표제지
목차
제1장 서론 15
1. 신약 개발 과정 및 최신 성공 전략 15
2. 약물동태학/약물동력학/계량약리학 20
2.1. 약물동태학(pharmacokinetics) 20
2.2. 약물동력학(pharmacodynamics) 25
2.3. 계량약리학(pharmacometrics) 30
3. 연구의 배경 43
3.1. 약물의 흡수 및 림프계 43
3.2. 장 림프 수송의 의미와 카일로마이크론 역할 45
3.3. 림프 흡수 예측의 필요 47
3.4. ex vivo 시험 및 in silico 모델을 통한 림프 흡수율의 예측 48
3.5. 림프 순환을 반영하는 생리학적 약물동태 모델 수립의 필요성 50
3.6. 연구 목적 51
제2장 연구방법 52
1. 문헌조사 및 Rat in vivo data 수집 52
2. 생리학적 약물동태 모델 도입 및 적용 57
2.1. PK 모델 구축 및 적용 57
2.2. PK 모델의 평가 및 검증(Model evaluation) 59
제3장 연구결과 60
1. 모델 적용을 위한 정보의 수집과 약물 선정 60
1.1. 림프 순환 지향성 조건 확인 및 약물의 선정 60
1.2. 림프 순환 지향성 Rat in vivo data 수집 65
1.3. 모델 적용 약물 별 카일로마이크론 결합률(%) 예측 90
2. 림프순환 반영 모델 적용 94
2.1. 림프순환 semi-PBPK 모델의 도입 94
2.2. 림프순환 메커니즘 약물 동태 모델을 통한 파라미터 산출 98
2.3. 림프순환 약물동태 모델의 검증 (Model validation) 103
2.4. 약물의 물리화학적 특성과 림프순환 약물동태 모델 파라미터의 상관성 126
2.5. 카일로마이크론 결합률(%)과 림프순환 약물동태 모델 파라미터의 상관성 127
제4장 결론 131
제5장 참고문헌 133
ABSTRACT 144
Table 1. Comparison between traditional drug development and model-based drug development. 19
Table 2. Compartmental pharmacokinetic model (model dependent analysis). 24
Table 3. The equations accounting for inter-individual and residual variabillity of Random effect. 40
Table 4. Rationale for drug selection. 53
Table 5. Various physical and chemical (physicochemical) properties of the Model compounds. 61
Table 6. Experimental information of rat in vivo pharmacokinetic study. 66
Table 7. Plasma concentration data of Acyclovir in Rats Following single oral administration of 19 mg/kg of Acyclovir. 68
Table 8. Plasma concentration data of Amiodarone in Rats Following single oral administration of 50 mg/kg of Amiodarone. 69
Table 9. Plasma concentration data of Amphotericin B in Rats Following single oral administration of 4.5 mg/kg of Amphotericin B. 70
Table 10. Plasma concentration data of BCY in Rats Following single oral administration of 13.2 mg/kg of BCY. 71
Table 11. Plasma concentration data of BET in Rats Following single oral administration of 13.2 mg/kg of BET. 72
Table 12. Plasma concentration data of Bexarotene in Rats Following single oral administration of 10 mg/kg of Bexarotene. 73
Table 13. Plasma concentration data of Cannabidiol in Rats Following single oral administration of 12 mg/kg of Cannabidiol. 74
Table 14. Plasma concentration data of dexanabinol in Rats Following single oral administration of 4.5 mg/kg of dexanabinol. 75
Table 15. Plasma concentration data of A phospholipid-valproic acid conjugate(DP-VPA) in Rats Following single oral administration of 100... 76
Table 16. Plasma concentration data of Halofantrine in Rats Following single oral administration of 8.33 mg/kg of Halofantrine. 77
Table 17. Plasma concentration data of Ibuprofen in Rats Following single oral administration of 10 mg/kg of Ibuprofen. 78
Table 18. Plasma concentration data of Indomethacin in Rats Following single oral administration of 22.5 mg/kg of Indomethacin. 79
Table 19. Plasma concentration data of Itraconazole in Rats Following single oral administration of 15 mg/kg of Itraconazole. 80
Table 20. Plasma concentration data of Ontazolast in Rats Following single oral administration of 100 mg/kg of Ontazolast. 81
Table 21. Plasma concentration data of Phenytoin in Rats Following single oral administration of 20 mg/kg of Phenytoin. 82
Table 22. Plasma concentration data of Probucol in Rats Following single oral administration of 100 mg/kg of Probucol. 83
Table 23. Plasma concentration data of PRS-211,220 in Rats Following single oral administration of 5 mg/kg of PRS-211,220. 84
Table 24. Plasma concentration data of RAC in Rats Following single oral administration of 13 mg/kg of RAC. 85
Table 25. Plasma concentration data of Retinoic acid in Rats Following single oral administration of 5 mg/kg of Retinoic acid. 86
Table 26. Plasma concentration data of Seocalcitol in Rats Following single oral administration of 47 ug/kg of Seocalcitol. 87
Table 27. Plasma concentration data of SN38-unde20 in Rats Following single oral administration of 10 mg/kg of SN38-unde20. 88
Table 28. Plasma concentration data of Tetrahydrocannabinol in Rats Following single oral administration of 12 mg/kg of Tetrahydrocannabinol. 89
