Pharmacokinetics (II)Pharmacokinetics (II)藥物動力學藥物動力學

鮑力恒鮑力恒

國防醫學院藥學系國防醫學院藥學系

階段階段 藥物探索藥物探索 藥物開發藥物開發 臨床前試臨床前試驗驗

PhaseⅠPhaseⅠ PhaseⅡPhaseⅡ PhaseⅢPhaseⅢ PhaseⅣPhaseⅣ

時程時程 XX 年年 1~31~3 年年 1~21~2 年年 0.5~10.5~1 年年 1~21~2 年年 2~32~3 年年 長期長期

目的目的 先導化合先導化合物探索物探索 , , 藥物設計藥物設計 ,, 藥物製藥物製備備 , , 活性活性篩選篩選

藥物最適藥物最適化化 , , 藥物藥物製劑開發製劑開發 ,, 藥劑開藥劑開發發

生物安全生物安全性及活性性及活性試驗試驗

安全性及安全性及劑量劑量

有效性及有效性及不良反應不良反應

確認有效確認有效性性 , , 長期長期使用之不使用之不良反應監良反應監測測

安全性安全性

取樣人數取樣人數 ---- ---- 實驗室及實驗室及動物試驗動物試驗

20~10020~100名健康志名健康志願者願者

100~400100~400名志願病名志願病患患

1000~3001000~30000 名志願名志願病患病患

長期觀察長期觀察服用者服用者

成功率成功率(%)(%)

-0.00-0.00 -0.1-0.1 2.52.5 7070 3333 2525

經費經費 (( 千千萬美元萬美元 ))

0.5~20.5~2 1~21~2 2.5~32.5~3 3~3.53~3.5 8~98~9 2020

Early and Late Phase StudiesⅠEarly and Late Phase StudiesⅠEarly Late

First administration First repeat dose Pilot pharmacokinetics/ p

harmacodynamics

Definitive pharmacokinetics/pharmacodynamicsBioavailabilityNew formulationsInteraction studies Drug/food Drug/drugMetabolic disposition Hepatic impairment Renal impairment Pharmacokinetics in the young and elderly

Single-dose pharmacokineticsRepeated-dose pharmacokineticsAbsolute systemic bioavailabilityFood effects Dose proportionality Mass balanceMetabolismTherapeutic monitoring during efficacy and safety studies

Phase 2 Clinical Studies Involving Pharmacokinetics

Phase 3 Clinical Studies Involving Pharmacokinetics

Therapeutic drug-level monitoring of safety and efficacy trials Special patient populationsRenal failureHepatic failureElderly versus young Drug interactionsBioavailability/bioequivalence of market-image versus clinical trial formulations

生體可用率與生體相等性生體可用率與生體相等性

學名藥與原開發廠學名藥與原開發廠國產藥品與國外進口藥品國產藥品與國外進口藥品

藥品含量 藥品主成份含量均一度 藥品之安定性 藥品之溶離試驗等 符合藥典之規定

體外品管之指標

A 廠 = B 廠 A廠藥效 = B 廠藥效

?

體內品管之指標 – 生體可用率

藥品有效成份由製劑中吸收進入全身血液循環或作用部位之量與速率之指標。

血漿

中藥

物濃

度

體內品管之指標 – 生體可用率 (BA)

時間

最高濃度：吸收之速率

曲線下之面積：吸收進入體內之量

以相同條件給予同一組人：–隨機交叉試驗方式，以減少個體間之差異

生體相等性 (BE)

試驗期一試驗期一 試驗期二試驗期二

第一組試驗者第一組試驗者 A A 藥藥 B B 藥藥

第二組試驗者第二組試驗者 B B 藥藥

A A 藥藥

生體相等性 (BE)

血漿

中藥

物濃

度

時間

- 原製造廠

- 非原製造廠

生體相等性 (BE) 之判斷血

漿中

藥物濃

度

時間

血漿中

藥物濃

度

時間血

漿中藥

物濃

度

時間

新劑型的研發

控釋劑型之設計控釋劑型之設計

藥物自控釋劑型中釋出之量：藥物自控釋劑型中釋出之量：藥物之藥動性質藥物之藥動性質治療濃度治療濃度用藥頻率用藥頻率

DDtottot = D = Dii + D + Dmm

DDi i :: 初始劑量初始劑量DDm m : : 維持劑量維持劑量 - - 以以 zero-order(kzero-order(k00)) 釋出維持釋出維持 ttdd 時間時間

