Physiologically-based pharmacokinetic model for clozapine in Korean patients with schizophrenia

Clozapine has been used as a treatment of schizophrenia. Despite its large interindividual variability, few reports addressed the physiologically-based pharmacokinetic modeling and simulation (PBPK M&S) of clozapine in patients. This study aimed to develop a PBPK M&S of clozapine in Korean patients with schizophrenia. PBPK modeling for clozapine was constructed using a population-based PBPK platform, the SimCYP® Simulator (V19;Certara, Sheffield, UK). The PBPK model was developed by optimizing the physiological parameters of the built-in population and compound libraries in the SimCYP® Simulator. The model verification was performed with the predicted/observed ratio for pharmacokinetic parameters and visual predictive checks (VPCs) plot. Simulations were performed to predict toxicities according to dosing regimens. From published data, 230 virtual trials were simulated for each dosing regimen. The predicted/observed ratio for the area under the curve and peak plasma concentration was calculated to be from 0.78 to 1.34. The observation profiles were within the 5th and 95th percentile range with no serious model misspecification through the VPC plot. A significant impact on age and gender was found for clozapine clearance. The simulation results suggested that 150 mg twice a day and 150 mg three times a day of clozapine have toxicity concerns. In conclusion, a PBPK model was developed and reasonable parameters were made from the data of Korean patients with schizophrenia. The provided model might be used to predict the pharmacokinetics of clozapine and assist dose adjustment in clinical settings.

Development and validation of a UPLC-MS/MS method for the quantification of acetaminophen in human plasma and its application to pharmacokinetic studies

We developed an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of acetaminophen concentration in human plasma. Following protein precipitated extraction, the analytes were separated and analyzed using an UPLC-MS/MS in the multiple reaction monitoring (MRM) mode with the respective [M+H]+ ions, m/z 152.06 → 110.16 for acetaminophen and m/z 180.18 → 138.12 for phenacetin (internal standard, IS). The method showed a linear response from 1 to 100 µg/mL (r > 0.9982). The limit of quantitation for acetaminophen in plasma was 1 µg/mL. The intra- and inter-day accuracy ranged in the ranges of 94.40–99.56% and 90.00–99.20%, respectively. The intra- and inter-day precision ranged in the ranges of 2.64–10.76% and 6.84–15.83%, respectively. This method was simple, reliable, precise and accurate and can be used to determine the concentration of acetaminophen in human plasma. Finally, this fully validated method was successfully applied to a pharmacokinetic study of acetaminophen in healthy volunteers following oral administration.

Comparative Cost Analysis for Surgical and Endovascular Treatment of Unruptured Intracranial Aneurysms in South Korea

OBJECTIVE: A cost comparison of the surgical clipping and endovascular coiling of unruptured intracranial aneurysms (UIAs), and the identification of the principal cost determinants of these treatments. METHODS: This study conducted a retrospective review of data from a series of patients who underwent surgical clipping or endovascular coiling of UIAs between January 2011 and May 2014. The medical records, radiological data, and hospital cost data were all examined. RESULTS: When comparing the total hospital costs for surgical clipping of a single UIA (n=188) and endovascular coiling of a single UIA (n=188), surgical treatment [mean+/-standard deviation (SD) : Won 8,280,000+/-1,490,000] resulted in significantly lower total hospital costs than endovascular treatment (mean+/-SD : Won 11,700,000+/-3,050,000, p<0.001). In a multi regression analysis, the factors significantly associated with the total hospital costs for endovascular treatment were the aneurysm diameter (p<0.001) and patient age (p=0.014). For the endovascular group, a Pearson correlation analysis revealed a strong positive correlation (r=0.77) between the aneurysm diameter and the total hospital costs, while a simple linear regression provided the equation, y (Won)=6,658,630+855,250x (mm), where y represents the total hospital costs and x is the aneurysm diameter. CONCLUSION: In South Korea, the total hospital costs for the surgical clipping of UIAs were found to be lower than those for endovascular coiling when the surgical results were favorable without significant complications. Plus, a strong positive correlation was noted between an increase in the aneurysm diameter and a dramatic increase in the costs of endovascular coiling.

