표제지
목차
제1장 서론 16
제1절 집단 약동학 모델 16
제2절 모델 평가 방법 18
제2장 배경 25
제1절 페노바르비탈의 임상 사용 25
제2절 페노바르비탈의 약물 동태학 및 소아 적용 26
제3절 페노바르비탈의 집단 약동학 모델 28
제4절 집단 약동학 모델의 외적 검증 연구 31
제5절 베이지안 추정을 통한 집단 약동학 모델 예측력 개선 33
제6절 신체 크기와 기관 성숙도 고려를 통한 집단 약동학 모델 예측력 개선 35
제7절 연구목적 36
제3장 실험방법 37
제1절 외적 검증을 위한 임상 자료 수집 37
제2절 집단 약동학 모델 선택 39
제3절 집단 약동학 모델 재구성 41
제4절 예측 기반 진단 43
제5절 시뮬레이션 기반 진단 44
제6절 베이지안 예측 46
제7절 신체 크기 및 성숙도 인자 평가 47
제4장 결과 및 고찰 48
제1절 외적 검증을 위한 임상 자료 48
제2절 집단 약동학 모델 논문 선택 50
제3절 예측 기반 진단 57
제4절 시뮬레이션 기반 진단 64
제5절 베이지안 예측 79
제6절 신체 크기 및 성숙도 인자 평가 84
제7절 고찰 93
제5장 결론 99
참고문헌 100
ABSTRACT 107
부록 109
APPENDIX 1. Control file for the Model by Moffett et al. 109
APPENDIX 2. Control file for the Model by Voller et al. 112
APPENDIX 3. Control file for the Model by Vucicevic et al. 114
APPENDIX 4. Control file for the Model by Marsot et al. 116
APPENDIX 5. Control file for the Model by Shellhaas et al. 118
APPENDIX 6. Control file for the Model by Yukawa et al. 120
APPENDIX 7. Control file for the Model by Grasela et al. 122
APPENDIX 8. R Script for GOF Plot 124
APPENDIX 9. R Script for Box Plot and Violin Plot 126
APPENDIX 10. R Script for VPC and pcVPC for 7 models 128
Table 1. Recent studies for external validation of published popPK models 32
Table 2. R coding for extracting the abstracts of the searched articles from Pubmed 40
Table 3. R coding for normalized prediction disposition error (NPDE) 45
Table 4. Demographic characteristics of external dataset 49
Table 5. Demographic characteristics of population PK models in published papers 52
Table 6. Population PK models in published papers 55
Table 7. Results of prediction based diagnostics 60
Table 8. Results of simulation based diagnostics using normalized prediction distribution errors, npde 65
Table 9. Summary of statistics of individual prediction error of Bayesian forecasting 83
Table 10. Results of prediction based diagnostics for the evaluated models after use of body size and maturation factors 85
Figure 1. Example of prediction-corrected Visual Predictive Check. Blue circles represent the observed data. The lines represent the median, upper and lower... 21
Figure 2. Example graphs plotted for NPDE. Quantile-quantile plot of NPDE versus the expected standard normal distribution (upper left).... 24
Figure 3. Overview of Bayesian parameter estimation in a typical PK project 34
Figure 4. Overview of literature search 51
Figure 5. GOF plots of population predicted concentrations (ug/mL) versus observed concentrations (ug/mL) of phenobarbital for the external dataset and population pharmacokinetic models. The red line represents the identity line (y=x). 58
Figure 6. Box plots of prediction errors (%) of population pharmacokinetic models of phenobarbital. (Thick solid line represents the mean error of zero and dot dashed line... 62
Figure 7. Violin plots of prediction errors of population PK models of phenobarbital. (The horizontal symmetrical lines represent Kernel Density Curve. The horizontal thick line... 63
Figure 8. Normalized prediction distribution error (npde) plots of external dataset for the model by Moffett et al. (Quantile-quantile (q-q) plot of npde versus the expected standard normal... 67
Figure 9. Normalized prediction distribution error (npde) plots of external dataset for the model by Voller et al. (Quantile-quantile (q-q) plot of npde versus the expected standard normal... 68
Figure 10. Normalized prediction distribution error (npde) plots of external dataset for the model by Marsot et al. (Quantile-quantile (q-q) plot of npde versus the expected standard... 69
Figure 11. Normalized prediction distribution error (npde) plots of external dataset for the model by Shellhaas et al. (Quantile-quantile (q-q) plot of npde versus the expected standard... 70
Figure 12. Normalized prediction distribution error (npde) plots of external dataset for the model by Yukawa et al. (Quantile-quantile (q-q) plot of npde versus the expected standard... 71
Figure 13. Normalized prediction distribution error (npde) plots of external dataset for the model by Grasela et al. (Quantile-quantile (q-q) plot of npde versus the expected standard... 72
Figure 14. Visual predictive check (VPC) plots of external dataset for the investigated models, Moffett et al. (A), Voller et al. (B), Marsot et al. C), Shellhaas et al. (D), Yukawa et al. (E),... 74
Figure 15. Prediction-corrected Visual predictive check (pcVPC) plots of external dataset for the investigated models, Moffett et al. (A), Voller et al. (B), Marsot et al. C), Shellhaas et al. (D),... 75
Figure 16. Conditional weighted residuals (CWRES) versus predicted concentrations (left) and time (right) of the investigated models of Moffett et al. (A), Voller et al. (B), Marsot et al. C),... 77
Figure 17. Residuals (RES) versus predicted concentrations (left) and time (right) of the investigated models of Moffett et al. (A), Voller et al. (B), Marsot et al. C), Shellhaas et al.... 78
Figure 18. Box plots of individual prediction errors of population pharmacokinetic models of phenobarbital with Bayesian forecasting in different number of prior measurements; 0, 1 2, 3 and all the observed measurements. (Solid line represents the mean error of 0 and dotdashed... 80
Figure 19. Box plots of individual prediction errors of population pharmacokinetic models by Vucicevic et al. with Bayesian forecasting in different number of prior measurements; 0, 1 2,... 82
Figure 20. Box plots of PE and GOF plots of PRED vs OBS of the model by Moffett et al. with and without incorporation of maturation function.... 86
Figure 21. Box plots of PE and GOF plots of PRED vs OBS of the model by Voller et al. with and without incorporation of size or maturation function.... 87
Figure 22. Box plots of PE and GOF plots of PRED vs OBS of the model by Marsot et al. with and without incorporation of maturation function.... 88
Figure 23. Box plots of PE and GOF plots of PRED vs OBS of the model by Shellhaas et al. with and without incorporation of maturation function.... 89
Figure 24. Box plots of PE and GOF plots of PRED vs OBS of the model by Yukawa et al. with and without incorporation of size or maturation function.... 90
Figure 25. Box plots of PE and GOF plots of PRED vs OBS of the model by Grasela et al. with and without incorporation of size or maturation function.... 91
Figure 26. Box plots of PE and GOF plots of PRED vs OBS of the model by Vucicevic et al. with and without incorporation of size or maturation function.... 92