3 - multiple exposure models.pptx

8/16/2019 3 - Multiple Exposure Models.pptx

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Multiple Exposure ModelsSukamto S M

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Single exposure

Single Bolus IV Inj.(Instant Abs)

t

C

t

C

Single ral !ose(1st rder Abs.)

t

C

!

Single IV In". orCont. #ung Exp.

($ero%rd. Abs.)

&

'!

&&

k&


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Multiple exposures

C

t

!1 ! !*

C!1 C! C!*

C + C!1 , C! , C!*

Multiple Instant Absorption Exposures(bolus IV or pseudo%instantaneous

absorption) *


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Multiple exposures

C

t!1 ! !*

C!1C! C!*

C + C!1 , C! , C!*

Multiple $ero%rder Absorption Exposures(IV in"usion- prolonged lung exposures- et.)

/


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Multiple exposures

C

t

!1 ! !*

C!1 C! C!*

C + C!1 , C! , C!*

Multiple 1st%rder Absorption Exposures(oral- im- ip- s- et.)

0


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Introdution

Examples

Mediine taken t2ree times a da3 e4er3 5 2r (τ

+ 5 2r)upational air exposure e4er3 da3 during 5 2r

6ork s2i"t (τ + /2r- + 52r)

Consumption o" ontaminated 7s2 one per

6eek (τ + 1 6eek or 8 da3s)

0

!

τ

!

2τ

!

3τ

!

4τ

!

5τ

!

6τ

!

7τ

!

8τ

!

9τ

!

10τ

!

τ + time period bet6eenexposures

9


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Introdution

6o main "ators:parameters t2atmust be onsidered in multipleexposures

◦ 2e si;e o" t2e drug dose◦ 2e "re


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E x a m p l e

Multiple bolus i4 injetions o" lidoaine (drug "or treating2eart attak patients- V + 1.1 #:kg- t1:-elim + 1.5 2r-

Ct2erapeuti + 1.0%9 mg:#- Ctoxi > 9 mg:#). A ? kg patient

enters t2e emergen3 room at 80& pm su@ering "rom a

2eart attak.!1 A bolus i4 injetion o" && mg lidoaine is administered

at 5&& pm.

! A seond bolus i4 injetion o" 0& mg lidoaine is

administered at 5*& pm.

!* A t2ird bolus i4 injetion o" *&& mg lidoaine is

administered at ?*& pm.

!etermine 62et2er t2is patients plasma lidoaine le4elsare 6it2in t2e t2erapeuti or toxi range at ea2 o" t2e

"ollo6ing time points◦ ust be"ore ?*& m in etion

5


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A n s 6 e r

Di4enV+ 1.1 #:kg ?kg + 1&1 #

k + &.9?*:1.52r + &.*? 2r%1

ust be"ore ?*& pm injetion

C + 1.1 mg:# , 1.8 mg:# + .5 mg:# (6it2int2erapeuti range)

C + C!1 1.0 2r ,C! 1.& 2r +&& mg

1&1 # e%&.*? 2r

%1 1.0 2r ,0& mg

1&1 # e%&.*?2r

%1 1.& 2r

?


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Ans6erImmediatel3 a"ter ?*& pm injetion

C + 1.1 mg:# , 1.8 mg:# , *.& mg:#+ 0.5 mg:#

(4er3 near toxi range)

At && am

C + &.1? mg:# , &.? mg:# , &.01 mg:#+ &.??mg:#

(belo6 t2erapeuti range)

C + C!1 1.0 2r ,C! 1.& 2r ,C!* & 2r

C +&& mg

1&1 # e%&.*? 2r

%1 1.0 2r ,0& mg

1&1 # e%&.*? 2r

%1 1.& 2r ,*&& mg

1&1 # e%&.*? 2r

%1 & 2r

1&


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Combination o" bolus IVinjetion and IV in"usion

C

t!bolus

!in"usion

Cbolus

Cin"usion

C + Cbolus , Cin"usionC&-bolus+ Css-in"usion

!uring t2e in"usion period "or t2is ase

C + Cbolus

, Cin"usion

+ Css

e%kt , Css

(1%e%kt) + Css

+

onstant 11


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e@ets o" a ne6 antibioti (V + &.0 #:kg- t1:-elim + .9 2r). 2e

drug is i4 in"used o4er an 5 2r period at a rate o" 1.& mg:2r. Inaddition- a *.80 mg dose o" t2e drug is gi4en b3 bolus i4injetion at t2e start o" t2e in"usion.