DDtottot = D = Dii + k + k0 0 ttdd

DDtottot = D = Dii - k - k00ttpp+ k+ k0 0 ttdd

ttd d : : 到達最高濃度所需之時間到達最高濃度所需之時間

控釋劑型之設計 – 劑量之計算

控釋劑型之設計 – 釋出之速控釋劑型之設計 – 釋出之速率率

到達穩定狀態到達穩定狀態Rate in = Rate outRate in = Rate out

藥物自體內清除之速率 ：藥物自體內清除之速率 ： ClClTT (ml/mi (ml/mi

n)n)ClClTT (ml/min) x C (ml/min) x Cpp (μg/ml) = μg/min (μg/ml) = μg/min

KK00 = Cl = ClTT C Cpp

Dtot = ClT Cp τ

Transdermal dosage formTransdermal dosage form穿皮製劑穿皮製劑

如何判斷是否該出方之實用性？

穿皮速率是否足夠？

體外穿皮試驗體外穿皮試驗流量 流量 (Flux)(Flux) ：單位時間內穿擴單位面：單位時間內穿擴單位面積之藥量積之藥量

體外實驗之結果體外實驗之結果

PCSdt

dMJ

此可視為單位面積藥物之給藥速率

治療濃度：治療濃度： CpCp藥物之清除率：藥物之清除率： ClCl

藥物自體內之清除速率：藥物自體內之清除速率： RR R = Cl*CpR = Cl*Cp

製劑面積大小 製劑面積大小 = Cl*Cp / J= Cl*Cp / J可知是否要製成背心穿在身上才會有效可知是否要製成背心穿在身上才會有效

臨床藥物治療監測臨床藥物治療監測Therapeutic Drug MonitoringTherapeutic Drug Monitoring

TDM TDM - Applied Pharmacokinetics- Applied Pharmacokinetics

Steady-stateSteady-state

Rate in = F . Dose / t

Unit : mg/hr

Rate out = Css . CL

Unit : mg/L . L/hr = mg/hr

例題：例題：•一男性 Asthma 病患： 40 歲，體重： 70 Kg ，如給予 Aminophylline IV infusion( 點滴 ) ，則其 Loading dose ( 初始劑量 )是多少 ?

•兩天以後，病患出院，改以口服之劑型，病患之服藥劑量應是多少？要多久服用一次？

Population PharmacokineticsPopulation Pharmacokinetics

Source of variabilitySource of variability

Drug is distributed in the bodyModern Drug Delivery

The drug.

Drug acts on the bodyPharmacodynamicsEfficacy and Toxicity

Clinical endpoint

Body acts on the drug, ADME, Pharmacokinetics

Clinical data are sparse and observational. Population mixed- effect Clinical data are sparse and observational. Population mixed- effect modeling method is a fundamental tool for characterizing the multi –modeling method is a fundamental tool for characterizing the multi –

dimensional relationships with sparse datadimensional relationships with sparse data

Time (h)

Dru

g C

on

cen

tra

tion

0 2 4 6 8 10 12

0.0

0.0

20

.04

0.0

6

Extensive PK

Time (h)

Dru

g C

on

cen

tra

tion

0 1 2 3 4 5 6

0.0

0.0

50

.10

0.1

50

.20

Sparse PK

Time (h)

Dru

g C

once

ntr

atio

n

0 1 2 3 4 5 6

0.0

0.0

50

.10

0.1

50

.20

Mixed Effects Modeling

ExposureExposure

Exposure

Effe

ct(%

)

0 2 4 6 8

02

04

06

08

01

00

Efficacy

Exposure

pro

ba

lity(

DLT

)

0 2 4 6 8 10 120

.00

.20

.40

.60

.81

.0

Safety

Choice of Dosage Regimen

PopulationPopulation approachapproach To utilize sparse data in data analysisTo utilize sparse data in data analysis To handle mixed data setsTo handle mixed data sets To screen covariates that impact drug’s kinetic To screen covariates that impact drug’s kinetic

and dynamic propertiesand dynamic properties To model random inter-subject, intra-subject, To model random inter-subject, intra-subject,

as well as inter-occasion variabilitiesas well as inter-occasion variabilities To estimate individual kinetic and/or dynamic To estimate individual kinetic and/or dynamic

parameters via post hocparameters via post hoc To simultaneously model kinetic, dynamic, and To simultaneously model kinetic, dynamic, and

safety datasafety data

SoftwareSoftware Software used for modeling: Software used for modeling:

