirodenafil and its major metabolite, N-dehydroxyethyl mirodenafil, were determined using LC-MS/MS and analyzed by a noncompartmental method. The results for mirodenafil coadministration with either ketoconazole or rifampicin were compared with those for mirodenafil alone. Adverse events (AEs) were identified by asking general health-related questions of the subjects, by physical examination, and by subject self-report throughout the study period. RESULTS Nineteen subjects were enrolled (mean [SD] age, 23.2 [2.76] years [range, 19-29 years]; weight, 69.3 [6.50] kg [range, 61.0-84.0 kg]; body mass index, 22.4 [1.77] kg/m(2) [range, 20.0-26.0 kg/m(2)]) and 18 subjects completed the study. One subject discontinued the study due to protocol violation and was replaced. The AUC(0-infinity) of mirodenafil increased 5.04-fold (90% CI, 3.78-6.72) and the metabolic ratio decreased 0.21-fold after pretreatment with ketoconazole compared with mirodenafil alone. After pretreatment with rifampicin, the AUC(0-infinity) of mirodenafil decreased 0.03-fold (90% CI, 0.02-0.05) and the metabolic ratio increased 2.9-fold. Twelve cases of headache, 6 of nasal congestion, 2 of feeling hot, 2 of epistaxis, and 1 each of dizziness, nausea, and somnolence were considered to be related to administration of mirodenafil. Twenty-eight AEs were reported in period 2 (in 68.4% of subjects), during which systemic exposure to mirodenafil was highest, whereas 7 AEs were reported in period 1 (in 31.6% of subjects) and 5 AEs in period 3 (in 16.7% of subjects). CONCLUSION In these healthy Korean male volunteers, the coadministration of ketoconazole and rifampicin resulted in significant changes in systemic exposure to mirodenafil.

Pharmacodynamic (hemodynamic) and pharmacokinetic comparisons of S-amlodipine gentisate and racemate amlodipine besylate in healthy Korean male volunteers: two double-blind, randomized, two-period, two-treatment, two-sequence, double-dummy, single-dose crossover studies.

BACKGROUND S-amlodipine gentisate, consisting entirely of the (S)-enantiomer, was developed to increase the potency and improve the safety profile of amlodipine. Regulatory requirements for marketing of S-amlodipine gentisate in Korea require comparison of this agent versus amlodipine racemate. OBJECTIVE This study was conducted to compare the pharmacodynamic (PD) and pharmacokinetic (PK) characteristics of the S-amlodipine formulation (S-amlodipine gentisate) and amlodipine racemate (amlodipine besylate). METHODS This study consisted of 2 separate substudies; PD and PK parameters were evaluated separately. Both studies were conducted using a doubleblind, randomized, 2-period, 2-treatment, 2-sequence, double-dummy, single-dose crossover design with S-amlodipine 5 mg and amlodipine racemate 10 mg, separated by a 2-week washout period. Blood pressure (BP) and heart rate were measured in the sitting position before dosing and at 1, 2, 4, 5, 6, 7, 8, 10, 12, 14, 24, 48, and 72 hours after oral administration of S-amlodipine or amlodipine racemate. Impedance cardiography parameters (stroke volume, cardiac index, and systemic vascular resistance) were measured before and at 1, 2, 4, 5, 6, 7, 8, 10, and 12 hours after dosing. For PK assessments, serial blood samples were collected before dosing and at 1, 2, 4, 6, 8, 10, 12, 14, 24, 48, 72, 96, 120, 144, and 168 hours after dosing, and drug concentrations were determined by HPLC-MS/MS. Adverse events (AEs) were collected using self-report or general health-related questions. RESULTS The PD study included 24 healthy men (mean [SD] age, 23.1 [3.1] years; weight, 69.2 [6.1] kg), and the PK study included 24 different healthy men (mean age, 25.1 [2.1] years; weight, 65.9 [5.9] kg). There were no statistically significant differences between the treatment groups in terms of systolic BP, diastolic BP, or heart rate by repeated-measures ANOVA. Likewise, in the analysis of impedance cardiography, the treatment groups did not display any significant differences in stroke volume, cardiac index, or systemic vascular resistance by repeatedmeasures ANOVA. The mean (SD) AUC(0-last) was 129.7 (62.8) ng . h/mL after dosing with S-amlodipine and 129.0 (59.6) ng . h/mL after dosing with amlodipine racemate. The geometric mean ratio (S-amlodipine: amlodipine racemate) of the S-amlodipine AUC(0-last) was 1.01 (90% CI, 0.90-1.13). In the PD study, 4 AEs in 3 volunteers (3/24; 12.5%) and 8 AEs in 5 volunteers (5/24; 20.8%) were reported after dosing with S-amlodipine and amlodipine racemate, respectively. In the PK study, 18 AEs in 11 volunteers (11/24; 45.8%) and 20 AEs in 9 volunteers (9/24; 37.5%) were reported after dosing with S-amlodipine and amlodipine racemate, respectively. Five volunteers reported AEs after dosing with both S-amlodipine and amlodipine racemate. For the PD and PK studies combined, 30 AEs were judged to be possibly related to S-amlodipine (16 cases) or amlodipine racemate (14 cases). Twenty AEs were judged not to be related to S-amlodipine (6 cases) or amlodipine racemate (14 cases). The most common AEs considered at least possibly related to the study drug in both studies were headache (18 cases) and nausea (3 cases). CONCLUSIONS In these single-dose studies, no significant differences were found in PD (hemodynamic) or PK parameters between S-amlodipine 5 mg and amlodipine racemate 10 mg. S-amlodipine had a safety profile comparable to that of amlodipine racemate in these healthy male volunteers.