Healthy Korean Male Subjects Research Articles

Pharmacokinetics and bioequivalence of tofacitinib 5 mg in healthy Korean male subjects.

Tofacitinib is an oral Janus kinase (JAK) inhibitor marketed as an immunomodulator that can effectively treat rheumatoid arthritis. This study aimed to compare the pharmacokinetics and evaluate the bioequivalence of tofacitinib free base (CKD-374) with those of tofacitinib citrate (Xeljanz). A randomized, open-label, single-dose, 2-sequence, 2-period crossover study was conducted in healthy Korean male subjects. A total of 36 subjects were randomized into two sequence groups. At each period, subjects were administered the test formulation (tofacitinib free base, 5 mg) or the reference formulation (tofacitinib citrate, 8.078 mg; as tofacitinib, 5 mg). The plasma samples were collected up to 12 hours post dose and analyzed by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration (Cmax) and area under the plasma concentration vs. time curve from dosing to the last measurable concentration (AUC0-t), were determined by non-compartmental analysis. The 90% confidence intervals (CIs) of the geometric mean ratios for Cmax and AUC0-t were calculated to evaluate pharmacokinetic equivalence. The 90% CIs of the geometric mean ratios of Cmax and AUC0-t for tofacitinib free base to tofacitinib citrate were 0.9144-1.1230 and 1.0245-1.0932, respectively. All reported adverse events were of mild intensity, and there were no serious adverse events. In healthy Korean male adult subjects, the pharmacokinetic parameters of tofacitinib free base and tofacitinib citrate were evaluated and met the pharmacokinetic bioequivalent criteria. Both formulations were safe and well-tolerated.

Comparison of the pharmacokinetic characteristics and bioequivalence between two nanosuspension formulations of megestrol acetate in healthy Korean male subjects.

ClinicalTrials.gov Identifier: NCT06147908.

Effects of food and ethnicity on the pharmacokinetics of venadaparib, a next-generation PARP inhibitor, in healthy Korean, Caucasian, and Chinese male subjects

AimVenadaparib is a next-generation poly(ADP-ribose) polymerase inhibitor under development for treating gastric cancer. This study aimed to evaluate the effects of food and ethnicity on the pharmacokinetics (PKs) and safety of venadaparib after a single oral administration in healthy Korean, Caucasian, and Chinese male subjects.MethodsIn this randomized, open-label, single-dose, two-sequence, two-period, and crossover study, Korean and Caucasian subjects received venadaparib 80 mg in each period (fasted or fed state) with a seven-day washout. In an open-label, single-dose study, Chinese subjects received venadaparib 80 mg only in the fasted state. Serial blood samples were collected up to 72 h post-dosing.ResultsTwelve subjects from each ethnic group completed the study. The geometric mean ratios (90% confidence intervals) of the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the last measurable time point (AUClast) of venadaparib for the fed to fasted state were 0.82 (0.7457–0.9094) and 1.02 (0.9088–1.1339) in Koreans, and 0.77 (0.6871–0.8609) and 0.96 (0.9017–1.0186) in Caucasians, respectively. No statistically significant differences were observed in Cmax (P-value = 0.45) or AUClast (P-value = 0.30) among the three ethnic groups. A single venadaparib dose was well-tolerated.ConclusionThe overall systemic exposure of venadaparib was not affected by the high-fat meal, despite delayed absorption with a decreased Cmax in the fed state. The PK profiles were comparable among the Korean, Caucasian, and Chinese subjects. A single venadaparib 80 mg dose was safe and well-tolerated in both fasted and fed states.

Pharmacokinetic Comparison of Ginsenosides between Fermented and Non-Fermented Red Ginseng in Healthy Volunteers.

