Earticle

This article aimed to introduce 'risk sharing' schemes for pharmaceuticals between drug manufacturers and healthcare payer. Published literature review was undertaken to summarize risk sharing concepts and collect information on existing scheme examples in other countries focusing on new anticancer drugs. Risk sharing schemes could be categorized into health outcomes-based and non-outcomes (financial) based ones. Outcome-based schemes could be broken down into performance-linked reimbursement and conditional coverage. Performance-linked reimbursement can be further broken into outcomes guarantee and pattern or process of care and conditional coverage included coverage with evidence development and conditional treatment continuation schemes. Non-outcome based schemes included market share and price volume at population level, and utilization caps and manufacturer funded treatment initiation at patient level. We reviewed the fifteen examples for anticancer drugs that risk sharing agreements in response to the inherent uncertainties and increased costs of eleven anticancer drugs. Of them, eight cases were coverage with evidence development schemes. The anticancer drugs except bevacizumab and cetuximab were all listed on the national health insurance formulary in Korea, with reimbursement criteria defined on the basis of approved indications and administrations. Risk sharing approach may be a useful tool to ensure values for drug expenditure, but there are a number of concerns such as high administration costs, lack of transparency and conflicts of interest, especially for performance-based health outcomes reimbursement schemes.

Background: This study was aimed to establish the systematic management methods of tar color additives used in Korea for drugs and quasi-drugs. Although tar color additives have been used in various areas, safety problems are continuously being reported by several studies. For that reason, major countries like US, Japan, Europe are trying to update the safety information of tar color additives and the related management methods, and Korea also need to complement them based on the updated information for their safer use. Method: This report includes the compared information of all legally used tar color additives of each country, such as color additive name, compound name and chemical abstracts service registry number. Conclusion: It is expected that these investigated results will be useful as the basic materials for proper management guidelines of tar color additives in Korea.

Background: For Korean pharmaceutical industry to continue to grow, it is requisite to enter the global markets of developed countries. However, the export volume has fallen short of 10% of the gross sales and the industry has only recently warming up to prepare the globalization along with suchlike the Columbus Project. Purpose: This research was conducted to identify the difficulties Korean pharmaceutical companies perceived and to discover the gap in the needs for the government aid the companies have been seeking in the purpose of entering the developed pharmaceutical markets. Method: A survey method was used for this research. Six experts were surveyed and provided comments for the pre-questionnaire. Then, a final questionnaire was developed consisting of 10 items on regulatory-related and another 10 items on non-regulatory-related factors in drug exportation using the Likert scale (1 to 5). The survey sample was 30 Korean companies which have participated in the Columbus Project since 2010. Results: Nineteen (63%) companies responded to the survey. Most companies perceived difficulty (mean = 4.19) over the entire pathway of the regulatory process of global markets. Clinical trials and post-marketing surveillance were remarked as the most difficult barrier to follow the regulatory globalization. Among non-regulatory related factors, marketing, arranging a distribution network, obtaining experts, and projecting a timeline in exportation were brought up as the most difficulty. Conclusion: Especially, cost and language barrier were considered as the main cause producing these difficulties across regulatory and non-regulatory processes and accordingly, securing both long term budget and experts at governmental level was suggested by the domestic pharmaceutical companies.

Background: Drugs should be evaluated in appropriate subjects representing potential population to take the drugs. This study focuses on gender factor and aims to make known the appropriateness of considering gender difference on clinical evaluation of drug with domestic data related to drug use. Methods: To understand gender difference shown in drug use, three types of domestic statistical data (prevalence of chronic disease, number of outpatient with major concerning disease, and consumption of medicine) were analyzed and compared according to gender. Results: Three of fifteen chronic diseases which were analyzed, showed significantly higher prevalence in women than in men, and three were vice versa. Meanwhile, the sex ratio of outpatients was significantly different in 22 major concerning diseases. Among the drug groups coded by Anatomical Therapeutic Chemical (ATC) Classification System, the consumption of most drug groups was generally higher in women than in men except for one group coded G (genito-urinary system and sex hormones). Conclusion: Gender difference should be considered in domestic clinical evaluation of drug and domestic guidance for reflecting gender difference should be established.