Population pharmacokinetic analysis of the multiple peaks phenomenon in sumatriptan

The objective of this study was to develop a population pharmacokinetic (PK) model for sumatriptan, which frequently shows an atypical absorption profile with multiple peaks. Sumatriptan, a selective agonist for the vascular serotonin (5-HT1) receptor that causes vasoconstriction of the cerebral arteries, is used for the acute treatment of migraine attack with or without aura. Despite its relatively high between-subject variability, few reports have addressed PK modeling of sumatriptan. Plasma data obtained after a single 50-mg oral dose of sumatriptan in 26 healthy Korean male subjects were used. Blood samples were collected 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 h after dosing. Plasma sumatriptan concentrations were analyzed using UPLC/MS/MS. Population PK analysis was performed using plasma concentration data for sumatriptan with NONMEM (ver. 7.2). A total of 364 concentrations of sumatriptan were captured by a one-compartment model with first-order elimination, and a combined transit compartment model and first-order absorption with lag time was successful in describing the PK with multiple peaks in the absorption phase of sumatriptan. The creatinine clearance as a covariate significantly (P < 0.01) influenced the absorption fraction (f ). The final model was validated through a visual predictive check and bootstrapping with no serious model misspecification.

Efficacy of Dual Energy X-ray Absorptiometry for Evaluation of Biomechanical Properties: Bone Mineral Density and Actual Bone Strength

INTRODUCTION: Bone mineral density (BMD) is an important index in diagnosis of osteoporosis and other metabolic bone diseases, prediction of fractures, and monitoring treatment. This study was to find a more feasible technique for prediction of osteoporotic fracture between dual energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT) and to reveal the actual change of bone strength when BMD was changed. METHODS: Ten of these 20 specimens were used as the demineralized group and the other 10 as the control. Each specimen was immersed in HCl solution at for a period of at least 10 minutes, up to 100 minutes, at an interval of 10 minutes for different levels of demineralization. BMD was measured using DXA and QCT. Uniaxial compression tests were conducted to measure biomechanical parameters. Pearson correlation analysis was used respectively between BMD and biomechanical parameters and between DXA and QCT. RESULTS: Elastic modulus (r=0.87) and yield stress (r=0.84) showed a statistically significant correlation with DXA BMD. Through correlation analysis with QCT BMD and elastic modulus, correlation coefficient showed hemi-vertebra (r=0.80) and trabecular (r=0.68). In yield stress, there was a statistically significant correlation in hemi-vertebra (r=0.87) and trabecular bone (r=0.84). CONCLUSION: DXA is a current standard technique not only for diagnosis of osteoporosis but also for prediction of fracture risk compared to QCT. Actual decrease of bone strength was much greater than that of BMD by both DXA and QCT.

A Study on Current Status of Clinical Trial Pharmacy in Domestic Clinical Trial Institution

BACKGROUND: There is a lack of research on the status of clinical trial pharmacy and clinical trial pharmacist (CTP) in Korea. This study was aimed to investigate the current status of clinical trial pharmacy and clinical trial pharmacists. METHODS: The survey was performed using the 41-item questionnaire designed to investigate information on the following; (1) current status of clinical trial pharmacy designated by Korea Food and Drug Administration, (2) current status of working condition, management, and satisfaction index of CTP. Data collected was analyzed by t-test and chi2. RESULTS: Among the CTPs who responded, 92.7% belonged to department of pharmacy, and 7.3% to clinical trial center. 90.2% of the respondents were women. Forty-two point seven percents of the respondents had more than 3 years of experience in the clinical trial field. 36.6% answered that the current number of CTPs in the institution was '2'. Sixty-three point four percents answered that they subsumed an additional post. Regarding the question on "whether the equipment and working environment of your clinical trials pharmacy is adequate", 65.1% of the respondents answered as 'Inadequate'. Ninety-eight point eight percents answered that work-related education is needed. Ninety-three point nine percents answered that the quality of clinical trials is related to the improvement of the working environment of CTP. CONCLUSION: Clinical trial pharmacy's facility and number of actually working CTP were insufficient. Proper and continuous education and training for CTPs are needed to improve the quality of clinical trials conducted in Korea, with strong institution support and timely regulation change.