Fermentation of red ginseng (RG) produces fermented red ginseng (FRG), thereby increasing the relative amount of downstream ginsenosides, including compound Y (CY), F2, Rh2, compound K (CK), compound O, protopanaxadiol (PPD), and protopanaxatriol (PPT). These downstream ginsenosides have beneficial pharmacological effects, and are easily absorbed by the human body. Based on these expectations, a randomized, single-dose, two-period, crossover clinical trial was planned to compare the pharmacokinetic characteristics of seven types (Rb1, CY, F2, CK, Rh2, PPD, and PPT) of ginsenoside components after FRG and RG administration. The safety and tolerability profiles were assessed in this clinical trial. Sixteen healthy Korean male subjects were administered 6 g of FRG or RG. All ginsenosides except Rb1 showed higher systemic exposure after FRG administration than after RG administration, based on comparisons of ginsenoside Cmax and area under the concentration-time curve (AUC) between FRG and RG. CK, the main ginsenoside component produced during the fermentation process, had 69.23/74.53-fold higher Cmax/AUClast after administration of FRG than RG, and Rh2 had 20.27/18.47-fold higher Cmax/AUClast after administration of FRG than RG. In addition, CY and F2 were detected in FRG; however, all plasma concentrations of CY and F2, except in one subject, were below the lower limit of quantification in RG. There were no clinically significant findings with respect to clinical laboratory tests, blood pressures, or adverse events. Therefore, regular administration of FRG may exert better pharmacological effects than RG.

Endogenous metabolic markers for predicting the activity of dihydropyrimidine dehydrogenase.

Five‐fluorouracil (5‐FU) is a chemotherapeutic agent that is mainly metabolized by the rate‐limiting enzyme dihydropyrimidine dehydrogenase (DPD). The DPD enzyme activity deficiency involves a wide range of severities. Previous studies have demonstrated the effect of a DPYD single nucleotide polymorphism on 5‐FU efficacy and highlighted the importance of studying such genes for cancer treatment. Common polymorphisms of DPYD in European ancestry populations are less frequently present in Koreans. DPD is also responsible for the conversion of endogenous uracil (U) into dihydrouracil (DHU). We quantified U and DHU in plasma samples of healthy male Korean subjects, and samples were classified into two groups based on DHU/U ratio. The calculated DHU/U ratios ranged from 0.52 to 7.12, and the two groups were classified into the 10th percentile and 90th percentile for untargeted metabolomics analysis using liquid chromatography‐quantitative time‐of‐flight‐mass spectrometry. A total of 4440 compounds were detected and filtered out based on a coefficient of variation below 30%. Our results revealed that six metabolites differed significantly between the high activity group and low activity group (false discovery rate q‐value < 0.05). Uridine was significantly higher in the low DPD activity group and is a precursor of U involved in pyrimidine metabolism; therefore, we speculated that DPD deficiency can influence uridine levels in plasma. Furthermore, the cutoff values for detecting DPD deficient patients from previous studies were unsuitable for Koreans. Our metabolomics approach is the first study that reported the DHU/U ratio distribution in healthy Korean subjects and identified a new biomarker of DPD deficiency.

Pharmacokinetic Interactions between Tegoprazan and Metronidazole/Tetracycline/Bismuth and Safety Assessment in Healthy Korean Male Subjects

PurposeTegoprazan is a potassium-competitive acid blocker used for gastric acid suppression, which may be used with Helicobacter pylori eradication therapies. The goal of this study was to evaluate the pharmacokinetic interaction between tegoprazan and triple-antibiotic therapy containing metronidazole, tetracycline, and bismuth. Methods: An open-label, 2-cohort, randomized, multiple-dose, crossover study was conducted in healthy subjects. In cohort 1, tegoprazan (100 mg/d) was administered orally with or without triple-antibiotic therapy (1500 mg/d metronidazole, 2000 mg/d tetracycline, and 1200 mg/d bismuth) for 7 days in each period. In cohort 2, triple-antibiotic therapy was administered orally with or without tegoprazan for 7 days in each period. Pharmacokinetic blood samples were collected within 24 h after the last dose. Safety assessments were performed. Findings: Eleven cohort 1 subjects and ten cohort 2 subjects were included in the pharmacokinetic analysis. The AUCτ and Cmax at steady state geometric mean ratios (90% CIs) were 0.78 (0.73–0.83) and 0.75 (0.68–0.82) for tegoprazan; 0.77 (0.68–0.88) and 0.84 (0.72–0.98) for tegoprazan metabolite M1; 1.03 (0.98–1.08) and 1.08 (0.99–1.18) for metronidazole; 0.63 (0.56–0.70) and 0.64 (0.56–0.74) for tetracycline; and 1.55 (0.99–2.44) and 1.38 (0.72–2.66) for bismuth, respectively. All reported adverse events were mild. ImplicationsChanges in the tegoprazan, tetracycline, and bismuth pharmacokinetic parameters were detected after concurrent administration. These changes were considered mainly due to the pharmacodynamic effect of tegoprazan. The adverse events were predictable and reported as frequent adverse events during triple-antibiotic therapy. There were no significant differences in safety or tolerability between quadruple therapy, including tegoprazan and triple-antibiotic therapy. ClinicalTrials.gov identifier: NCT04066257.