Purpose: The aim of study was to investigate the racial or ethnic differences in FDA-approved medications. Methods: Data on racial-based differences of drugs in PDR (Physician’s Desk Reference) were analyzed by searching with keywords, “ETHNIC” and “RACE”. Results: There were descriptions related to “ETHNIC” in product directions of 53 cases and “RACE” in 266 cases in 2010 PDR. After excluding 30 cases of duplicates, 289 cases were shown of which 28 cases were verified to demonstrate racial or ethnic differences. Drug category showing the higher racial or ethnic differences was cardiovascular drugs (7), followed by alimentary tract and metabolism drugs (6), nervous system drugs (5), and antineoplastic and immunomodulating agents (3). Pharmacokinetic differences between race and ethnicity were observed most frequently; differences in AUC or Cmax showed in 15 drugs and clearance differences in 7 drugs. Conclusions: This study identified the racial differences in medication usage in PDR. Therefore, the results can contribute to safe use of medication in real clinical settings in regards to the racial or ethnic differences.

Objectives: Among many new drugs that are under investigation with intent to treat cancer, oral kinase inhibitors are proven to be effective in numerous clinical trials and easy to administer. Due to these advantages the use of oral kinase inhibitors is increasing. Oral kinase inhibitors are metabolized by CYP450 which can result either increase of adverse effect or decrease of drug effect by drug interaction when used concurrently with other agents. In this research, the medication records of patients on oral kinase inhibitors from Oct. 2010 to Nov. 2011 were reviewed to investigate potential drug interactions. Methods: From Oct. 2010 to Nov. 2011, cancer patients in Inha University Hospital who took oral kinase inhibitors more than once were included. The patients' medication records were reviewed to list out concurrent medications that have interaction potential with oral kinase inhibitors, the frequency of concurrent use, and the severity of interaction result using Micromedex® and Lexicomp-online® as references. Results: As a result, 90 cases of drug with interaction potential were prescribed by Micromedex® and 179 cases by Lexicomp-online® data. In case of severity, 33.3% by Micromedex® and 26.3% by Lexicomp-online® were categorized as Major and 65.6% by Micromedex® and 72.6% by Lexicomp-online® as Moderate. The number of adverse events was 92 cases which 58.7% were on skin and 19.6% on Gastro-intestinal tract. Conclusions: Considerable number of drug with interaction potential was used though each oral kinase inhibitors showed differences in extent. Hence there exists the risk of drug interaction in patients taking oral kinase inhibitors with other drugs.

Purpose: This study compared the performance of new NONMEM estimation methods using a population analysis dataset collected from a clinical study that consisted of 40 individuals and 567 observations after a single oral dose of glimepiride. Method: The NONMEM 7.2 estimation methods tested were first-order conditional estimation with interaction (FOCEI), importance sampling (IMP), importance sampling assisted by mode a posteriori (IMPMAP), iterative two stage (ITS), stochastic approximation expectation-maximization (SAEM), and Markov chain Monte Carlo Bayesian (BAYES) using a two-compartment open model. Results: The parameters estimated by IMP, IMPMAP, ITS, SAEM, and BAYES were similar to those estimated using FOCEI, and the objective function value (OFV) for diagnosing the model criteria was significantly decreased in FOCEI, IMPMAP, SAEM, and BAYES in comparison with IMP. Parameter precision in terms of the estimated standard error was estimated precisely with FOCEI, IMP, IMPMAP, and BAYES. The run time for the model analysis was shortest with BAYES. Conclusion: In conclusion, the new estimation methods in NONMEM 7.2 performed similarly in terms of parameter estimation, but the results in terms of parameter precision and model run times using BAYES were most suitable for analyzing this dataset.

