Comparison of Pharmacodynamics between Tegoprazan and Dexlansoprazole Regarding Nocturnal Acid Breakthrough: A Randomized Crossover Study

Background/Aims@#Tegoprazan, a novel potassium-competitive acid blocker, is expected to overcome the limitations of proton pump inhibitors and effectively control nocturnal acid breakthrough. To evaluate the pharmacodynamics of tegoprazan versus dexlansoprazole regarding nocturnal acid breakthrough in healthy subjects. @*Methods@#In a randomized, open-label, single-dose, balanced incomplete block crossover study, 24 healthy male volunteers were enrolled and randomized to receive oral tegoprazan (50, 100, or 200 mg) or dexlansoprazole (60 mg) during each of two administration periods, separated by a 7- to 10-day washout period. Blood samples were collected for pharmacokinetic parameter analysis; gastric monitoring was performed for pharmacodynamic parameter evaluation. @*Results@#All 24 subjects completed the study. Average maximum plasma concentration, area under the plasma concentration–time curve, and mean time with gastric pH >4 and pH >6 for tegoprazan demonstrated dose-dependent incremental increases. All the tegoprazan groups reached mean pH ≥4 within 2 hours, whereas the dexlansoprazole group required 7 hours after drug administration. Based on pharmacodynamic parameters up to 12 hours after evening dosing, 50, 100, and 200 mg of tegoprazan presented a stronger acid-suppressive effect than 60 mg of dexlansoprazole. Moreover, the dexlansoprazole group presented a comparable acid-suppressive effect with the tegoprazan groups 12 hours after dosing. @*Conclusions@#All the tegoprazan groups demonstrated a significantly faster onset of gastric pH increase and longer holding times above pH >4 and pH >6 up to 12 hours after evening dosing than the dexlansoprazole group.

Brief introduction to parametric time to event model

This tutorial explains the basic concept of parametric time to event (TTE) models, focusing on commonly used exponential, Weibull, and log-logistic model. TTE data is commonly used as endpoint for treatment effect of a drug or prognosis of diseases. Although nonparametric Kaplan-Meier analysis has been widely used for TTE data analysis, parametric modeling analysis has its own advantages such as ease of simulation, and evaluation of continuous covariate. Accelerated failure time model is introduced as a covariate model for TTE data together with proportional hazard model. Compared to proportional hazard model, accelerated failure time model provides more intuitive results on covariate effect since it states that covariates change TTE whereas in proportional hazard model covariates affect hazard.

Trends of clinical trials from 2017 to 2019 in Korea: an integrated analysis based on the Ministry of Food and Drug Safety (MFDS) and the Clinical Research Information Service (CRIS) registries

Public disclosure of approved clinical trials in a reliable registry can provide the transparency of the study. Although the registration of clinical trials has increased remarkably, the integrity of the data is not always satisfactory. In this study, we analyzed public clinical trial databases updated by the Ministry of Food and Drug Safety (MFDS) and Clinical Research Information Service (CRIS) registry to provide an overview of the trends of clinical trials approved between 2017 and 2019 in Korea. Information on clinical trials approved between January 1, 2017 and December 31, 2019 was collected from two databases. Trial information was categorized and summarized by study phase, therapeutic area, and location of the participating centers. A total of 655 to 715 clinical trials were newly approved annually by MFDS during the period from 2017 to 2019. Phase 1 clinical trials accounted for the largest proportion (31.0%), followed by phase 3 (29.5%), investigator-initiated trials (24.1%), phase 2 (14.6%), and phase 4 (0.5%). The number of clinical trials classified as an Antineoplastic and immunomodulating agent was the greatest (40.1%) regardless of the study phase. The similar result was obtained from CRIS registry where therapeutic area Neoplasms (15.9%) accounted for the largest number. The number of clinical trials performed in Seoul and Gyeonggi-do was approximately 70% of the total trials. In conclusion, our study provided a comprehensive overview of clinical trials in Korea from 2017 to 2019. The discrepancy between clinical trial registries could be resolved by introducing standardized database and guidelines.