Pharmacokinetics and Safety of Extended-release Ranolazine in Korean and White Healthy Subjects

PurposeRanolazine, an inhibitor of late inward sodium current, is an antianginal agent. In this study, the pharmacokinetic (PK) properties and tolerability of single- and multiple-dose ranolazine were compared between healthy Korean and white subjects. MethodsAn open-label, ascending single- and multiple-dose study was conducted with healthy male Korean and white subjects. Subjects were administered 375–750 mg of ranolazine once in a single-dose and twice daily in multiple-dose based on their dose groups. Blood samples for the PK assessment were collected up to 48 h after dosing. The geometric mean ratio and its 90% confidence interval in Korean to white subjects for Cmax, Cmax,ss, AUClast, and AUC0–12h,ss of ranolazine were calculated. A population PK analysis was also performed. Safety profiles were assessed throughout the study. FindingsA total of 70 Korean and 48 white subjects completed the study. Ranolazine exposure was similar between Korean and white subjects in all dose groups; however, ranolazine exposure at 750 mg was observed to increase by up to 29% in Korean subjects compared with that in white subjects. On the basis of previous studies, these differences in ranolazine exposure between the 2 ethnic groups may not result in any clinically significant difference. Furthermore, ethnicity was not significantly correlated with the PK properties of ranolazine in the ranolazine PK model. In addition, no significant difference was found in the safety profile of ranolazine between the 2 ethnic groups. ImplicationsThe PK properties of ranolazine had no clinically significant difference, and no difference was found in the safety profiles of ranolazine between Korean and white subjects. It is anticipated that ranolazine can be administered in Korean subjects without dose adjustment. ClinicalTrials.gov identifier: NCT02817932.

Pharmacokinetic properties and bioequivalence of gefitinib 250 mg in healthy Korean male subjects.

Gefitinib is an anti-cancer drug used to treat non-small cell lung cancer. The objective of this study was to compare the pharmacokinetics and evaluate the bioequivalence of 2 orally administered gefitinib 250 mg tablets in healthy Korean subjects. A randomized, open-label, single-dose, crossover bioequivalence study was conducted. A total of 50 healthy male volunteers were randomized into 2 sequence groups. During each treatment, the subjects received the test or reference formulation of 250 mg gefitinib with a washout period of 21 days. The plasma samples were collected at pre-dose and up to 144 hours post-dose, and plasma drug concentrations were measured using validated liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated, and the formulations were considered as bioequivalent if the 90% confidence intervals (CIs) of the geometric mean ratios were within the bioequivalence limits of 0.8 to 1.25. Forty-one subjects completed the study and were included in the pharmacokinetic analysis. The 90% CIs of the geometric mean ratios of the test formulation to the reference formulation were 0.8115 to 0.9993 for maximum plasma concentration and 0.9119 to 1.0411 for area under the plasma concentration versus time curve from dosing to the last measurable concentration. There were no serious or unexpected adverse events during the study. In healthy Korean adult subjects, the test and reference formulations of gefitinib 250 mg had similar pharmacokinetic parameters and similar plasma concentration-time profiles. The test formulation of gefitinib met the regulatory criteria for assuming bioequivalence. Both formulations were safe and well-tolerated.

Pharmacokinetic/Pharmacodynamic Interaction Between Evogliptin and Pioglitazone in Healthy Male Subjects.