Background: Secondary hyperparathyroidism (SHPT) is common in patients with chronic kidney disease, affecting most of those who are receiving dialysis. Cinacalcet, a novel calcimimetic, targets the calcium-sensing receptor to lower PTH levels in dialysis patients. Objective: This study aimed to assess efficacy, safety and appropriateness of use of cinacalcet in dialysis patients. Method: This retrospective study was performed on total 24 cases with identified intact parathyroid hormone (iPTH), serum calcium and phosphorus levels before and 4 weeks after cinacalcet initiation at a teaching hospital from July 1st, 2011 to October 31st, 2012. Results: Cinacalcet decreased iPTH by 19% from baseline after 4weeks treatment and it was statistically significant (p<0.001). Cinacalcet also significantly decreased iPTH levels regardless of dialysis modality (hemodialysis group versus peritoneal dialysis group) and severity of SHPT (iPTH 300-800 pg/ml group versus iPTH >800 pg/ml group). Serum calcium, phosphorus and Ca x P levels were decreased without statistical significance. Gastrointestinal events, headache and hypocalcemia were the most common side effects. Monitoring for iPTH and serum calcium was not performed appropriately. 43.7% patients initiated cinacalcet therapy at serum calcium level< 9.0 mg/dl. Conclusion: In conclusion, cinacalcet lowers parathyroid hormone levels with no serious side effects. However, it is required to avoid cinacalcet treatment in patients with low serum calcium levels and monitor iPTH and serum calcium levels during cinacalcet administration.

Purpose: Warfarin is the most widely used anticoagulant drug for preventing cardiovascular diseases after ischemic stroke and thromboembolism related to atrial fibrillation, artificial heart valves, deep vein thrombosis, and pulmonary embolism. Warfarin is commonly used in combination with other drugs such as diuretics in order to treat the comorbidity. Although several warfarin-diuretics interactions have been reported, the results are conflicting. Therefore, the initial aim of this study was to identify the effects of diuretics on the warfarin response in patients with atrial fibrillation. Methods: One hundred forty six patients with atrial fibrillation who were on anticoagulation therapy with warfarin and maintained INR levels of 2-3 for three consecutive times were followed up, retrospectively. Stable warfarin doses and INR per stable warfarin dose were compared according to age, gender, comorbidity, and concurrent medication. The stable warfarin dose was defined as the maintenance dose of warfarin of the measured patient whose INR was within the target INR range more than 3 times consecutively. Results: The differences of stable warfarin doses in patients with (3.22±1.21 mg/day) and without (3.58±1.14 mg/day) diuretics were marginally significant (P=0.069). On the other hand, stable warfarin doses were 2.97±1.10 mg/day in patients with thiazide (n=36) and 3.58±1.14 mg/day in patients without diuretics (n=82), which was statistically significant (p=0.009). INR values per stable warfarin dose in patients with diuretics and thiazide were 0.84±0.31 and 0.90±0.34, respectively, which were statistically different from those without diuretics (0.72±0.21, P=0.010 and P=0.006, respectively). Age, gender, and concurrent use of thiazide diuretics were found to have significant influence on the warfarin response from multivariate analysis. Conclusion: Our study showed that the concurrent use of thiazide diuretics could increase the response of warfarin in patient with atrial fibrillation. Therefore, clinicians should be aware that warfarin dose needs to be adjusted when it is used with thiazide diuretics concomitantly.