Steady-State Pharmacokinetic Properties of Tamsulosin in Healthy Male Volunteers

BACKGROUND: To evaluate the pharmacokinetic properties of daily oral doses of tamsulosin administered to fasted healthy Korean male volunteers for 5 days. METHODS: In a randomized, open-label, multiple-dose, two-period, crossover study, all 44 subjects were randomly assigned in a 1:1 ratio to receive a newly developed generic capsule formulation (test) or a branded capsule formulation (reference) of tamsulosin 0.2 mg, followed by a 10-day washout period and administration of the other formulation. Plasma concentrations of tamsulosin were assessed after administration of five-day multiple doses, using HPLC-MS/MS. Clinical and laboratory adverse events (AE) were assessed. RESULTS: The mean (SD) pharmacokinetic properties with the test and reference formulations were as follows: Css,max, 9.0 (2.9) and 8.4 (2.6) ng/mL, respectively; median (range) tmax, 4 (2-6) and 5 (2-7) hours; AUCtau, 93.7 (31.5) and 88.2 (29.3) ng x h/mL; and t(1/2), 9.5 (2.6) and 10.0 (2.7) hours. The volume of distribution and clearance after oral administration of tamsulosin were 0.5 L/kg, and 0.04 L/h/kg, respectively. The accumulation ratios for 0.2 mg once-daily dosing regimen were 1.2. The 90% CIs of the geometric mean ratios for the log-transformed AUCtau (1.005-1.131) and Css,max (1.000-1.136) values were within the acceptable range for bioequivalence. No serious AE was reported during the study. Both formulations were well tolerated. CONCLUSION: The results demonstrate that the Css,max and AUCtau values in the fasted subjects were higher than those in the fed from other study, with a shorter tmax values.

Targeted Plasma Metabolite Profiling of Metformin in Healthy Korean Volunteers

BACKGROUND: Metformin is an effective oral antihyperglycaemic agent for type 2 diabetes mellitus, with a variety of metabolic effects. In addition to controlling blood glucose level, it has been appeared to decrease the long-period complications of diabetes, including macrovascular disease. Few reports have addressed the metabolite profiling of metformin. The study was to evaluate if targeted metabolic profiling approach is sensitive enough to predict the therapeutic effects of metformin after a single oral dose. METHODS: A randomized, open-label, single-dose study was conducted in twenty eight healthy Korean male volunteers. To determine the concentrations of endogenous metabolites in their pre-dose and post-dose plasma samples, blood samples were collected before and at 2 and 6 h after a single oral dose of 500 mg metformin. Both Modular P/Modular D analyzer and ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS)-based metabolic profiling was performed. RESULTS: We quantified pre-dose and post-dose creatinine, blood urea nitrogen (BUN), lactic acid, 7 amino acids (lysine, glutamic acid, alanine, valine, leucine, phenylalanine, tryptophan), and 5 lysophosphatidylcholines (14:0, 16:0, 17:0, 18:0, and 18:1) using autoanalyser and UPLC-MS/MS. The postdose levels of alanine, lactic acid, glutamic acid, lysine, valine, leucine, phenylalanine, tryptophan, and lysoPC (18:1) were slightly decreased with statistical significance, but there is no clinical significance. CONCLUSION: In order to explore the potential endogenous metabolites associated with the therapeutic effects of metformin, further study including non-targeted (global) metabolite profiling is needed.

Targeted Plasma Metabolite Profiling of Metformin in Healthy Korean Volunteers

BACKGROUND: Metformin is an effective oral antihyperglycaemic agent for type 2 diabetes mellitus, with a variety of metabolic effects. In addition to controlling blood glucose level, it has been appeared to decrease the long-period complications of diabetes, including macrovascular disease. Few reports have addressed the metabolite profiling of metformin. The study was to evaluate if targeted metabolic profiling approach is sensitive enough to predict the therapeutic effects of metformin after a single oral dose. METHODS: A randomized, open-label, single-dose study was conducted in twenty eight healthy Korean male volunteers. To determine the concentrations of endogenous metabolites in their pre-dose and post-dose plasma samples, blood samples were collected before and at 2 and 6 h after a single oral dose of 500 mg metformin. Both Modular P/Modular D analyzer and ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS)-based metabolic profiling was performed. RESULTS: We quantified pre-dose and post-dose creatinine, blood urea nitrogen (BUN), lactic acid, 7 amino acids (lysine, glutamic acid, alanine, valine, leucine, phenylalanine, tryptophan), and 5 lysophosphatidylcholines (14:0, 16:0, 17:0, 18:0, and 18:1) using autoanalyser and UPLC-MS/MS. The postdose levels of alanine, lactic acid, glutamic acid, lysine, valine, leucine, phenylalanine, tryptophan, and lysoPC (18:1) were slightly decreased with statistical significance, but there is no clinical significance. CONCLUSION: In order to explore the potential endogenous metabolites associated with the therapeutic effects of metformin, further study including non-targeted (global) metabolite profiling is needed.