AimEvogliptin is a newly developed oral glucose-lowering medication of the dipeptidyl peptidase 4 (DPP-4) inhibitor class for type 2 diabetes mellitus. The combination of a DPP-4 inhibitor with pioglitazone is a promising therapeutic option. The aim of the present study was to evaluate the pharmacokinetic and pharmacodynamic interaction between evogliptin and pioglitazone.Materials and MethodsA randomized, open-label, multiple-dose, three-treatment, three-period, six-sequence crossover study was conducted in healthy Korean male subjects. All subjects received evogliptin 5 mg once daily for 7 days (EVO), pioglitazone 30 mg once daily for 7 days (PIO) and co-administration of evogliptin 5 mg and pioglitazone 30 mg once daily for 7 days (EVO+PIO) according to the assigned sequence and period. Serial blood samples were collected for 24 hours for pharmacokinetic analysis and 3 hours after the oral glucose tolerance test for the pharmacodynamic analysis.ResultsThirty-four subjects completed the study. EVO+PIO and EVO showed a similar maximum plasma concentration at steady state (Cmax,ss) and area under the concentration-time curve during the dosing interval at the steady state (AUCτ,ss) of evogliptin, with geometric mean ratios (GMRs) (90% confidence interval (CI)) of 1.01 (0.97–1.05) and 1.01 (0.98–1.04), respectively. EVO+PIO and PIO showed a similar Cmax,ss and AUCτ,ss of pioglitazone, with GMRs (90% CI) of 1.07 (0.99–1.17) and 1.08 (0.99–1.17), respectively. Reduction of the glucose level after EVO+PIO was larger compared to PIO and similar with EVO.ConclusionConcomitant administration of evogliptin and pioglitazone showed similar glucose-lowering effects with those of evogliptin alone without pharmacokinetic interactions when compared to the intake of each drug alone.

A study on age- and gender-dependent differences in distance and angle between the internal carotid artery and basilar artery

BACKGROUND: Variations or malformation of the internal carotid artery (ICA) and basilar artery (BA) can be risk factors during simple surgery. So medically the focus has been on information about the positional relationship between the blood vessels based on the distance and angle between the ICA and BA.OBJECTIVE: This study measured the distance and angle between the ICA and BA in 188 healthy Korean male and female subjects in their 20s and 40s and analyzed the differences in terms of age and gender.METHODS: Magnetic resonance images were obtained; the distance between the right ICA and BA was defined as R1 [cm], the distance between the left ICA and BA was defined as L2 [cm], and the distance between the right ICA and left ICA was defined as M3 [cm]. The angles between the right and left ICA and BA were defined as AR1 [degree] and AR2 [degree], respectively.RESULTS: With increasing age, R1 and M3 became shorter in both men and women, and L2 became shorter only in women.CONCLUSION: The results of this study provide data on the average distance and angle between the ICA and BA of healthy Korean men and women in their 20s and 40s, which may later be used to support the diagnosis of relevant brain diseases and simple routine surgical procedures.

Comparative pharmacokinetics of a montelukast/levocetirizine fixed-dose combination chewable tablet versus individual administration of montelukast and levocetirizine after a single oral administration in healthy Korean male subjects .

Asthma patients often have co-existing symptoms of allergic rhinitis and are often prescribed with both asthma and rhinitis treatments such as montelukast and levocetirizine. The objective of this study was to compare the pharmacokinetic profiles of a montelukast/levocetirizine fixed-dose combination chewable tablet with individual administration of montelukast and levocetirizine in healthy subjects. A randomized, open-label, single-dose crossover study was conducted in healthy male subjects. One of the following treatments was administered in each period: co-administration of 1 chewable tablet of montelukast 5 mg and 1 tablet of levocetirizine 5 mg or administration of 1 chewable tablet of montelukast/levocetirizine 5/5 mg fixed-dose combination. Serial blood samples were collected up to 48 hours post dose. Plasma drug concentrations were measured by liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve from dosing to the last measurable concentration (AUClast), were determined by non-compartmental analysis. The geometric least-square mean (GLSM) ratios and associated 90% confidence intervals (CIs) of Cmax and AUClast were calculated to evaluate pharmacokinetic equivalence. A total of 22 subjects were included in pharmacokinetic analysis. The GLSM ratios and 90% CIs of Cmax and AUClast were 1.0054 (0.9535-1.0601) and 1.0628 (1.0013-1.1281) for montelukast and 1.0105 (0.9488-1.0764) and 1.0396 (0.9935-1.0879) for levocetirizine, respectively. The pharmacokinetic parameters of montelukast and levocetirizine when administered as separate tablets or as a fixed-dose combination were compared, and the parameters met the pharmacokinetic equivalence criteria. (ClinicalTrials.gov Identifier: NCT03371849).