Table 29. PLS model derived variable importance on projection (VIP) for each molecular descriptor and multivariate linear regression coefficients 90
Table 30. Classification of Chylomicron association rates. 91
Table 31. Prediction of Chylomicron association 92
Table 32. Information of parameters used in final moel. 96
Table 33. Final estimated parameters of semi-physiological based pharmacokinetic model considered lymphatic circulation of drugs. 99
Table 34. Multivariate analysis for correlation between FL and physicochemical properties. 126
Table 35. Comparison of CM(Chylomicron) association % with Model based parameters. 128
Figure 1. Drug discovery scheme. 16
Figure 2. Process of drug development. 16
Figure 3. Failures in translational research: preclinical and clinical Trials. 18
Figure 4. Pharmacokinetics & Pharmacodynamics. 23
Figure 5. Concepts of Clinical Pharmacokinetics (Pharmacokinetics vs. Pharmacodynamics). 26
Figure 6. Pharmacodynamics - Emax (The maximum effect of drug, Asscociated with drug 'efficacy'), EC₅₀ (Drug concentration of half...[이미지참조] 29
Figure 7. Application of pharmacometrics. 32
Figure 8. Naive pooled analysis method. Line : Population prediction. 34
Figure 9. Standard Two Stage Method. 35
Figure 10. Prediction of drug plasma concentration using nonlinear mixed effect modeling method.... 37
Figure 11. Example of Fixed effect. 38
Figure 12. Total variability : Nonlinear Mixed Effect Modeling. 40
Figure 13. PBPK modeling strategy in drug discovery and development. 42
Figure 14. Drug absorption via the intestinal lymphatic system and portal vein. The rate of flow of portal blood, however, is some... 44
Figure 15. Schematic diagram of the intestinal lymphatic transport pathway. Highly lipophilic drugs and prodrugs with appropriate... 46
Figure 16. Lymphatic availability of tested drugs (% of dose) vs. degree of association of drugs with isolated CM in the ex vivo model... 48
Figure 17. Correlation of experimental uptake by chylomicrons with predicted affinity of external set used in the validation of the... 49
Figure 18. Structures of Model compounds. 63
Figure 19. Plasma concentration of Acyclovir after oral administration of microemulsion, n=3 (A) : Logarithmic scale, (B) :... 68
Figure 20. Mean±SD plasma concentration versus time profiles of amiodarone after 50 mg/kg oral lipid-fed (n=6; Peanut oil) rats (A) :... 69
Figure 21. Plasma Amphotericin B concentration-time plot (mean±SD) following oral administration in Peceol/DSPE-PEG2000 (2.5... 70
Figure 22. In vivo pharmacokinetic profiles of BCY following oral administration in rats (n=5). (A) : Logarithmic scale, (B) : Normal scale 71
Figure 23. In vivo pharmacokinetic profiles of BET following oral administration in rats (n=5) (A) : Logarithmic scale, (B) : Normal scale. 72
Figure 24. Plasma concentration-time profiles of BEX following oral administration at 10 mg/kg (in linoleic acid) in rats (mean ± SD, n=... 73
Figure 25. Plasma concentration-time profiles of cannabidiol (CBD) following oral long-chain triglyceride (LCT)-based formulation (12... 74
Figure 26. Plasma dexanabinol concentration–time plot following PO administration in LCT solution(n=6) of dexanabinol in the dose of 4.5... 75
Figure 27. Plasma concentration–time profiles of DP-VPA following oral administration of 100 mg/kg DP-VPA Long chain triglyceride... 76
Figure 28. Plasma concentration–time profiles of halofantrine in rats after oral administration of Hf in LCT lipid-based formulations. (mean... 77
Figure 29. Plasma concentration profile of Ibuprofen following single oral administration of Ibuprofen to fasted male rats as suspension... 78
Figure 30. Mean arterial plasma concentration–time profiles of IDM after oral administration of IDM suspended in SES (Tween 85: EO, 3:7)... 79
Figure 31. Plasma concentration–time profile of itraconazole in rats after oral administration of SEDDS of itraconazole at a dose equivalent... 80
Figure 32. Plasma ontazolast C vs t profiles, as a function of formulation, following oral gavage dosing of 100 mg/kg to rats. (mean... 81
