• Korean Journal of Clinical Pharmacy
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• v.26 no.2
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• pp.150-162
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• 2016

Objective: First-in-human dose estimation is an essential approach for successful clinical trials for drug development. In this study, we systematically compared first-in-human dose and human pharmacokinetic parameter estimation approaches. Methods: First-in-human dose estimation approaches divided into similar drug comparison approaches, regulatory guidance based approaches, and pharmacokinetic based approaches. Human clearance, volume of distribution and bioavailability were classified for human pharmacokinetic parameter estimation approaches. Results: Similar drug comparison approaches is simple and appropriate me-too drug. Regulatory guidance based approaches is recommended from US Food and Drug Administration (FDA) and European Medicines Agency (EMA) regarding no-observed-adverse-effect level (NOAEL) or minimum anticipated biological effect level (MABEL). Pharmacokinetic based approaches are 8 approaches for human clearance estimation, 5 approaches for human volume of distribution, and 4 approaches for human bioavailability. Conclusion: This study introduced and compared all methods for first-in-human dose estimation. It would be useful practically to estimate first-in-human dose for drug development.

• Communications for Statistical Applications and Methods
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• v.19 no.6
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• pp.877-884
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• 2012

Phase I trials determine the maximum tolerated dose(MTD) and the recommended dose(RD) for subsequent Phase II trials. In this paper, a MTD estimation method applied to a biased coin design is proposed for Phase I Clinical Trials. The suggested MTD estimation method is compared to the SM3 method and the NM method (Lee and Kim, 2012) using a Monte Carlo simulation study.

• Communications for Statistical Applications and Methods
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• v.18 no.2
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• pp.179-187
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• 2011

The purpose of a Phase I clinical trial is to estimate the maximum tolerated dose, MTD, of a new drug. In this paper, the MTD estimation method is suggested by curve fitting the dose-toxicity data to an S-shaped curve. The suggested MTD estimation method is compared with established MTD estimation procedures using a Monte Carlo simulation study.

• Journal of Radiation Protection and Research
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• v.45 no.2
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• pp.53-68
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• 2020

Background: International organizations such as the World Health Organization (WHO) and the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) reported public exposure doses due to radionuclides released in the Fukushima nuclear accident a few years after the event. However, the reported doses were generally overestimated due to conservative assumptions such as a longer stay in deliberate areas designated for evacuation than the actual stay. After these reports had been published, more realistic dose values were reported by Japanese scientists. Materials and Methods: The present paper reviews those reports, including the most recently published articles; and summarizes estimated effective doses (external and internal) and issues related to their estimation. Results and Discussion: External dose estimation can be categorized as taking two approaches-estimation from ambient dose rate and peoples' behavior patterns-and measurements using personal dosimeters. The former approach was useful for estimating external doses in an early stage after the accident. The first 4-month doses were less than 2 mSv for most (94%) study subjects. Later on, individual doses came to be monitored by personal dosimeter measurements. On the basis of these measurements, the estimated median annual external dose was reported to be < 1 mSv in 2011 for 22 municipalities of Fukushima Prefecture. Internal dose estimation also can be categorized as taking two approaches: estimation from whole-body counting and estimation from monitoring of environmental samples such as radioactivity concentrations in food and drinking water. According to results by the former approach, committed effective dose due to ¹³⁴Cs and ¹³⁷Cs could be less than 0.1 mSv for most residents including those from evacuated areas. Conclusion: Realistic doses estimated by Japanese scientists indicated that the doses reported by WHO and UNSCEAR were generally overestimated. Average values for the first-year effective doses for residents in two affected areas (Namie Town and Iitate Village) were not likely to reach 10 mSv, the lower end of the doses estimated by WHO.

• The Korean Journal of Applied Statistics
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• v.27 no.7
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• pp.1115-1123
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• 2014

The main purpose of phase I clinical trials is to estimate the Maximum Tolerated Dose (MTD), which minimizes side effect and assures safety of a new drug by evaluating the toxicity at each dose-level. The conventional MTD estimation methods is Standard method (Storer, 1989; Korn et al., 1994), Accelerated Titration Designs (Simon et al., 1997) and DM method (Dixon and Mood, 1948) etc. In this paper, MTD estimation method with de-escalation is suggested phase I clinical trials. The proposed MTD estimation method is compared to Accelerated Titration Designs, SM3 without de-escalation method and SM3 with de-escalation method using a Monte Carlo simulation.