Pharmacokinetics of bioactive components after oral administration of Bojungikgi-tang in Korean subjects

The purpose of this study to establish the safety and efficacy data of Bojungikgi-tang (BJIGT) soft extract by determining the clinical pharmacokinetics (PKs) of its main ingredients and their active metabolites after oral administration. A randomized, open-label, single-dose, single-center study on 12 healthy Korean male subjects was conducted. The plasma concentration of the active ingredients in BJIGT soft extract was determined in UPLC-MS/MS. Phoenix WinNonlin (version 8.1, Pharsight®, a Certara™ Company, Princeton, NJ, USA) was used to conduct compartmental and non-compartmental (NCA) analyses to assess PK parameters. The PK parameters of ginsenoside Rb1 (Rb1) and glycyrrhizin (GL) were well described with 1-compartment analysis without lag time, and the 1-compartment model with combined transit compartment model and first-order absorption was used to evaluate the parameters of glycyrrhetinic acid (GLA). PK parameters of Rb1, GL and GLA including the clearance (CL/F), the volume of distribution (V/F), the rate of absorption (Ka), the maximum concentration (Cmax), time to reach maximum concentration (Tmax), the area under the curve of a plasma concentration versus time profile (AUC0-inf), and the elimination half-life (T1/2) were successfully estimated. This is the first report to evaluate the PKs of major active ingredients and their metabolites after oral administration of BJIGT soft extract to Korean subjects.

Pharmacokinetic Evaluation by Modeling and Simulation Analysis of a Donepezil Patch Formulation in Healthy Male Volunteers.

IntroductionThis study characterized the pharmacokinetics (PKs) of a donepezil patch formulation currently under development, using mixed effect modeling analysis, and explored optimal patch dosing regimens in comparison with the donepezil oral formulation.MethodsPK data used in this analysis were from 60 healthy Korean male subjects participating in two Phase I studies, where subjects received single or multiple doses of donepezil of 43.75, 87.5, and 175 mg via patches, and 12 of them received a single oral dose of 10 mg of donepezil, followed by a single dose of donepezil via a patch. Donepezil PKs were analyzed by nonlinear mixed effect modeling using NONMEM software.ResultsA well-stirred model with two-compartment distribution and delayed absorption was chosen as the best model for the oral formulation. The PKs of donepezil after the patch applications were best described by a two-compartment linear model with zero-order absorption (D2) and absorption delay. The relative bioavailability (BA) of donepezil after the patch application compared with oral dosing was described to be affected by the duration of patch application.ConclusionPK simulations based on the chosen PK models suggested that, overall, donepezil exposure in plasma is similar whether with 10 mg of oral donepezil every 24 h or a 175 mg patch every 72 h, and likewise with 5 mg of oral donepezil every 24 h or an 87.5 mg patch every 72 h.

Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation of Lornoxicam to Develop Personalized Drug Optimization regarding to CYP2C9 Genetic Polymorphism