Performance of a mixture model by the degree of a missing categorical covariate when estimating clearance in NONMEM

The accuracy and predictability of mixture models in NONMEM® may change depending on the relative size of inter-individual differences and the size of the differences in the parameters between subpopulations. This study explored the accuracy of mixture models when dealing with missing a categorical covariate under various situations that may occur in reality. We generated simulation data under various scenarios where genotypes representing extensive metabolizers (EM) and poor metabolizers (PM) of drug-metabolizing enzymes affect the clearance of a drug by different degrees, and the inter-individual variations in clearance are different for each scenario. From each simulated datum, a specific proportion of the covariate (genotype information) was randomly removed. Based on these simulation data, the proportion of each individual subpopulation and the clearance were estimated using a mixture model. Overall, the clearance estimate was more accurate when the difference in clearance between subpopulations was large, and the inter-individual variations were small. In some scenarios that showed higher ETA or epsilon shrinkage, the clearance estimates were significantly biased. The mixture model made better predictions for individuals in the EM subpopulation than for individuals in the PM subpopulation. However, the estimated values were not significantly affected by the tested ratio, if the sample size was secured to some extent. The current simulation study suggests that when the coefficient of variation of inter-individual variations of clearance exceeds 40%, the mixture model should be used carefully, and it should be taken into account that shrinkage can bias the results.

Evolving role of modeling and simulation in drug development

Pharmacokinetic-pharmacodynamic model is a kind of language that quantitatively describes the drug-related outcomes in the form of mathematical formula. Various outcomes can be subjected to modeling analysis if they can be expressed in numbers. Empirical models have been widely and successfully applied in drug development and research. However, a more competitive drug development environment requires more accurate and predictive models in the early stages of drug development. Accordingly, the subjects of PK-PD modeling have been extended from clinical data to preclinical and in vitro data in the discovery stage. More mechanistic and predictive models, such as physiologically based pharmacokinetic and quantitative system-based pharmacology models, are being increasingly used owing to the growing need to characterize drugs more accurately at the earliest. This tutorial briefly introduces the essential concepts of PK-PD modeling and simulation and describes the recent changing roles of PK-PD model for application in novel drug development process.

Pharmacokinetic Equivalence of the High Dose Strength Fixed-Dose Combination Tablet of Gemigliptin/Metformin Sustained Release (SR) and Individual Component Gemigliptin and Metformin XR Tablets in Healthy Subjects

BACKGROUND: In type 2 diabetes mellitus therapy, fixed-dose combination (FDC) can offer not only benefits in glucose control via the combined use of agents, but also increase patient compliance. The aim of this study was to assess the pharmacokinetic equivalence of the high dose of the FDC tablet (gemigliptin/metformin sustained release [SR] 50/1,000 mg) and a corresponding co-administered dose of individual tablets. METHODS: This study was randomized, open-label, single dose, two treatments, two-period, crossover study, which included 24 healthy subjects. Subjects received the FDC or individual tablets of gemigliptin (50 mg) and metformin XR (1,000 mg) in each period. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of the FDC tablet and co-administration of individual tablet for both gemigliptin and metformin were calculated. RESULTS: The GMRs (FDC tablets/co-administration; 90% CIs) for Cmax and AUClast of gemigliptin were 1.079 (0.986–1.180) and 1.047 (1.014–1.080), respectively. For metformin, the GMRs for Cmax, and AUClast were 1.038 (0.995–1.083) and 1.041 (0.997–1.088), respectively. The 90% CIs for GMRs of Cmax and AUClast for gemigliptin and metformin fell entirely within bounds of 0.800–1.250. Both administration of FDC tablet and co-administration of individual tablets were well tolerated. CONCLUSION: FDC tablet exhibited pharmacokinetic equivalence and comparable safety and tolerability to co-administration of corresponding doses of gemigliptin and metformin XR as individual tablets. Trial registry at ClinicalTrials.gov, NCT02056600.

Prediction of the human in vivo antiplatelet effect of S- and R-indobufen using population pharmacodynamic modeling and simulation based on in vitro platelet aggregation test

