1. 2014. 3. 21. Lee,Sang-Hwi Pharmacokinetics (PK)

2. Overview Pharmacokinetics (PK) studies the concentration time course of compounds and metabolites in vivo Key parameters are volume of distribution (Vd), area under the curve (AUC), clearance (Cl), t 1/2, C max and bioavailability (BA). PK data are heavily used by discovery teams and correlated to pharmacodynamic s(PD). -2-

3. -3- Intravenous Intramuscular Intraperitoneal Subcutaneous

4. -4- Introduction to PK Drug-Drug interaction

5. -5- (IV 투여시에만 존재 )

6. Volume of Distribution (V d ) (unit : L/kg) -6- f u, blood : fraction of compound unbound in blood f u,tissue : fraction of compound unbound in tissue 체내에서의 약물 분포 약물투여량 (dose) 과 약물의 초기농도 (C 0 ) 에 의해서 결정되는 가상적인 파라미터 적절한 약물용량을 결정 하는데 중요한 파라미터 High nonspecific tissue binding, higher lipophilicity, lower PPB  Enhance V d (↑) V d = Dose / C 0 (iv 에서의 초기농도 ) V d = V blood + V tissue (f u blood /f u tissue )  Tightly bound in blood (↑)  f u blood (↓) V blood (predominate)  Tightly bound in tissue (↑)  f u tissue (↓) V tissue (predominate)

7. -7- Highly hydrophilic Highly lipophilic moderately lipophilic and moderately bound to plasma protein and tissue componets BloodTissue

8. Area Under the Curve (AUC), (unit : μg/ml·h) -8- 생체시스템으로 투여된 약물이 전신순환계에 노출된 약물의 양 정맥투여시 C L 결정하는데 직접적으로 사용 경구투여시 약물의 생체시스템에 노출된 양을 결정함으로써 전체적인 약물의 약효와 독성 발현전 도를 예측할 수 잇는 중요한 체내 동태 파라미터 Oral exposure usually is lower than IV exposure because of additional barriers (permeation, solubility, intestinal decomposition) limit intestinal absorption, first-pass metabolism and biliary extraction that eliminate compound material before it reaches bloodstream

9. How rapidly the compound is extracted from systemic circulation(bloodstream) and eliminated. Clearance = elimination + metabolism -9- Clearance (C l ) (unit : ml/min/kg) Systemic clearance (Cl S ) = Cl R + Cl H Cl = Dose/AUC iv = (µg/kg)/(µg·min/ml) = ml/min/kg

10. -10- Clearance (CI) Clearance by an organ : Cl = Q * E (Q : blood flow into the organ / E : extraction ratio by the organ) if clearance is determined, it can be used to estimate the dose for the therapeutic effect. correlated to half-life

11. Half-life (t½) -11- Time for blood concentration to reduce by half 혈중약물 농도가 ½ 로 줄여드는데 필요한 시간 약물의 투여간격을 결정하는데 주요한 파라미터 t 1/2 = 0.693 / k (k : elimination rate constant from the slope) = 0.693 X (V d /Cl)

12. Bioavailability (%F) The fraction of dose that reaches systemic circulation unchanged 전신순환계에 도달하는 약물의 용량을 나타내는 비율 정맥주사투여 (IV) 의 경우와 비교하여 전신순환계로의 노출정도 -12- < 100% bioavailability 이유 ? 1) incomplete intestinal absorption or first-pass metabolism 2) enzymatic or pH-induced decomposition in the intestine or blood F(%) = (AUC PO /AUC IV ) X (Dose IV /Dose PO ) X 100%

13. -13- Bioavailability of XXXX in RccHan Wistar rat BA(%) = (AUC po /AUC iv )X(Dose iv /Dose po )X100 = (4.01/2.07)X(1/5)X100 = 37.5% PK parameters of XXXX Animal RccHan Wistar Rat ( ♂ ) Animal RccHan Wistar Rat ( ♂ ) BioanalysisLLE BioanalysisLLE Admin. Comp.XXXX Admin. Comp.XXXX Detected Com p. XXXX Detected Com p. XXXX Vehicle DMSO : PEG400 : Tween80 : 0.1M NaHCO 3 = 10 : 20 : 10 : 60 Vehicle DMSO : PEG400 : Tween80 : 0..1M NaHCO 3 = 10 : 20 : 10 : 60 Admin. Routei.v Admin. Routepo Dose (mg/kg)1 5 ParameterRat No.#1#2Mean ParameterRat No.#1#2Mean t1/2_Lambda_z (h)8.172.635.40 Tmax (h)4.002.003.00 AUCall (ug·h/mL)2.541.592.07 Cmax (ug/ml)0.510.620.56 AUCINF(observed) (h·ug/mL)2.711.722.21 t1/2_Lambda_z (h)5.224.284.75 Cl(observed) (mL/h/kg)369582476 AUCall (ugh/ml)3.534.484.01 MRTINF(observed) (h)5.481.933.70 AUCINF (observed) (ugh/ml)3.694.614.15 Vss(observed) (mL/kg)202511221573 BA(%) 37.5

14. Problem ( 단위 일치에 특히 조심 !!!) -14- F(%) = (AUC PO /AUC IV ) X (Dose IV /Dose PO ) X 100%

15. -15- Cl= Dose/AUCIV = (1mg/kg) / (1000ng·h/mL) = (10 -3 g/kg) / (4000X10 -9 gX60min/mL) = (10 -3 g/kg) / (24X10 -5 g·min/mL) = (100g/kg) / (24g·min/mL) = 4.2 mL/min/kg m=10 -3 μ =10 -6 n =10 -9 Cl = Dose/AUC iv V d = Dose / C 0 Vd= Dose/C0 = (1mg/kg) / (1000ng/mL) = (10 -3 g/kg) / (10 -6 g/0.001L) = (10 -3 g/kg) / (10 -3 g/L) = 1 L/kg F(%) = (AUC PO /AUC IV ) X (Dose IV /Dose PO ) X 100%

16. -16- (IV 투여시에만 존재 )

17. General PK Parameter Goals for Discovery Compounds -17-

18. Pharmacokinetic Parameters of Selected Drug Compounds -18- High C L  Low BA

19. -19-

20. -20- prodrug