Title Page
ABSTRACT
Contents
List of Abbreviations 16
Chapter 1. Introduction 18
1.1. Study Background 18
1.2. Purpose of Research 21
Chapter 2. Methods 23
2.1. Clinical Study and Data Collection 23
2.1.1. Study Design and Population 23
2.1.2. PK Sample Collection and Bioanalytical Assay 27
2.1.3. PD Sample Collection and Bioanalytical Assay 30
2.2. Development of the Population PK Model 34
2.2.1. Base PK model development 34
2.2.2. Covariate PK model 35
2.2.3. Model validation 39
2.2.4. PK simulation in renal impairment patients 39
2.2.5. PD model of evogliptin 40
Chapter 3. Results 42
3.1. Clinical Study and Data Collection 42
3.1.1. Clinical study results 42
3.1.2. Pharmacokinetic results 45
3.1.3. Pharmacodynamic results 47
3.2. Development of the Population PK Model 49
3.2.1. Base model 49
3.2.2. Covariate model 54
3.2.3. Model validation 59
3.2.4. PK simulation 62
3.2.5. PD model of evogliptin 67
Chapter 4. Discussion 72
Chapter 5. Conclusion 82
Bibliography 83
Abstract in Korean 86
Table 1. Summary of clinical studies and available data from CKD, ESRD patients and healthy subjects 33
Table 2. Potential covariates and considered covariates in the stepwise analysis 38
Table 3. Summary of demographics and baseline characteristics 44
Table 4. Summary of PK parameters 46
Table 5. Summary of PD parameters 48
Table 6. Base model and stepwise covariate selection 53
Table 7. Parameter estimates of the population PK and PD parameters 56
Table 8. Simulated PK parameter of evogliptin in severe CKD and ESRD patients on HD 64
Figure 1. Proposed mechanisms for the effect of uremia on the non-renal clearance 22
Figure 2. Clinical study design of (A) Part I, and (B) Part II 26
Figure 3. Mean plasma evogliptin concentration-time profile after a single oral administration of evogliptin 5 mg. 51
Figure 4. Pharmacokinetic/pharmacodynamic model of evogliptin. 52
Figure 5. Individual predicted evogliptin concentration vs time overlapped with observed data 58
Figure 6. Goodness-of-fit of the final PK model for evogliptin. 60
Figure 7. Simulation results for the time-concentration profile of evogliptin after a single oral administration. (A) linear, (B) log scale. 61
Figure 8. The box diagram of Cmax and AUC0-120 simulated in different scenarios.[이미지참조] 66
Figure 9. Mean E(DPP-4 % inhibition)-time profiles after a single oral administration of evogliptin 5 mg.... 69
Figure 10. Observed DPP-4 inhibition and pharmacokinetic profiles, stratified by (A) time and (B) subject group 70
Figure 11. Observed data overlaid with simulated data of the PD model. Red line indicates the median, and blue box indicate 5 and 95%... 71