Indobufen (Ibustrin®), a reversible inhibitor of platelet aggregation, exists in two enantiomeric forms in 1:1 ratio. Here, we characterized the anti-platelet effect of S- and R-indobufen using response surface modeling using NONMEM® and predicted the therapeutic doses exerting the maximal efficacy of each enantioselective S- and R-indobufen formulation. S- and R-indobufen were added individually or together to 24 plasma samples from drug-naïve healthy subjects, generating 892 samples containing randomly selected concentrations of the drugs of 0–128 mg/L. Collagen-induced platelet aggregation in platelet-rich plasma was determined using a Chrono-log Lumi-Aggregometer. Inhibitory sigmoid I(max) model adequately described the anti-platelet effect. The S-form was more potent, whereas the R-form showed less inter-individual variation. No significant interaction was observed between the two enantiomers. The anti-platelet effect of multiple treatments with 200 mg indobufen twice daily doses was predicted in the simulation study, and the effect of S- or R-indobufen alone at various doses was predicted to define optimal dosing regimen for each enantiomer. Simulation study predicted that 200 mg twice daily administration of S-indobufen alone will produce more treatment effect than S-and R-mixture formulation. S-indobufen produced treatment effect at lower concentration than R-indobufen. However, inter-individual variation of the pharmacodynamic response was smaller in R-indobufen. The present study suggests the optimal doses of R-and S-enantioselective indobufen formulations in terms of treatment efficacy for patients with thromboembolic problems. The proposed methodology in this study can be applied to the develop novel enantio-selective drugs more efficiently.

Mechanistic ligand-receptor interaction model: operational model of agonism

This tutorial explains the basic principles of mechanistic ligand-receptor interaction model, which is an operational model of agonism. A growing number of agonist drugs, especially immune oncology drugs, is currently being developed. In this tutorial, time-dependent ordinary differential equation for simple E(max) operational model of agonism was derived step by step. The differential equation could be applied in a pharmacodynamic modeling software, such as NONMEM, for use in non-steady state experiments, in which experimental data are generated while the interaction between ligand and receptor changes over time. Making the most of the non-steady state experimental data would simplify the experimental processes, and furthermore allow us to identify more detailed kinetics of a potential drug. The operational model of agonism could be useful to predict the optimal dose for agonistic drugs from in vitro and in vivo animal pharmacology experiments at the very early phase of drug development.

Erratum: Comparison of various estimation methods for the parameters of Michaelis-Menten equation based on in vitro elimination kinetic simulation data

There are some errors in the published article. The authors would like to make corrections in the original version of the article.

Comparison of various estimation methods for the parameters of Michaelis-Menten equation based on in vitro elimination kinetic simulation data

The Michaelis-Menten equation is one of the best-known models describing the enzyme kinetics of in vitro drug elimination experiments, and takes a form of equation relating reaction rate (V) to the substrate concentration ([S]) via the maximum reaction rate (Vmax) and the Michaelis constant (Km). The current study was conducted to compare the accuracy and precision of the parameter estimates in the Michaelis-Menten equation from various estimation methods using simulated data. One thousand replicates of simulated [S] over serial time data were generated using the results of a previous study, incorporating additive or combined error models as a source of random variables in the Monte-Carlo simulation using R. From each replicate of simulated data, Vmax and Km were estimated by five different methods, including traditional linearization methods and nonlinear ones without linearization using NONMEM. The relative accuracy and precision of the estimated parameters were compared by the median values and their 90% confidence intervals. Overall, Vmax and Km estimation by nonlinear methods (NM) provided the most accurate and precise results from the tested 5 estimation methods. The superiority of parameter estimation by NM was even more evident in the simulated data incorporating the combined error model. The current simulation study suggests that NMs using a program such as NONMEM provide more reliable and accurate parameter estimates of the Michaelis-Menten equation than traditional linearization methods in in vitro drug elimination kinetic experiments.

Efficacy and Safety of a New 10% Intravenous Immunoglobulin Product in Patients with Primary Immune Thrombocytopenia (ITP)

BACKGROUND: In the current study, we aimed to investigate the efficacy and safety of intravenous immunoglobulin (IVIg)-SN 10%, a new 10% IVIg formulation, in adult patients with severe primary immune thrombocytopenia (ITP; platelet count < 20 × 109/L). METHODS: Patients diagnosed as primary ITP, aged 19 years old or more, and had a platelet count of < 20 × 109/L by screening complete blood cell count performed within 2 weeks of study commencement were eligible. Patients received IVIg-SN 10% at a dose of 1 g/kg/day for two consecutive days. Response was defined as the achievement of a platelet count of ≥ 50 × 109/L at day 8. RESULTS: Out of 81 eligible patients, 31 patients were newly diagnosed, 7 patients had persistent ITP, and 43 patients had chronic ITP. In intent-to-treat analysis, 61.3 patients (75.7%) achieved response and satisfied the pre-defined non-inferiority condition. Median time to response was 2 days and mean duration of maintaining response after the completion of IVIg therapy was 9.13 ± 8.40 days. Response rates were not found to be dependent on the phase of ITP or previous treatment for ITP. The drug was well tolerated and the frequency of mucocutaneous bleeding decreased during the study period. CONCLUSION: In summary, IVIg-SN 10% formulation was found to be safe and effective in adult ITP patients (Trial registry at ClinicalTrials.gov, NCT02063789).