Estimate t2e initial plasma drug onentration just a"ter t2e bolusi4 injetion is administered.

Ans6er

C& + !:V + *.80 mg:&.10 # + *& mg:#

Estimate t2e plasma drug onentration at - 5- and 1 2r a"tert2e start o" t2e in"usion.

Ans6er

Css-in"usion + *& mg:#F k + &.9?*:.9 + &.8 2r%1

Glasma drug onentration at 2r a"ter t2e start o" in"usion

C + Csse%kt , Css(1 H e

%kt) + *&(e%&.8)J , *&(1 H e%&.8)J + 18./5 , 1.01


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oxiolog3 tests are per"ormed in 0& g rats to determine t2ee@ets o" a ne6 antibioti (V + &.0 #:kg- t1:-elim + .9 2r). 2e drug

is i4 in"used o4er an 5 2r period at a rate o" 1.& mg:2r. In addition-a *.80 mg dose o" t2e drug is gi4en b3 bolus i4 injetion at t2estart o" t2e in"usion.

Glasma drug onentration at 5 2r a"ter t2e start o" in"usion C + Csse

%kt , Css(1 H e%kt) + *&(e%&.85)J , *&(1 H e%&.85)J + *./9 ,

9.0/ + *& mg:#

Glasma drug onentration at 1 2r a"ter t2e start o" in"usion C + Csse

%kt + *&e%&.8/ + 1&.1? mg:#

1*


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ne%Compartment Instantaneous

Absorption(Bolus IV or pseudo%instant Absorption)

1/


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ne%Compartment InstantaneousAbsorption (Bolus IV or pseudo%instantAbsorption)

C

t

Stead3%StateCss

At t1:- elim 0&K to stead3stateAt t1:- elim 80K to stead3

stateAt 8t1:- elim ??K to stead3

stateAt 1&t1:- elim ??.?K to

! ! ! ! ! ! ! ! ! ! !

C

t

Lt2

!ose

CL-max

CL-min

Css-max

Css-min

Stead3%

State

Css-a4

10


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CL-max +'!V

1 H e%Lkτ

1 H e%kτCss-max+

'!V

11 H e%kτ

2e maximum onentration "or an3 gi4en exposure inter4alours at t + &

2e minimum onentration "or an3 gi4en exposure inter4alours at t + τ

CL-min +'!

V

1 H e%Lkτ

1 H e%kτ

e%kτ +CL-max e%kτ

Css-min +'!V

11 H e%kτ

e%kτ +Css-maxe%kτ

2e a4erage onentrationduring at stead3%state anbe de7ned b3

Css-a4e+

CssdtM

&

τ

dtM&

τ +'!

Vkτ + '!

C# τ

"or & N t N τ

o alulate onentrationa"ter t2e Nth dose

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'inall3- onsider 62at 2appens i" t2e exposuresstop ourring a"ter t2e Nth dose or a"ter stead3%state 2as been rea2ed

! ! ! !

C

t

Lt2!ose

Conentrations an be predited "or an3 time a"ter exposuresstop b3 using t2e 7nal CL e


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Exposures stop a"ter stead3%state isrea2ed

! ! ! ! ! ! ! ! !

C

t

Stead3%State

Conentrations an be predited "or an3 time a"ter

exposures stop b3 using t2e 7nal Css e


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2e "ollo6ing general relations2ipst2en appl3

I" τ O t1:-elim- t2ere is a lot o" 2emial buildup +> 2ig2eronentrations

I" τ > t1:-elim- t2ere is little 2emial buildup +> lo6er

onentrations'! P +> C P (more 2emial absorbed duringea2 inter4al)

t1:-elim P +> C P (less 2emial eliminated during

ea2 inter4al)

k P +> C Q (more 2emial eliminated duringea2 inter4al)

τ P +> C Q (2emial enters t2e bod3 less

o"ten) 1?