• Journal of Radiation Protection and Research
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• v.46 no.1
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• pp.14-23
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• 2021

Background: For radiological protection and control, the International Commission on Radiological Protection (ICRP) provides the nominal risk coefficients related to radiation exposure, which can be extrapolated using the excess relative risk and excess absolute risk obtained from the Life Span Study of atomic bomb survivors in Hiroshima and Nagasaki with the dose and dose-rate effectiveness factor (DDREF). Materials and Methods: Since it is impossible to directly estimate the radiation risk at doses less than approximately 100 mSv only from epidemiological knowledge and data, support from radiation biology is absolutely imperative, and thus, several national and international bodies have advocated the importance of bridging knowledge between biology and epidemiology. Because of the accident at the Tokyo Electric Power Company (TEPCO)'s Fukushima Daiichi Nuclear Power Station in 2011, the exposure of the public to radiation has become a major concern and it was considered that the estimation of radiation risk should be more realistic to cope with the prevailing radiation exposure situation. Results and Discussion: To discuss the issues from wide aspects related to radiological protection, and to realize bridging knowledge between biology and epidemiology, we have established a research group to develop low-dose and low-dose-rate radiation risk estimation methodology, with the permission of the Japan Health Physics Society. Conclusion: The aim of the research group was to clarify the current situation and issues related to the risk estimation of low-dose and low-dose-rate radiation exposure from the viewpoints of different research fields, such as epidemiology, biology, modeling, and dosimetry, to identify a future strategy and roadmap to elucidate a more realistic estimation of risk against low-dose and low-dose-rate radiation exposure.

• Nuclear Engineering and Technology
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• v.38 no.3
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• pp.231-238
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• 2006

Whole-body exposure to high-dose radiation causes injury involving multiple organs that depends on their sensitivity to radiation. This acute radiation syndrome (ARS) is caused by a brief exposure of a major part of the body to radiation at a relatively high dose rate. ARS is characterized by an initial prodromal stage, a latent symptom-free period, a critical or manifestation phase that usually takes one of four forms (three forms): hematologic, gastrointestinal, or cardiovascular and neurological (neurovascular), depending upon the exposure dose, and a recovery phase or death. One of the most important factors in treating victims exposed to radiation is the estimation of the exposure dose. When high-dose exposure is considered, initial dose estimation must be performed in order to make strategy decisions for treatment as soon as possible. Dose estimation can be based on onset and severity of prodromal symptoms, decline in absolute lymphocyte count post exposure, and chromosomal analysis of peripheral blood lymphocytes. Moreover, dose assessment on the basis of calculation from reconstruction of the radiation event may be required. Experience of a criticality accident occurring in 1999 at Tokai-mura, Japan, showed that ARS led to multiple organ failure (MOF). This article will review ARS and discuss the possible mechanisms of MOF developing from ARS.

• Journal of Radiation Protection and Research
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• v.47 no.3
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• pp.143-151
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• 2022

Background: After the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident, biological alterations in the natural biota, including morphological changes of fir trees in forests surrounding the power plant, have been reported. Focusing on the terminal buds involved in the morphological formation of fir trees, this study developed a method for estimating the absorbed radiation dose rate using radionuclide distribution measurements from tree organs. Materials and Methods: A phantom composed of three-dimensional (3D) tree organs was constructed for the three upper whorls of the fir tree. A terminal bud was evaluated using Monte Carlo simulations for the absorbed dose rate of radionuclides in the tree organs of the whorls. Evaluation of the absorbed dose targeted ¹³¹I, ¹³⁴Cs, and ¹³⁷Cs, the main radionuclides subsequent to the FDNPP accident. The dose contribution from each tree organ was calculated separately using dose coefficients (DC), which express the ratio between the average activity concentration of a radionuclide in each tree organ and the dose rate at the terminal bud. Results and Discussion: The dose estimation indicated that the radionuclides in the terminal bud and bud scale contributed to the absorbed dose rate mainly by beta rays, whereas those in 1-year-old trunk/branches and leaves were contributed by gamma rays. However, the dose contribution from radionuclides in the lower trunk/branches and leaves was negligible. Conclusion: The fir tree model provides organ-specific DC values, which are satisfactory for the practical calculation of the absorbed dose rate of radiation from inside the tree. These calculations are based on the measurement of radionuclide concentrations in tree organs on the 1-year-old leader shoots of fir trees. With the addition of direct gamma ray measurements of the absorbed dose rate from the tree environment, the total absorbed dose rate was estimated in the terminal bud of fir trees in contaminated forests.

• The Korean Journal of Applied Statistics
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• v.32 no.5
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• pp.741-752
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• 2019

The purpose of a Phase I Clinical Trial is to determine the maximum tolerated dose (MTD). MTD is important because it affects subsequent clinical trials; however, the existing method has a problem due to an inadequate dose allocated to patients. In this paper, an MTD estimation method is proposed to complement the problems of the existing MTD estimation method. The suggested method applies the initial acceleration step to the modified continual reassessment method. Monte Carlo Simulation Study is adapted to compare a suggested MTD estimation method with the standard design and the modified continual reassessment method.

• Journal of the Korean Data and Information Science Society
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• v.23 no.6
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• pp.1085-1091
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• 2012

Phase I clinical trials are designed to identify an appropriate dose; the maximum tolerated dose, which assures safety of a new drug by evaluating the toxicity at each dose-level. The adjusted maximum tolerated dose estimation is presented by stopping rule in phase I clinical trial on this research. The suggested maximum tolerated dose estimation is compared to the standard method3 and NM method using a Monte Carlo simulation study.