Forensic science meets clinical pharmacology: pharmacokinetic model based estimation of alcohol concentration of a defendant as requested by a local prosecutor's office

Drunk driving is a serious social problem. We estimated the blood alcohol concentration of a defendant on the request of local prosecutor's office in Korea. Based on the defendant's history, and a previously constructed pharmacokinetic model for alcohol, we estimated the possible alcohol concentration over time during his driving using a Bayesian method implemented in NONMEM®. To ensure generalizability and to take the parameter uncertainty of the alcohol pharmacokinetic models into account, a non-parametric bootstrap with 1,000 replicates was applied to the Bayesian estimations. The current analysis enabled the prediction of the defendant's possible blood alcohol concentrations over time with a 95% prediction interval. The results showed a high probability that the alcohol concentration was ≥ 0.05% during driving. The current estimation of the alcohol concentration during driving by the Bayesian method could be used as scientific evidence during court trials.

The Effect of Having a Regular Doctor as a Primary Care Provider on Emergency Room Utilization in South Korea / 가정의학회지

BACKGROUND: Because primary care is the cornerstone of an effective health care system, many developed countries have striven to establish and strengthen their primary care systems. However, the primary care system in South Korea is not well established, and primary care research is still in its infancy. This study aimed to show the benefits of regular doctors as primary care providers in South Korea by analyzing the effect of regular doctor visits on emergency room (ER) visits. METHODS: We analyzed cross-sectional data on 11,293 adults aged 18 years and over collected from the 2013 Korea Health Panel Survey (beta version 1.0). We classified those participants with and without regular doctors into the treatment and control groups, respectively, and estimated the average treatment effect (ATE) of having a regular doctor on ER visits. We used counterfactual framework and propensity score analysis to adjust for unevenly distributed confounding covariates between treatments and control groups. RESULTS: The estimated conditional ATE of a regular doctor on ER visits was statistically insignificant in the general population (-0.4%; 95% confidence interval [CI], -2.0 to 1.2) and in the subgroup of patients with hypertension (-1.8%; 95% CI, -4.5 to 0.9). However, in patients with diabetes mellitus (DM), the estimated ATE was statistically significant (-5.0; 95% CI, -9.2 to -0.7). CONCLUSION: In the total study population, having a regular doctor did not result in a significant difference in ER visits. However, there was a decrease in ER visits in patients with DM in South Korea.

Emergency Department Visits Can Be Reduced by Having a Regular Doctor for Adults with Diabetes Mellitus: Secondary Analysis of 2013 Korea Health Panel Data

Chronic diseases pose a major challenge to population health worldwide. Diabetes is a major chronic disease that is managed overwhelmingly in primary care. There is an increasing recognition of the role that primary care physicians play to achieve high-quality care for patients with diabetes. By analyzing 2013 Korean Health Panel data, the authors aimed to determine the current status of having a regular doctor (RD) for adults (aged 18 years or older) with diabetes. In addition, the association of having a RD with the experience of emergency department (ED) visits was determined in this study. Among adults with diabetes, those with RD accounted for 41.0%. The older the age group and the higher the Charlson comorbidity index score, the higher the percentage of adults with diabetes had RD. Even for those with RD, coordination of care was very poor (positive answer: 27.1%). After adjustment for confounding variables, those having (vs. not having) a RD (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.35–0.94), especially those whose RDs delivered good comprehensiveness of care (OR, 0.47; 95% CI, 0.26–0.84) or worked at a primary care clinic (OR, 0.43; 95% CI, 0.22–0.81), and those whose longitudinal relationship with a RD was 5 years or less (OR, 0.45; 95% CI, 0.22–0.91) were less likely to have ED visits within the last year. In conclusion, health care policies that promote having a RD who delivers high-quality primary care could decrease unnecessary ED visits by diabetic adults. This can partly reduce ED overcrowding in Korea.

