Title Page
Contents
국문초록 7
ABSTRACT 9
Ⅰ. Introduction 11
Ⅱ. Methods 16
1. BDQ & M2 PBPK model development and validation 16
2. PK/PD model development from whole-blood bactericidal activity (WBA) 23
3. PBPK/PD model simulate bactericidal activity in interstitial lung space according to different dosing regimen and dose suggestion 24
Ⅲ. Results 26
1. PBPK model development and validation 26
2. PK/PD model development 31
3. PBPK/PD model simulate bactericidal activity in interstitial lung space according to different dosing regimen and dose suggestion 35
3.1. PK profile prediction in infection site (Lung) using PBPK model 35
3.2. WBA (PD) prediction in infection site by linking PBPK model and PD model 37
3.3. Probability of target attainment (PTA) 40
Ⅳ. DISCUSSION 42
References 49
Table 1. Bedaquiline clinical data study 18
Table 2. Bedaquiline PBPK model input parameters 20
Table 3. M2 PBPK model input parameters 22
Table 4. Predicted and observed PK parameters of BDQ and M2 after single oral dose 400mg BDQ (Training dataset). 28
Table 5. Predicted and observed PK parameters of BDQ and M2 after single oral doses (validation dataset). 30
Table 6. Estimates of the population PK/PD parameters 32
Table 7. Calculated CFR for the different simulated dosing regimens 41
Figure 1. Work flow of bedaquiline PBPK model development and validation. 17
Figure 2. Result of PBPK model of BDQ and M2 in training dataset. 27
Figure 3. Result of PBPK model of BDQ and M2 in validation dataset. 29
Figure 4. Result of PBPK model of BDQ in validation dataset. 30
Figure 5. Basic Goodness-of-fit of PK/PD model. 34
Figure 6. Visual predictive check plot of PK/PD model. 35
Figure 7. Simulated concentration-time profile of BDQ and M2 in venous blood after administration of different dosing... 36
Figure 8. Simulated concentration-time profile of BDQ and M2 in lung interstitial space after administration of different... 37
Figure 9. Simulated mycobactericidal activity of different dosing regimen in lung interstitial space across MIC. 39
Figure 10. Probability of achieving WBA 〈0 for the simulated BDQ dosing regimens according to MIC distribution. 41