Results of 2012 KoNECT Certification Program of the Human Resource Project

BACKGROUND: In recent years, clinical trials have considerably increased and relevant education programs to clinical trials have been developed and implemented since 2008 in Korea. To enhance the quality as well as global competitiveness of clinical trial professionals (CTPs), a certification program of the human resource is needed. Accordingly, in Korea the first and the second certification examinations were implemented in February and October 2012, respectively. In this paper, introduction of the certification program of the human resource is described, and results of the certification examinations and questionnaire survey are presented. METHODS: Data including the examination results and questionnaire survey was collected by cooperative officials in Korea National Enterprise for Clinical Trials. Applicants who were selected eligible for examination by the steering committee were asked to complete questionnaires provided with the test papers on the day of the certification examination. RESULTS: In the first certification examination, a total of 221 eligible participants completed the examination. 99.5 % of the participants responded the questionnaire survey. In the second examination, a total of 223 applicants participated. The examination consisted of 50 multiple-choice questions with cut-off score of 70 per cent score.176 & 194 CTPs passed the first & second examinations respectively. CONCLUSION: This paper that described the results of the two certification tests and questionnaire surveys might be helpful in establishment and activation of the certification program in the future. Quality improvement of CTPs and international competitiveness of clinical trial in Korea can be anticipated by the certification program.

Results of 2012 KoNECT Certification Program of the Human Resource Project

BACKGROUND: In recent years, clinical trials have considerably increased and relevant education programs to clinical trials have been developed and implemented since 2008 in Korea. To enhance the quality as well as global competitiveness of clinical trial professionals (CTPs), a certification program of the human resource is needed. Accordingly, in Korea the first and the second certification examinations were implemented in February and October 2012, respectively. In this paper, introduction of the certification program of the human resource is described, and results of the certification examinations and questionnaire survey are presented. METHODS: Data including the examination results and questionnaire survey was collected by cooperative officials in Korea National Enterprise for Clinical Trials. Applicants who were selected eligible for examination by the steering committee were asked to complete questionnaires provided with the test papers on the day of the certification examination. RESULTS: In the first certification examination, a total of 221 eligible participants completed the examination. 99.5 % of the participants responded the questionnaire survey. In the second examination, a total of 223 applicants participated. The examination consisted of 50 multiple-choice questions with cut-off score of 70 per cent score.176 & 194 CTPs passed the first & second examinations respectively. CONCLUSION: This paper that described the results of the two certification tests and questionnaire surveys might be helpful in establishment and activation of the certification program in the future. Quality improvement of CTPs and international competitiveness of clinical trial in Korea can be anticipated by the certification program.

Application of Method to Measure Calcineurin Activity in Healthy Human Volunteers after Cyclosporine Administration

BACKGROUND: Calcineurin-inhibitors have wide inter-individual variation in drug response. Although therapeutic drug monitoring has been conducted to optimize personalized regimen, toxicity or rejection may occur. In this study, pharmacologic effect was evaluated by measuring calcineurin activity in peripheral blood after administration of a single dose of cyclosporine in healthy volunteers. METHODS: 7 healthy Korean male subjects received cyclosporine 200 mg and blood samples were drawn immediately before and at 1, 1.5, 4, 6, 12 h after dosing to measure calcineurin activity. The blood concentrations of cyclosporine were determined for 24 hours. Calcineurin activity assay was done with Calcineurin cellular activity assay kit (Calbiochem, USA). Frozen whole blood samples in liquid N2 were thawed and lysed with lysis buffer. 50 microL of phosphate standard curve samples were added to each well of a 96-well plate and 10 microL of diluted lysate were added to the well with RII phosphopeptide substrate. After incubating for 30 min, reaction was terminated by adding 100 microL GREEN(TM) reagent. Absorbance was read at 620 nm using spectrophotometer. We evaluated percent change in calcineurin activity from baseline level in relation to the lowest level. RESULTS: Decrease of calcineurin activity was confirmed after cyclosporine administration (mean +/- SD: 58.9 +/- 48.6 (%)). Significant correlation was shown between calcineurin activity change and pharmacokinetic parameters (AUClast: r = 0.834, p value = 0.01, Cmax: r = 0.774, p value = 0.02). CONCLUSION: In this study, we confirmed the pharmacologic effect and its correlation with pharmacokinetics after administration of a single dose of cyclosporine by measuring calcineurin activity in peripheral blood in healthy volunteers.