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Example Calulations % Et2osuximide is anantion4ulsant drug gi4en orall3 t2at "ollo6s psuedo%instantaneous absorption kinetis- 6it2 V + &.8 #:kg-

t1:-elim + /0 2r- and ' + 1&&K. Estimate t2e "ollo6ing "ora 0 kg 6oman taking 1&&& mg o" et2osuximide oneper da3.

a) Glasma onentration / 2r a"ter 7"t2 dose

b) Lumber o" da3s needed to rea2 ??K o" stead3%state

onditions

) Maximum stead3%state onentration

d) Minimum stead3%state onentration

e) A4erage stead3%state onentration

") Conentration /5 2r a"ter stopped taking drug atstead3%state onditions

&

V + &.8 #:kg 0 kg + *8./ #

k + &.9*?:t1:-elim + &.9*?:/02r + &.&10/ 2r%1

L + 0

t + / 2r

τ

+ / 2r


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C +'!

V

1 H e%Lkτ

1 H e%kτ

e%ktM +1.& 1&&& mg

*8./ #

1 H e%0 &.&10/2r

%1 / 2r

1 H e% &.&10/2r%1 / 2r

e% &.&10/2r%1 / 2r +95.0 mg:

Plasma concentration 4 hr after fth dose:

Number of days needed to reach 99% ofsteady-state conditions:

8Rt1:-elim + 8 (/0 2r) + *10 2r + 1*.1 da3s

Maximum steady-stateconcentration:Css-max+

'!V

11 H e%kτ

+1.& 1&&& mg

*8./ # 1

1 H e%&.&10/2r%1 / 2r

+59.0 mg:

Minimum steady-state concentration:

Css-min +Css-maxe%kτ + 59.0 mg:# e%&.&10/2r%1 / 2r +0?.5 mg:

1


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Average steady-state concentration:

oncentration 4! hr after sto""ed ta#ingdrug at steady-state conditions:

Css-a4e+'!Vkτ

+1.& 1&&& mg

*8./ # &.&10/2r%1 / 2r +8.* mg:

C + Css-maxe%ktM + 59.0 mg:# e%&.&10/2r %1 /5 2r +/1.* mg:

Lote t2at t2e t2erapeuti plasma onentration range "oret2osuximide is /&%1&& mg:#- so t2at t2is dosage s2edule

keeps plasma le4els 6it2in t2e desired range at stead3%state.


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$ne-om"artment ero-$rderAbsor"tion&'( infusion) continuous lungex"osure*

*


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C

t

Lt2!ose

CL-max

CL-min

CL(tM)

Css-max

Css-min

Css(tM)

Stead3%State

ko ko ko ko ko ko ko ko ko ko ko

2e onentration during t2e exposure period (&N t N ) o" t2e Lt2 inter4al or at stead3%state isgi4en b3

62ere t + time sine t2e start o" t2e most reent exposure

"or & N t N

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2e onentration during t2e post%

exposure period( N t N τ) o" t2e Lt2 inter4al or atstead3%state is gi4en b3

"or N t N τ

0


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2e maximum onentration duringea2 inter4al ours 62en t +

CL-max +

koVk 1 H e

%k

1 H e%Lkτ

1 H e%kτ

Css-max+koVk

1 H e%k 11 H e%kτ

2e minimum onentration during ea2

inter4al ours at t + &

CL-min +koVk

1 H e%k 1 H e% LH1 kτ

1 H e%kτ e%k τ%

Css-min

+ko

Vk 1 H e%k 1

1 H e%kτ e%k τ%

Css-a4e +'!Vkτ

+ '!C# τ

9


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62ere t is t2e time sine t2e start o" t2e last exposure period

Conentrations during t2e 7nal exposure period are t2e sameas gi4en pre4iousl3 "or t2e exposure period o" t2e Lt2

I" exposures stop a"ter t2e Lt2 dose- t2enonentrations a"ter exposures stop are gi4enb3

"or t

I" exposures stop a"ter stead3%state isrea2ed- t2en onentrations a"terexposures stop are gi4en b3

"or t

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$ne-om"artment +irst-$rderAbsor"tion &oral) im) i") sc) etc*

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! ! ! ! ! ! ! ! ! ! !