Lornoxicam is a non‐steroidal anti‐inflammatory drug (NSAID) of oxicam class that has analgesic and anti‐inflammatory effects. Lornoxicam decreases various prostaglandin synthesis via inhibition of cyclo‐oxygenase (COX). Lornoxicam is primarily metabolized to 5’‐hydroxy lornoxicam through cytochrome P450 2C9 (CYP2C9) enzyme. Polymorphism of the CYP2C9 enzyme, e.g., CYP2C9*3 and CYP2C9*13, are associated with decreased activity of CYP2C9. Consequently, the difference of CYP2C9 activity by polymorphism triggers diverse drug concentration and response despite equal dose administration. For individual drug optimization, we develop a predictable pharmacokinetic model based on physiological characteristics related to CYP2C9 activity. In our research, 13 healthy Korean male subjects were included in the pharmacokinetic study of lornoxicam. All subjects were divided into three different CYP2C9*1/*1, CYP2C9*1/*3, and CYP2C9*1/*13 groups. 8mg dose of lornoxicam was administered to individual subjects. After administration, venous blood samples were collected and analyzed by HPLC‐UV method. Pharmacokinetic parameter values were predicted using PBPK software, PK‐Sim® 8. Vmax and Km parameter values were adjusted to reflect a difference in CYP2C9 activity based on in vitro CYP2C9 kinetic studies of lornoxicam. Simulated pharmacokinetic data were compared to our clinical data for the development and verification of the lornoxicam model and assessed for validity using a 99.998% confidence interval and two‐fold error criteria. In our clinical trial, pharmacokinetic parameters, e.g., AUCinf, Cmax, Tmax, and half‐life, were considerably changed in CYP2C9*1/*3 and CYP2C9*1/*13 groups compared to CYP2C9*1/*1 group. Firstly, AUCinf, Cmax, Tmax, and half‐life values are 2730.2, 655.7, 2.2, 2.74 in CYP2C9*1/*1 group, secondly 5464, 815.3, 1.6, 4.99 in CYP2C9*1/*3, finally 5315, 935.1, 2.3, 5.19 in CYP2C9*1/*13 respectively. For predicted data for this is as follows: 3099.2, 640.9, 1.5, 2.9 in CYP2C9*1/*1, 5312.5, 748.3, 1.6, 5.2 in CYP2C9*1/*3, 5551, 782.7, 1.6, 4.17 in CYP2C9*1/*13. Based on these result, simulated values were within suitable assessment for model development. Values for verification conducted simulation in Chinese ethnic also were fit in the assessment. Therefore, the PBPK model of lornoxicam was confirmed development successfully. Unfortunately, we could not find pharmacokinetic profiles in the ethnic group except the Chinese. So, we verified the PBPK model by conducting simulation only in Chinese ethnic. Because of this limitation, we expect to be able to develop a more validated model through the verification of various ethnic in further studies.PBPK model of lornoxicam in CYP2C9*1/*1 genotypes.Figure 1PBPK model of lornoxicam in CYP2C9*1/*3 genotypes. Km and Vmax values were scaledFigure 2

Pharmacokinetics and Safety of Two Voriconazole Formulations after Intravenous Infusion in Healthy Korean Volunteers.

BackgroundVoriconazole, a triazole antifungal agent exhibits broad-spectrum antifungal activity. It is used to treat severe, invasive fungal infections, including invasive aspergillosis and candidemia. The aim of this study was to assess the pharmacokinetic equivalence of a test formulation (Vorico® Injection) and reference formulation (Vfend® IV) of voriconazole.Materials and MethodsThis was a randomized, open-label, single-dose, three-group, two-treatment, two-sequence, two-period, crossover phase I trial with 7-day washout periods (ClinicalTrials.gov identifier NCT02631954). Twenty-four healthy Korean male subjects were recruited. In each group, eight subjects were randomized in a 1:1 manner to receive a single dose of 200 mg test or reference formulation intravenously over 1.5 h. Blood samples were collected over 24 h post-dose, and plasma drug concentrations were determined by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were determined using a non-compartmental analysis, and safety was evaluated.ResultsTwenty-three subjects completed the study. The geometric mean ratio (90% confidence interval) of the test formulation to reference formulation was 0.9570 (0.8178 – 1.1199) for the maximum plasma concentration (Cmax) and 1.0720 (1.0262 – 1.1198) for the area under the concentration–time curve from dosing to the last quantifiable concentration (AUClast). The mean plasma concentration–time profiles, pharmacokinetic parameters, and safety were comparable between the two formulations.ConclusionEquivalent pharmacokinetic characteristics that satisfied the criteria of bioequivalence and similar safety profiles were observed for both test and reference formulations of voriconazole.

Population pharmacokinetic analysis of tramadol and O-desmethyltramadol with genetic polymorphism of CYP2D6.