Development of a validated liquid chromatography-tandem mass spectrometry assay for the quantification of simvastatin acid, the active metabolite of simvastatin, in human plasma

Simvastatin is a lipid-lowering drug that is metabolized to its active metabolite simvastatin acid (SA). We developed and validated a sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) method to quantitate SA in human plasma using a liquid-liquid extraction method with methanol. The protonated analytes generated in negative ion mode were monitored by multiple reaction monitoring. Using 500-mL plasma aliquots, SA was quantified in the range of 0.1-100 ng/mL. Calibration was performed by internal standardization with lovastatin acid, and regression curves were generated using a weighting factor of 1/χ2. The linearity, precision, and accuracy of this assay for each compound were validated using quality control samples consisting of mixtures of SA (0.1, 0.5, 5, and 50 ng/mL) and plasma. The intra-batch accuracy was 95.3-107.8%, precision was -2.2% to -3.7%, and linearity (r2) was over 0.998 in the standard calibration range. The chromatographic running time was 3.0 min. This method sensitively and reliably measured SA concentrations in human plasma and was successfully used in clinical pharmacokinetic studies of simvastatin in healthy Korean adult male volunteers.

Prospective validation of a novel dosing scheme for intravenous busulfan in adult patients undergoing hematopoietic stem cell transplantation

The objective of this study was to externally validate a new dosing scheme for busulfan. Thirty-seven adult patients who received busulfan as conditioning therapy for hematopoietic stem cell transplantation (HCT) participated in this prospective study. Patients were randomized to receive intravenous busulfan, either as the conventional dosage (3.2 mg/kg daily) or according to the new dosing scheme based on their actual body weight (ABW) (23×ABW(0.5) mg daily) targeting an area under the concentration-time curve (AUC) of 5924 µM·min. Pharmacokinetic profiles were collected using a limited sampling strategy by randomly selecting 2 time points at 3.5, 5, 6, 7 or 22 hours after starting busulfan administration. Using an established population pharmacokinetic model with NONMEM software, busulfan concentrations at the available blood sampling times were predicted from dosage history and demographic data. The predicted and measured concentrations were compared by a visual predictive check (VPC). Maximum a posteriori Bayesian estimators were estimated to calculate the predicted AUC (AUC(PRED)). The accuracy and precision of the AUC(PRED) values were assessed by calculating the mean prediction error (MPE) and root mean squared prediction error (RMSE), and compared with the target AUC of 5924 µM·min. VPC showed that most data fell within the 95% prediction interval. MPE and RMSE of AUCPRED were -5.8% and 20.6%, respectively, in the conventional dosing group and −2.1% and 14.0%, respectively, in the new dosing scheme group. These fi ndings demonstrated the validity of a new dosing scheme for daily intravenous busulfan used as conditioning therapy for HCT.

Pharmacodynamic Comparison of Two Formulations of Voglibose 0.3-mg Tablet

BACKGROUND: Voglibose, an inhibitor of alpha-glucosidase of the small intestine brush border, is used to treat type 2 diabetic patients. Bioequivalence test based on pharmacokinetic parameters is difficult because voglibose does not cross the enterocytes after ingestion. This study was conducted to establish bioequivalence of two formulations of 0.3-mg voglibose with pharmacodynamic endpoints. METHODS: This study was an open, single-dose, randomized, 6-sequence, 3-period crossover design in healthy volunteers. In each period, subjects received placebo or three tablets of either test formulation or reference formulation with sucrose, with a 7-day washout period each dosing period. Serial blood samples were collected after each administration. The maximum concentrations of serum glucose and serum insulin (C(max)(G) and C(max)(I)) and the area under the serum concentration - time curve from dosing to 2 or 4 hours after dosing for serum glucose and insulin (AUC(0-2h)(G), AUC(0-4h)(G), AUC(0-2h)(I) and AUC(0-4h)(I), respectively) were determined by noncompartmental analysis. Formulation-related differences were tested in accordance with the Korean regulatory bioequivalence criteria. RESULTS: A total of 54 subjects completed study in accordance with protocol. The geometric mean ratios (GMRs) of the test formulation to the reference formulation for Cmax(G), AUC(0-2h)(G), AUC(0-4h)(G), C(max)(I), AUC(0-2h)(I) and AUC(0-4h)(I) were 0.945, 1.014, 0.995, 0.937, 0.985 and 0.983, respectively and the 90% confidence intervals (CIs) of corresponding values were 0.985-1.026, 0.991-1.038, 0.977-1.014, 0.830-1.057, 0.901-1.078 and 0.911-1.014, respectively. CONCLUSION: This single-dose study found that two formulations of 0.3-mg voglibose did not meet the regulatory criteria for bioequivalence in these healthy volunteers.