C

t

Lt2!ose

CL-max

CL-min

CL(tM)

Css-max

Css-min

Css(tM)

Stead3%State

2e onentrations during t2e Lt2 inter4al isgi4en b3

"or & N t Nτ

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2e maximum onentration during ea2 inter4al ours 62en t +tmax

CL-max +'!V

ka

ka H k

1 H e%Lkτ

1 H e%kτ e%ktMmax H

1 H e%Lkaτ

1 H e%kaτ e%katMmax

Css-max+'!V

ka

ka H k 1

1 H e%kτ e%ktMmax H 1

1 H e%kaτ e%katMmax

T2ere tmax +

#n (ka:k) (1%e%kτ):1%e%kaτ)J

ka % k

2e minimum onentration during ea2inter4al ours at t + &

CL-min +'!V

kaka H k

1 H e%Lkτ

1 H e%kτ H 1 H e

%Lkaτ

1 H e%kaτ

Css-min +'!

V

ka

ka H k 1

1 H e%kτ H 1

1 H e%kaτ

Css-a4e +'!Vkτ

+ '!C# τ

*&


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I" exposures stop a"ter stead3%state isrea2ed- t2en onentrations a"terexposures stop are gi4en b3

62ere t is t2e time sine t2e last dose

"or t &

I" exposures stop a"ter t2e Lt2 dose- t2enonentrations a"ter exposures stop are

gi4en b3

62ere t is t2e time sine t2e last dose

"or t &

*1


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An experimental arti7ial Ua4or additi4e is being testedb3 administering a && mg oral dose t6ie a da3 (e4er31 2r) in * kg rabbits. Gre4ious single dose

toxiokineti experiments indiate V + ./ #:kg- ' +88K- t1:-elim + 5.9 2r- and t1:-abs + 1.* 2r. sing t2e

repetiti4e dosing one%ompartment 7rst%orderabsorption e


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An experimental arti7ial Ua4or additi4e is being tested b3administering a && mg oral dose t6ie a da3 (e4er3 1 2r) in *kg rabbits. Gre4ious single dose toxiokineti experimentsindiate V + ./ #:kg- ' + 88K- t1:-elim + 5.9 2r- and t1:-abs + 1.*

2r. sing t2e repetiti4e dosing one%ompartment 7rst%orderabsorption e


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An experimental arti7ial Ua4or additi4e is being tested b3administering a && mg oral dose t6ie a da3 (e4er3 1 2r) in *kg rabbits. Gre4ious single dose toxiokineti experimentsindiate V + ./ #:kg- ' + 88K- t1:-elim + 5.9 2r- and t1:-abs + 1.*

2r. sing t2e repetiti4e dosing one%ompartment 7rst%orderabsorption e


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1&t1:-elimination +

1&5.9 + 59 2r W*.9

da3;;;;......;;;;.....;;;;;..;;;;..;;;;.;;;...;;;...;;;..;;;;;.;;;;....;;;;.....;;;;.......;;;

;;;....;;;;;

*0


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Xuis

1) Gemberian obat oral seara umum mengikuti kinetika absorpsiorde nol

) bat generik bermerek adala2 obat generik 3ang namadagangn3a sama dengan nama ;at akti"n3a

*) Bioa4ailabilitas relati" membandingkan obat A 3ang diberikandengan rute non%IV dan obat B 3ang diberikan dengan rute IV

/) Metabolisme lintas pertama melibatkan organ 2ati0) bat dengan aturan pakai / x 1 memiliki nilai τ = 0 jam

9) ntuk menentukan aturan pakai obat- maka nilai t1: obat

memainkan peran penting

8) Sebua2 obat dengan t1: + jam- maka untuk menapai ??K

kadar tunak 6aktu 3ang dibutu2kan adala2 & jam

5) Genambang 3ang bekerja di pertambangan dari pukul 5 sampaipukul 1 selama 0 2ari seminggu memiliki nilai + / jam

?) ika nilai τ > t1: - maka akan terjadi akumulasi obat dalam tubu2

1&)Lotasi Css-7nal menunjukkan nilai konsentrasi plasma setela2 obat

di2entikan dan kadar tunak belum terapai

*9


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3 - multiple exposure models.pptx

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