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.
Adult ; Delivery of Health Care ; Developed Countries ; Diabetes Mellitus ; Emergencies* ; Emergency Service, Hospital* ; Humans ; Hypertension ; Korea* ; Primary Health Care* ; Propensity Score ; Treatment Outcome

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.

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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.
Animals ; Felodipine ; In Vitro Techniques ; Kinetics ; Pharmacology

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.
In Vitro Techniques ; Pharmacology

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.
Bias (Epidemiology) ; Genotype ; Sample Size

PURPOSE: To evaluate the role of bile duct obstuction in the development of atrophy of the liver, using ananimal model. MATERIALS AND METHODS: Seven rabbits were divided into two groups : group 1(n=5), in which therewas selective bile duct ligation, and group 2(n=2), which underwent a sham operation. Each group was evaluated using CT for changes in hepatic volume after selective bile duct ligation or a sham operation. In group I, the diameter of dilated bile duct was measured 2, 4, 8, 12 and 16 weeks after bile duct ligation, while gross andhistologic change were evaluated in all cases. RESULTS: In group 1, bile duct dilatation was seen on CT two weeks after selective bile duct ligation, and did not change significantly during follow-up. In four of five cases, CT revealed no evidence of significant atrophy of the involved segment. Pathologic specimens, however, revealed dilatation of the bile duct, periductal fibrosis, infiltration of chronic inflammatory cells, and periportalfibrosis. One of five cases showed segmental liver atrophy after selective bile duct ligation. In addion to the above pathologic findings, there was obstruction of the portal vein by foreign body reaction. In group 2, no evidence of dilated bile duct or liver atrophy was revealed by CT or pathologic specimen after a sham operation. CONCLUSION: During long-term follow-up of 16 weeks, obstruction of the bile duct did not play a major role in the development of lobar atrophy in the rabbit.
Animals ; Atrophy ; Bile Ducts* ; Bile* ; Dilatation ; Fibrosis ; Follow-Up Studies ; Foreign-Body Reaction ; Ligation* ; Liver ; Portal Vein ; Rabbits

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.
Adult* ; Chronic Disease ; Comorbidity ; Confounding Factors (Epidemiology) ; Delivery of Health Care ; Diabetes Mellitus* ; Emergencies* ; Emergency Service, Hospital* ; Health Policy ; Humans ; Korea* ; Physicians, Primary Care ; Primary Health Care

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.
Bayes Theorem ; Blood Alcohol Content ; Driving Under the Influence ; Forensic Sciences* ; Korea ; Pharmacology, Clinical* ; Social Problems ; Uncertainty

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.
alpha-Glucosidases ; Cross-Over Studies ; Eating ; Enterocytes ; Glucose ; Humans ; Inositol ; Insulin ; Intestine, Small ; Microvilli ; Sucrose ; Tablets ; Therapeutic Equivalency