Comparison of Pharmacokinetic Characteristics and Safety Between JW Amlodipine(R) Tablet 5 mg and Novarsc(R) Tablet 5 mg in Healthy Male Volunteers

BACKGROUND: Amlodipine is a third-generation dihydropyridine calcium channel blocker, which has proven to be a useful drug against hypertension or angina. METHODS: This randomized, open-label, two-period, two-treatment, single-dose, crossover study was conducted in twenty healthy male volunteers. Subjects were administered 5 mg of the test or reference formulation. After 2-week washout period, the other formulation was administered. Blood samples were collected up to 144 hours after drug administration, and plasma amlodipine concentrations were determined by validated liquid chromatography-tandem mass spectrometry. Drug safety was assessed using measurement of vital signs, physical examinations, laboratory test, electrocardiograms, and adverse event monitoring. RESULTS: All subjects were completed this study. The geometric mean ratios of Cmax and AUClast were 1.078 (90 % CI, 0.968 - 1.200) and 1.095 (90 % CI, 1.011 - 1.186), respectively. There were no serious adverse events were reported by both formulations. CONCLUSION: This study showed the test and reference formulations had similar pharmacokinetics and safety profiles.

Bioequivalence of HCP1104, a New Fixed Dose Combination Drug and Co-administration of Eperisone 50 mg and Aceclofenac 100 mg: A Partial Replicated Crossover Study Design to Estimate the Pharmacokinetics of Highly Variable Drugs

BACKGROUND: This clinical study was conducted to compare pharmacokinetics of eperisone and aceclofenac of HCP1104, a new fixed dose combination drug with those in co-administration of eperisone 50 mg and aceclofenac 100 mg. The study used a partial replicated study design to characterize intra-subject variability of eperisone when co-administrated with aceclofenac. METHODS: A partial replicated crossover design was employed in 30 subjects. Each subject received a single dose of co-administration of eperisone 50 mg and aceclofenac 100 mg on two occasions and a single dose of 1 capsule of HCP1104. Blood samples were obtained for 24 hrs after dosing, and plasma was assayed for eperisone and aceclofenac by Liquid chromatography-electrospray ionization-mass spectrometry. RESULTS: Using an average bioequivalence criterion, the 90 % confidence limits for Ln-transformed Cmax and AUClast for aceclofenac fell wihin the acceptable range of 80 - 125 %. Point estimates of eperisone AUClast and Cmax were 1.0152 and 1.0490, respectively and the 90 % confidence interval for Cmax was 0.8499 - 1.3025. The within-subject coefficient of variation of Cmax for the reference was 50.198 %. Acceptance range for eperisone Cmax based on new bioequivalence guidance for highly variable drugs was extended to 0.6984 - 1.4319. CONCLUSION: The extent of exposure and rate of absorption of both eperisone and aceclofenac with a single dose of HCP1104 capsule were equivalent to those with co-administration of a marketed eperisone 50 mg tablet and a marketed aceclofenac 100 mg tablet under fasting conditions in healthy adult males.

Validation of LC-MS/MS Method for Determination of Bivalirudin in Human Plasma: Application to a Pharmacokinetic Study

BACKGROUND: Bivalirudin is a direct thrombin inhibitor for patients with unstable angina undergoing percutaneous coronary intervention. METHODS: A sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) method was developed and validated for the determination of bivalirudin, in human plasma using nafarelin as internal standard (IS). Chromatographic separation was performed using a Shiseido MG3 mm column (2.0 x 50 mm) with a gradient mobile phase consisting of water and acetonitrile containing 0.1 % formic acid at a flow rate of 0.4 mL/min, and total run time was within 5 min. Detection and quantification was performed by the mass spectrometer using a multiple reaction-monitoring mode at m/z 1091.0 --> 650.3 for bivalirudin, and m/z 662.1 --> 249.3 for IS. RESULTS: The assay was linear over a concentration range of 10 - 10000 ng/mL with a lower limit of quantification of 10 ng/mL in human plasma. CONCLUSION: This method was successfully applied for pharmacokinetics study after intravenous administration of bivalirudin to healthy Korean male volunteers.