S-PLUSS-PLUS WinNonMix WinNonMix PpharmPpharm SAAM II Pop SAAM II Pop NONMEMNONMEM OtherOther

Software used for model automation: Software used for model automation: ExposeExpose WinBugs WinBugs WAMWAM OtherOther

Software validationSoftware validation Software modificationSoftware modification Custom softwareCustom software

Examples: Pediatric PKExamples: Pediatric PK Number of subject are limited Number of subject are limited Measurements are sparse, unbalanced, and very limited.Measurements are sparse, unbalanced, and very limited. PK characteristics may differ from those of Adults or unknPK characteristics may differ from those of Adults or unkn

ownown CL may be a function of Age, or BSACL may be a function of Age, or BSA Vd may be a function of WTVd may be a function of WT Poor protocol compliancePoor protocol compliance Product development time lineProduct development time line Cost in increasing N vs. increasing nCost in increasing N vs. increasing n Competitors marketCompetitors market Age or WT data treated as groups vs. as continuous variaAge or WT data treated as groups vs. as continuous varia

bles.bles.

Sampling time optionsSampling time options

0

1

2

3

4

5

6

0 5 10 15 20 25 30

Time (hours)

Co

nc.

(ug

/ml)

0

1

2

3

4

5

6

0 5 10 15 20 25 30

Time (hours)

Co

nc.

(ug

/ml)

0

1

2

3

4

5

6

0 5 10 15 20 25 30

Time (hours)

Co

nc.

(ug

/ml)

0

1

2

3

4

5

6

0 5 10 15 20 25 30

Time (hours)

Co

nc.

(ug

/ml)

Sampling OptionsSampling Options

0

2

4

6

8

10

12

14

0 10 20 30 40 50 60 70 80 90 100

Time (hours)

Co

nc.

(u

g/m

l)

0

2

4

6

8

10

12

14

0 10 20 30 40 50 60 70 80 90 100

Time (hours)

Co

nc.

(u

g/m

l)

0

2

4

6

8

10

12

14

0 10 20 30 40 50 60 70 80 90 100

Time (hours)

Co

nc.

(u

g/m

l)

0

2

4

6

8

10

12

14

0 10 20 30 40 50 60 70 80 90 100

Time (hours)

Co

nc.

(u

g/m

l)

Pediatric PK studyPediatric PK study

TIME

DV

0 5 10 15 20

05

10

15

Conc vs. Time, STS method

TIME

DV

0 5 10 15 20

02

46

810

Conc vs. Time, POP method

Results - Ped. Study (cont.)Results - Ped. Study (cont.)0

24

68

10

12

1 2 3 4

Group

CL

PPK method

02

46

81

01

2

1 2 3 4

Group

CL

s

STS method

Results - Ped. Study (cont.)Results - Ped. Study (cont.)0

20

40

60

80

1 2 3 4

Group

V

PPK method

02

04

06

08

0

1 2 3 4

Group

Vs

STS method

Results - Ped. Study (cont.)Results - Ped. Study (cont.)0

12

34

5

1 2 3 4

Group

KA

PPK method

01

23

45

1 2 3 4

Group

KA

s

STS method

Results - Ped. Study (cont.)Results - Ped. Study (cont.)

CL

CL

s

2 4 6 8 10

24

68

10

12

14

Regression CLpop vs CL

Results - Ped. Study (cont.)Results - Ped. Study (cont.)

V

Vs

0 20 40 60

02

04

06

08

0

Regression Vpop vs V

PK-PD modelingPK-PD modeling

CARDIOVASCULAR EFFECT AND SIMULTANEOUS PHARMACOKINETIC AND

PHARMACODYNAMIC MODELING OF PIMOBENDAN IN HEALTHY NORMAL SUBJECTS

KAI-MIN CHU, OLIVER YOA-PU HU, AND SHYH-MING SHIEHPharmaceutical Research Institute, National Defense Medical Center (O.Y.-P.H.)

and Division of Cardiology, Department of Medicine,Tri-Service General Hospital, National Defense Medical Center (K.-M.C., S.-M.S.),

Taipei, Taiwan, Republic of China(Received September 11, 1998; accepted February 10, 1999)

This paper is available online at http://www.dmd.org

Pimobendan is an inotropic agent with vasodilator properties.

There was a delay between the peaking time of plasma pimo concentration and the Emax (changes in LVESD)

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