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Pharmacokinetics Pharmacodynamics

Pharmacokinetics Pharmacodynamics. 가톨릭의대 약리학교실 서울성모병원 임상약리학과 임 동 석. Pharmacokinetic Phase. Pharmacodynamic Phase. Engineer’s view of human body. 투여경로에 따른 혈중약물농도 변화. C max. T max. PK begins at…. First Order Kinetics ln C = ln C(0) - kt ; C = C(0) exp(-kt) ; dC/dt = -kC.

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Pharmacokinetics Pharmacodynamics

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  1. Pharmacokinetics Pharmacodynamics 가톨릭의대 약리학교실 서울성모병원 임상약리학과 임 동 석

  2. Pharmacokinetic Phase Pharmacodynamic Phase

  3. Engineer’s view of human body

  4. 투여경로에 따른 혈중약물농도 변화 Cmax Tmax

  5. PK begins at…

  6. First Order Kineticsln C = ln C(0) - kt ; C = C(0) exp(-kt) ; dC/dt = -kC

  7. 실제로 정맥주사된 대부분의 약물은

  8. 이렇게 설명한다

  9. Distribution to peripheral tissues

  10. 약물의 단백결합 • 주로 albumin 또는 AAG (α1 acid glycoprotein) • Free fraction (단백질과 결합하지 않은 약물의 분율) • 높을수록 Vd 커짐

  11. Vd에 영향을 미치는 인자들 • 단백결합률: • 높을수록 말초까지 분포하는데 시간 오래 걸림 • 분자량: • 모세혈관을 빠져나가지 못할 정도로 크면 분포용적=혈장 용적, 예) mannitol • 단백질 약물에서는 예외 (why ?) • 지용성: 높을수록 Vd 커짐 • 조직 결합률: • 혈관 외의 신체 조직에 잘 결합할수록 Vd 커짐 (지용성이 높은 것과 동일한 원리)

  12. Albumin • total intravascular mass: 120 g. (serum conc. 40 g/L) • total extravascular mass: 160 g (interstitial conc. 14 g/L) • a circulation of albumin from the intravascular to extravascular space, returning via the lymphatic vessels. • circulation half-life of around 16–18 h. • 4–5% of intravascular albumin leaves the intravascular compartment per hour Aliment Pharmacol Ther 2002; 16 (Suppl. 5): 6–11.

  13. Distribution of body fluids • Total Body Water (TBW) : 60% of wt (42 L) • depends on fatty tissue. • newborn (80 - 85%), child (75%), adult males (63%) • lowest adult females (53%) and in adults with a large volume of adipose tissue • ICF: 2/3 of TBW, 40% of wt (28 L) • ECF: 1/3 of TBW, 20% of wt (14 L) • interstitial fluid (16%, = 10 L) • plasma (4%, = 2.8 L). *blood =

  14. Physiological significance: Vd • Aminoglycoside: Vd = ECF ? • Urea, antipyrine, ethanol: Vd=TBW ? • Corrected by proteinbinding: Vd = ECF + fu (TBW – ECF) • Corrected by tissue binding (lipophilicity) Vd = ECF + Φ ∙ fu (TBW – ECF)

  15. Extravascular Dose Flip-Flop Phenomenon

  16. Time to reach plateau ? • Q: 한꺼번에 Css 까지 농도를 높이고 싶다면? • A: loading dose ; Ass = Css x Vd Q: 위 식에서 e –kN 가 충분히 작아지는 (0에 가까워지는) 시간 (t = N)은? A: 4 half-life

  17. Concept of Clearance • 방안의 공기 속에 먼지가 100 mg/L의 농도로 존재한다. • 30분간 진공청소기를 돌리고 나서 청소기 필터에 걸린 먼지의 양을 측정해 보니 5 mg 들어있었다. • 이 청소기의 방안 공기에 대한 CL은 얼마인가 ?

  18. 그런데 먼지의 농도가 공기가 청소되어 가면서 시간에 따라 점점 감소한다면 CL은 어떻게 구하겠는가 ?

  19. Concept of Clearance • Rate of elimination = CL x Concentration 이고 • Amount excreted within the interval of dt = CL x C x dt • 무한대 시간 동안 몸 안에서 제거된 약물의 총량 = Dose • AUC: Area Under the Concentration - Time curve • k (elimination rate constant) = CL/V • CL = kV • t1/2 = 0.693V/CL = 0.693/k • (C = C(0) exp(-kt) 인 관계에서 유도된다)

  20. 생체이용률 (F; bioavailability) F = f  (1  ER) 정맥투여시에는 F=1 , ER=CLH/Q F=AUCoral/AUCiv *100(%)

  21. Non-linear Pharmacokinetics When Km << C, Zero order When Km >> C, First order : 1st Order kinetics

  22. Therapeutic Range, Therapeutic Window

  23. PK Summary • Bioavailability (F) • 투여량에서 실제 전신순환혈로 흡수되는 비율 • First order kinetics (대부분의 약물) • 4 half-life 지나면 대부분 제거, • 4 half-life 지나면 steady state 도달 • Zero order kinetics • No half-life, no constant clearance • Vd (분포용적) • Vd가 클수록, 조직 속에 숨어 있는 약물의 분율 (fraction) 이 높다는 뜻

  24. Monoclonal antibody • Target mediated drug disposition • Elimination in peripheral compartments • FcRN: longer half-life of IgG

  25. Pharmacodynamics

  26. Biomarker, surrogate endpoints

  27. PD models • Dose • Exposure • concentration • AUC

  28. PK-PD relation • Counter-clockwise hyteresis

  29. Why counter-clockwise hysteresis ? • Effect compartment model = direct model • Turnover model = physiological model, indirect model

  30. Effect compartment model Direct Effect model*effect compartment modellink model <We assume like this …> • Drug entering the Effect comp. ; 鳥 足 之 血 • One way ticket - The river of no return • At steady state, Cp = Ce *; Sheiner LB et al.Clin Pharmacol Ther 1979; 25:358-371

  31. Turnover model:Warfarin Data • PKPD Studies in Healthy Subjects • 1.5 mg/kg single oral dose • Total racemic warfarin plasma concentration • Prothrombin complex activity (PCA) • 32 subjects, 250 concentrations, 232 PCA • O'Reilly RA, Aggeler PM, Leong LS. Studies of the coumarin anticoagulant drugs: The pharmacodynamics of warfarin in man. Journal of Clinical Investigation 1963;42(10):1542-1551 • O'Reilly RA, Aggeler PM. Studies on coumarin anticoagulant drugs Initiation of warfarin therapy without a loading dose. Circulation 1968;38:169-177

  32. Warfarin Observations

  33. Kout Kin Response Elimination Synthesis

  34. Kout Kin Response Elimination Synthesis

  35. FDA published this in Mar, 2004

  36. http://www.fda.gov/oc/initiatives/criticalpath/presentations/bio200501_files/800x600/bio200501.htmlhttp://www.fda.gov/oc/initiatives/criticalpath/presentations/bio200501_files/800x600/bio200501.html

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