Title Page
Contents
국문초록 7
ABSTRACT 9
Abbreviation 14
I. Introduction 15
II. Purpose 23
III. Material and Method 24
A. Software 24
B. Data 25
C. Pharmacokinetic Modeling 25
1) Donepezil (DNP) 25
2) Rivastigmine (RVS) 29
D. PK/PD Modeling 31
1) Donepezil (DNP) 31
2) Rivastigmine (RVS) 31
E. Statistical Analysis 31
IV. Results and Discussions 33
A. Results 33
1) Donepezil 33
2) Rivastigmine 49
B. Discussions 72
V. Conclusions 76
VI. Reference 77
Table 1. Donepezil data for PK/PD modeling 27
Table 2. Donepezil PBPK modeling parameters for rat and human 28
Table 3. Rivastigmine data for PK/PD modeling 30
Table 4. Comparison of the observed data and predicted data using PK parameter for Donepezil rat model. 34
Table 5. Comparison of the observed data and predicted data using PK parameter for Donepezil human model. 38
Table 6. Comparison of the observed data and predicted data using PD parameter for Donepezil rat model. 42
Table 7. Comparison of the observed data and predicted data using PD parameter for Donepezil human model. 46
Table 8. Comparison of the observed data and predicted data using PK parameter for Rivastigmine healthy rat model. In addition, it indicates the... 50
Table 9. Comparison of the observed and predicted data using PK parameter for Rivastigmine healthy human model. In addition, it indicates the... 54
Table 10. Comparison of the observed data and predicted data using PD parameter for Rivastigmine Healthy rat model. 57
Table 11. Comparison of the observed data and predicted data using PD parameter for Rivastigmine Healthy human model. 60
Table 12. Comparison of the observed data and predicted data using PK parameter for Rivastigmine amnesic Rat model. In addition, it indicates the... 63
Table 13. Comparison of the observed data and predicted data using PK parameter for Rivastigmine Alzheimer's Disease patient model. In addition, it... 66
Table 14. Comparison of the observed data and predicted data using PD parameter for Rivastigmine disease model. 69
Figure 1. Schematic diagram of acetylcholine release course and cholinergic hypothesis in AD. 16
Figure 2. Molecular structure of donepezil. 18
Figure 3. Molecular structure of rivastigmine. 20
Figure 4. Simulated and observed plasma concentration-time profiles of Donepezil in rat after single oral dose (11.7mg/kg). 35
Figure 5. Simulated and observed plasma concentration-time profiles of Donepezil in rat after single oral dose (17.9mg/kg). 36
Figure 6. Overlay of observed (circles) plamsa concentration and simulated (lines) plasma concentration-time profiles of Donepezil... 39
Figure 7. Overlay of observed (circles) plamsa concentration and simulated (lines) plasma concentration-time profiles of Donepezil... 40
Figure 8. Simulated and observed acetylcholinesterase inihibition(%) profiles of Donepezil in rat after single oral dose(11.7mg/kg). 43
Figure 9. Simulated and observed acetylcholinesterase inihibition(%) profiles of Donepezil in rat after single oral dose (17.9mg/kg). 44
Figure 10. Simulated and observed acetylcholinesterase inihibition(%) profiles of Donepezil in human after single oral dose (4mg). 47
Figure 11. Simulated and observed acetylcholinesterase inihibition(%) profiles of Donepezil in human after single oral dose (6mg). 48
Figure 12. Simulated and observed plasma concentration-time profiles of Rivastigmine in rat after single oral dose (1.08mg/kg). 51
Figure 13. Simulated plasma concentration-time profiles of Rivastigmine in Healthy rat after single oral dose (0.4 mg/kg). 52
Figure 14. Simulated plasma concentration-time profiles of Rivastigmine in Healthy Human after single oral dose (3mg). 55
Figure 15. Simulated and observed cortex acetylcholine increases(%) profiles of Rivastigmine in rat after single oral dose(0.4mg/kg). 58
Figure 16. Simulated and observed acetylcholinesterase inihibition in Brain (%) profiles of Rivastigmine in Human after single oral dose(3mg). 61
Figure 17. Simulated plasma concentration-time profiles of Rivastigmine in amnesic Rat after single oral dose (2.5mg/kg). 64
Figure 18. A graph showing the predicted plasma concentration-time profile of rivastigmine in Alzheimer's disease after oral administration... 67
Figure 19. Simulated and observed acetylcholinesterase inihibition(%) profiles of Donepezil in human after single oral dose (6mg). 70
Figure 20. Simulated acetylcholinesterase inhibition (%) profiles of donepezil after single oral administration of each concentration in... 71
Figure 21. Schematic illustration of the developed PK/PD model for acetylcholinesterase Inhibitor drugs. Boxes indicate compartments, Conc_Central, Central drug concentration;... 75