Aim: Tramadol is widely used to treat acute, chronic, and neuropathic pain. Its primary active metabolite, O-desmethyltramadol (M1), is mainly responsible for its µ-opioid receptor-related analgesic effect. Tramadol is metabolized to M1 mainly by the cytochrome P450 (CYP) 2D6 enzyme, and to other metabolites by CYP3A4 and CYP2B6. The aim of this study was to develop a population pharmacokinetic (PK) model of tramadol and its metabolite using healthy Korean subjects.Methods: Data on plasma concentrations of tramadol and M1 were obtained from 23 healthy Korean male subjects after a twice-daily oral dose of 100 mg of tramadol, every 12 hrs, for a total of 5 times. Blood samples were collected at 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hrs after last administration. Plasma tramadol concentrations were then analyzed using LC/MS. Population PK analysis of tramadol and its metabolite was performed using a nonlinear mixed-effects modeling (NONMEM).Results: A one-compartment model with combined first-order and zero-order absorption was well fitted to the concentration–time curve of tramadol. M1 was well described by the one-compartment model as an extension of the parent drug (tramadol) model. Genetic polymorphisms of CYP2D6 correlated with the clearance of tramadol, and clearance from the central compartment to the metabolite compartment.Conclusion: The parent-metabolite model successfully characterized the PK of tramadol and its metabolite M1 in healthy Korean male subjects. These results could be applied to evaluate plasma tramadol concentrations after various dosing regimens.

Pharmacokinetic and bioequivalence study of sugar-coated and film-coated eperisone tablets in healthy subjects: A randomized, open-label, three-way, reference-replicated crossover study

Eperisone hydrochloride is used in the treatment of musculoskeletal disorders as a muscle relaxant via blocking of calcium channels. In this study, we aimed to investigate the within-subject variability (CVwR) of reference eperisone formulation for highly-variable drugs and to perform bioequivalence study of two oral formulations (sugar- and film-coated tablets) of eperisone hydrochloride 50 mg in healthy subjects by reference-replicated crossover study. 36 healthy Korean male subjects were recruited, and 33 subjects completed the study. A randomized, single-dose, open-label, three-way, three-sequence, reference formulation-replicated, crossover bioequivalence study was conducted to determine the bioequivalence of eperisone. Blood samples were collected before dosing and at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after dosing. The plasma concentration of eperisone was determined using liquid chromatography-tandem mass spectrometry. The CVwR of eperisone reference product was 33.17% for AUCt and 50.21% for Cmax. The acceptance limit for Cmax was scaled to 0.6984 - 1.4319 according to CVwR. The 90% confidence intervals for the test/reference geometric mean ratio were 0.8275 - 1.1692 for AUCt and 0.7587 - 1.1652 for Cmax, which were within the accepted bioequivalence limits. Single oral doses of eperisone hydrochloride 50 mg were generally well tolerated in healthy adult subjects in this study. The newly developed film-coated tablet can be interchanged with the original sugar-coated tablet of eperisone. In addition, the reference scaling methods are more effective and economical than the classical method for assessing BE of HVDs. .

Bioequivalence of a fixed-dose repaglinide/metformin combination tablet and equivalent doses of repaglinide and metformin tablets .

This study was conducted to determine whether a fixed-dose combination (FDC) tablet of repaglinide/metformin (2/500mg) is equivalent to coadministration of equivalent doses of individual (EDI) tablets of repaglinide (2mg) and metformin (500mg) in healthy Korean male subjects. This study was conducted as an open-label, randomized, single-dose, two-period, two-sequence crossover design in 50 healthy Korean male subjects who received an FDC tablet or EDI tablets. Plasma concentrations of repaglinide and metformin were determined for up to 24hours using a validated UPLC-MS/MS method. Bioequivalence was assessed according to current guidelines issued by the U.S. Food and Drug Administration (FDA) and Korean legislation. Tolerability was also evaluated throughout the study via subject interview, vital signs, and blood sampling. Point estimates (90% CIs) for AUC_0-t, AUC_0-∞, and C_max based on EDI tablets were 110.07 (102.25-118.49), 109.90 (101.70-118.39), and 112.60 (101.49-124.85), respectively, for repaglinide. They were 95.18 (89.62-101.05), 95.00 (89.74-100.65), and 98.44 (92.72-104.50), respectively, for metformin. These results satisfied the bioequivalence criteria of 80.00-125.00% proposed by the FDA and Korean legislation. Results of pharmacokinetic analysis suggested that repaglinide and metformin in FDC tablets were bioequivalent to EDI tablets of repaglinide (2mg) and metformin (500mg) in healthy Korean male subjects. Both formulations appeared to be well tolerated. .

