• Title, Summary, Keyword: Dose Estimation

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Comparative Study of First-in-Human Dose Estimation Approaches using Pharmacometrics (약물계량학을 이용한 초기임상1상 시험 용량 예측 방법에 대한 비교연구)

  • Baek, In-hwan
    • 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.

Maximum Tolerated Dose Estimation Applied Biased Coin Design in a Phase I Clinical Trial

  • Kim, Yu Rim;Kim, Dongjae
    • 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.

Individual Doses to the Public after the Fukushima Nuclear Accident

  • Ishikawa, Tetsuo
    • 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.

Maximum Tolerated Dose Estimate by Curve Fitting in Phase I Clinical Trial (제1상 임상시험에서 곡선적합을 이용한 MTD 추정법)

  • Heo, Eun-Ha;Kim, Dong-Jae
    • 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.

Thyroid Doses in Children from Radioiodine following the Accident at the Fukushima Daiichi Nuclear Power Plant

  • Kim, Eunjoo;Kurihara, Osamu
    • Journal of Radiation Protection and Research
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    • v.45 no.1
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    • pp.2-10
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    • 2020
  • Background: Huge amounts of radionuclides were released into the environment due to the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident, which caused not only serious contamination on the ground, but also radiation exposure to the public. One problem that remains in performing the dose estimation is the difficulty of estimating the internal thyroid dose due to the intake of radioiodine (mainly, 131I) because of limitations to the human data available. Materials and Methods: The relevant papers were collected and reviewed by the authors. The results of thyroid dose estimates from different studies were tabulated for comparison. Results and Discussion: The thyroid dose estimates from the studies varied widely. The dose estimates by the United Nations Scientific Committee on the Effects of Atomic Radiation were higher than the others due to the ingestion dose being based on conservative assumptions. The dose estimates by Japanese experts were mostly below 20-30 mSv. The recent studies suggested that exposure on March 12, 2011 would be crucial for late evacuees from the areas near the FD-NPP because of the possible intake of short-lived radionuclides other than 131I. Further multilateral studies are vital to reduce uncertainties in the present dose estimations. Conclusion: The estimation of the thyroid doses to Fukushima residents still has many uncertainties. However, it is considered unlikely that the thyroid doses exceeded 50 mSv except in some extreme cases. Further multilateral studies are thus necessary to reduce the uncertainties in the present dose estimations.

Transmission Dose Estimation Algorithm for in vivo Dosimetry

  • Yun, Hyong-Geun;Huh, Soon-Nyung;Lee, Hyoung-Koo;Woo, Hong-Gyun;Shin, Kyo-Chul;Ha, Sung-Whan
    • Journal of Radiation Protection and Research
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    • v.28 no.1
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    • pp.59-63
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    • 2003
  • Purpose : Measurement of transmission dose is useful for in vivo dosimetry of QA purpose. The objective of this study is to develope an algorithm for estimation of tumor dose using measured transmission dose for open radiation field. Materials and Methods : Transmission dose was measured with various field size (FS), phantom thickness (Tp), and phantom chamber distance (PCD) with a acrylic phantom for 6 MV and 10 MV X-ray Source to chamber distance (SCD) was set to 150 cm. Measurement was conducted with a 0.6 cc Farmer type ion chamber. Using measured data and regression analysis, an algorithm was developed for estimation of expected reading of transmission dose. Accuracy of the algorithm was tested with flat solid phantom with various settings. Results : The algorithm consisted of quadratic function of log(A/P) (where A/P is area-perimeter ratio) and tertiary function of PCD. The algorithm could estimate dose with very high accuracy for open square field, with errors within ${\pm}0.5%$. For elongated radiation field, the errors were limited to ${\pm}1.0%$. Conclusion : The developed algorithm can accurately estimate the transmission dose in open radiation fields with various treatment settings.

Maximum Tolerated Dose Estimation with Dose De-Escalation Design in a Phase I Clinical Trials (제 1상 임상시험에서 용량 감량을 허용하는 MTD 추정법)

  • Jang, Eunah;Kim, Dongjae
    • 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.

RADIATION DAMAGE IN THE HUMAN BODY ACUTE RADIATION SYNDROME AND MULTIPLE ORGAN FAILURE

  • AKASHI, MAKOTO;TAMURA, TAIJI;TOMINAGA, TAKAKO;ABE, KENICHI;HACHIYA, MISAO;NAKAYAMA, FUMIAKI
    • 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.

Maximum tolerated dose estimation using continual reassessment method in Phase I Clinical Trial (연속재평가방법에 가속화 단계를 적용한 MTD 추정법)

  • Kwon, Dohee;Kim, Dongjae
    • 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.

Adjusted maximum tolerated dose estimation by stopping rule in phaseⅠclinical trial (제 1상 임상시험에서 멈춤 규칙을 이용한 수정된 최대허용용량 추정법)

  • Park, Ju Hee;Kim, Dongjae
    • 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.