Figure 33. Mean serum concentration of phenytoin as a function of time following oral administration of 20mg/kg dose in the form of a... 82
Figure 34. Plasma concentration-time profile of probucol in rats after oral administration of 100 mg/kg in oil vehicles (0.5 ml; arachis... 83
Figure 35. Plasma PRS-211,220 concentration–time plot following PO administration in LCT solution n (n=6) of PRS-211,220 in the dose of... 84
Figure 36. In vivo pharmacokinetic and biodistribution profiles of RAC following oral administration in rats. RAC was administered at... 85
Figure 37. In vivo pharmacokinetic and biodistribution profiles of Retinoic acid following oral administration in rats. Retinoic acid was... 86
Figure 38. Serum concentration-time profiles following oral administration of 47 ug/kg of 3H-seocalcitol (equal to 40 MBq/kg) to... 87
Figure 39. Plasma exposure of SN38-unde20 following PO dosing of SN38-unde20-SMEDDS.(10 mg/kg) (mean ± SD, n=4). (A) : Logarithmic... 88
Figure 40. Plasma conc.-time profiles of △9-tetrahydrocannabinol (THC) following oral long-chain triglyceride (LCT)-based formulation... 89
Figure 41. Scheme of the developed final PK model to describe lymphatic circulation. 97
Figure 42. Visual predictive check plot of semi-physiological based pharmacokinetic model for Acyclovir (A), Amiodarone (B). 104
Figure 43. Visual predictive check plot of semi-physiological based pharmacokinetic model for Amphotericin B (A), BCY (B). 105
Figure 44. Visual predictive check plot of semi-physiological based pharmacokinetic model for BET (A), Bexarotene (B). 106
Figure 45. Visual predictive check plot of semi-physiological based pharmacokinetic model for CBD (A), Dexanabinol (B). 107
Figure 46. Visual predictive check plot of semi-physiological based pharmacokinetic model for DP-VPA (A), Halofantrine (B). 108
Figure 47. Visual predictive check plot of semi-physiological based pharmacokinetic model for Ibuprofen (A), Indomethacin (B). 109
Figure 48. Visual predictive check plot of semi-physiological based pharmacokinetic model for Itraconazole (A), Ontazolast (B). 110
Figure 49. Visual predictive check plot of semi-physiological based pharmacokinetic model for Phenytoin (A), Probucol (B). 111
Figure 50. Visual predictive check plot of semi-physiological based pharmacokinetic model for PRS-211,220 (A), RAC (B). 112
Figure 51. Visual predictive check plot of semi-physiological based pharmacokinetic model for Retinoic acid (A), Seocalcitol (B). 113
Figure 52. Visual predictive check plot of semi-physiological based pharmacokinetic model for SN38-unde20 (A), THC (B). 114
Figure 53. Goodness of fit plot of semi-physiological based pharmacokinetic model for Acyclovir (A), Amiodarone (B). 115
Figure 54. Goodness of fit plot of semi-physiological based pharmacokinetic model for Amphotericin B (A), BCY (B). 116
Figure 55. Goodness of fit plot of semi-physiological based pharmacokinetic model for BET (A), Bexarotene (B). 117
Figure 56. Goodness of fit plot of semi-physiological based pharmacokinetic model for CBD (A), Dexanabinol (B). 118
Figure 57. Goodness of fit plot of semi-physiological based pharmacokinetic model for DP-VPA (A), Halofantrine (B). 119
Figure 58. Goodness of fit plot of semi-physiological based pharmacokinetic model for Ibuprofen (A), Indomethacin (B). 120
Figure 59. Goodness of fit plot of semi-physiological based pharmacokinetic model for Itraconazole (A), Ontazolast (B). 121
Figure 60. Goodness of fit plot of semi-physiological based pharmacokinetic model for Phenytoin (A), Probucol (B). 122
Figure 61. Goodness of fit plot of semi-physiological based pharmacokinetic model for PRS-211,220 (A), RAC (B). 123
Figure 62. Goodness of fit plot of semi-physiological based pharmacokinetic model for Retinoic acid (A), Seocalcitol (B). 124
Figure 63. Goodness of fit plot of semi-physiological based pharmacokinetic model for SN38-unde20 (A), THC (B). 125
Figure 64. Chylomicron association (%) vs. parameter plot (A) : FL vs, CM association (%) (B) : KLC vs CM association (%), (C) : CL vs CM association. 130