Effects of diltiazem, a moderate inhibitor of CYP3A4, on the pharmacokinetics of tamsulosin in different CYP2D6 genotypes.

Tamsulosin, a selective antagonist of the α1-adrenoceptor, is primarily metabolized by CYP3A4 and CYP2D6, and tamsulosin exposure is significantly increased according to the genetic polymorphism of CYP2D6. In this study, we investigated the effects of diltiazem, a moderate inhibitor of CYP3A4, on the pharmacokinetics of tamsulosin in subjects with different CYP2D6 genotypes. Twenty-three healthy Korean male subjects with CYP2D6*wt/*wt (*wt = *1 or *2) and CYP2D6*10/*10 were enrolled in the prospective, open-label, two-phase parallel pharmacokinetic study. On the first day of study (day 1), each subject received a single 0.2mg oral dose of tamsulosin. After a washout period of 1week, on day 8, the subjects were given a 60mg oral dose of diltiazem three times daily for four days. On day 10, 1h after the morning dose of diltiazem, they received a single 0.2mg oral dose of tamsulosin. The pharmacokinetic parameters of tamsulosin in those with and without diltiazem treatment were compared in subjects with different CYP2D6 genotypes. After diltiazem treatment, the Cmax and AUCinf of tamsulosin in each CYP2D6 genotype group were significantly increased (p < 0.0001 for all). The CL/F of tamsulosin was also significantly decreased after diltiazem treatment (both p < 0.0001). However, diltiazem did not affect the t1/2 of tamsulosin in each genotype group. In conclusion, diltiazem significantly increases exposure to tamsulosin regardless of the genotype of CYP2D6. Dose adjustment in the daily maintenance dose of tamsulosin may improve tolerability and safety in patients receiving diltiazem.

Pharmacokinetics and tolerability of eletriptan hydrobromide in healthy Korean subjects.

BackgroundMigraine is one of the most common headache disorders that greatly affect the quality of life. Selective serotonin (5-HT) receptor agonists such as triptamine-based drugs called triptans are used for treatment of migraine.PurposeThis study aimed to evaluate the pharmacokinetic (PK) and tolerability profiles of eletriptan hydrobromide (eletriptan HBr), a selective 5-hydroxytryptamine (also known as serotonin) 1B/1D receptor agonist, in Koreans and compare the results to those observed in non-Koreans in a previously published study.Patients and methodsA randomized, open-label, single, and repeated-dose study was conducted in 16 healthy Korean male subjects using a four-treatment, four-period, and four-sequence crossover design (NCT01139515). The subjects received one of the following four treatments in each period: a single dose of 20, 40, 80 mg eletriptan HBr or a repeated oral dose of 40 mg 2 h apart. Blood samples were collected before and up to 26 h after dosing for quantification of plasma eletriptan concentration by high-performance liquid chromatography tandem–mass spectrometry. The PK parameters were estimated using noncompartmental methods. Ethnicity differences between Korean and non-Korean subjects were identified using geometric mean ratios and 90% confidence intervals (CIs) of dose-normalized maximum plasma concentration (Cmax) and dose-normalized area under the plasma concentration versus time curve from 0 h to the last measurable concentration (AUC0–t).ResultsAfter single-dose administration of eletriptan HBr to Korean subjects, the mean Cmax and AUC0–t increased linearly with dose. Comparable total systemic exposures were observed in the 2 h apart 40 mg repeated and single 80 mg dose. The geometric mean ratios (90% CIs) of the dose-normalized Cmax and AUC0–t of Korean subjects were similar to those of non-Korean subjects reported in the literature. The adverse events observed were transient and mild in severity.ConclusionEletriptan HBr showed linear PK and was well tolerated in Korean subjects. The PK and tolerability of eletriptan HBr did not differ between Korean and non-Korean subjects.