Background: Colorectal cancer shows a significant increase in South Korea due to westernization of diet, lack of dietary fiber, drinking and smoking, irregular defecation. There are surgery, chemotherapy, radiation therapy in treatment of colorectal cancer. There may be a medication errors in the process of chemotherapy because of its high toxicity, narrow therapeutic index and the health status of cancer patients. Consequently medication errors can cause increasing the risk of death, prolonging hospital stay and increasing the cost. Among medication errors on medication use process, prescribing errors are of particular concern due to higher risk of serious consequences. It is important for pharmacist to prevent the prescribing errors before reaching patient. Therefore we analyzed the prescriptions of colorectal cancer, classified prescribing errors, suggested guideline to reduce prescribing errors and verified the importance of pharmacist's role in prevention of medication errors activity. Methods: We collected the numbers of prescriptions of colorectal cancer(n=2,373) through anticancer management program and EMR and analyzed the errors of prescriptions by categories from Oct 1st 2011 to Sep 30th 2012 at Chungbuk National University Hospital. We reviewed the prescriptions as follows - patients' characteristics, the result of test, previous prescriptions, characteristics of antineoplastic agents and patients' allergy, drug sensitivity, adverse events. Prescriptions are classified into inpatient and outpatient and analyzed the errors of prescriptions by categories (dosage form, dose, input, diluents, regimen, product). Results: Total prescription number of inpatient and outpatient of colorectal cancer was 1,193 and 1,180 and that of errors was 107(9%) and 22(1.9%), respectively. In case of errors of categories, the number of errors of dosage form is 69 and 8, errors of dose is 15 and 5, errors of input is 9 and 9 in inpatient and outpatient prescriptions, respectively. Errors of diluents is 8, errors of regimen is 3, errors of product is 3 in only inpatient prescriptions. In case of errors of categories by inpatient department, the number of errors of dosage form is 34 and 35, errors of dose is 7 and 8, errors of input is 6 and 3, errors of diluents is 4 and 4, errors of regimen is 2 and 1, errors of product is 2 and 1 in SG and HO, respectively. In case of outpatient department, the number of errors of dosage form is 8 in HO, errors of dose is 5 in HO, errors of input is 5 and 4 in SG and HO, respectively. Conclusions: The rate of errors of inpatient is higher than that of outpatient. Junior doctors are engaged in prescriptions of inpatient and pharmacist need to pay attention to review all prescriptions. If prescribing errors are discovered, pharmacist should contact the prescriber and correct the errors without delay. The guideline to reduce prescribing errors might be upgrading software of anti cancer management program, education for physicians as well as pharmacists and calling prescriber's attention to preventing recurrence of errors.

Objective: The study evaluated the impact of pharmacist inventions with the implementation of pharmacistinvolved nutritional support service at neonate intensive care unit in a tertiary teaching hospital. Method: A retrospective and observational study was carried out. The total of 58 infants in neonate intensive care unit was enrolled between January 2011 and October 2012. The pharmacist-involved total parenteral nutritional program was initiated in June of 2012. During the program, pharmacist actively participated in the multidisciplinary round with performing the interventions from reviewing the amount of combined total parenteral nutrition and enteral fluid intakes, the amount of total calories, the glucose infusion rate, and the amounts of proteins per weight in kilogram. The outcome was compared with the results from the control group which reflected the prior period of the program initiation. Result: The number of days of regaining birth weight was significantly shorter (14.5 vs. 19 days, p=0.049) and the percentage of total calorie days with >90 kcal/kg/day was increased significantly (40 vs. 13%, p=0.008) in intervention group compared to the values in control group. In addition, the total mean daily caloric intakes (84.78±13.8 vs. 74.86±15.36 kcal/kg/day, p=0.018) was significantly higher in intervention group than those results in control group. There were no significant differences in safety parameters between two groups related to nutritional services of necrotizing enterocolitis, intraventricular hemorrhage, proven sepsis, and also parenteral nutrition-induced hepatotoxicity. Conclusion: Pharmacist-involved total parenteral nutrition managed program was successfully implemented. The outcome showed the improved effectiveness of total parenteral nutrition with pharmacist interventions and no differences in adverse reactions. This could prove the positive effects of pharmacist involvement on nutritional therapy for neonate population.

Lamivudine and adefovir are medications used to treat hepatitis B. We observed the occurrence of tinnitus after administering lamivudine and adefovir to a 49-year-old hepatitis B patient for two months. The patient had no comorbidities and no history of ear diseases, including tinnitus, and was not taking any other medications. In general, neither lamivudine nor adefovir are known to induce tinnitus as an adverse reaction. A literature search revealed that this is the first case in which tinnitus occurred after lamivudine and adefovir were administered to a hepatitis B patient. Therefore, we believe that this case is clinically valuable and decided to report it.