TUGAS FARMAKOKINETIKA

MULTIPLE EXPOSURE MODELS HOMEWORK

Oleh :
Nurul Iftikhan

FAKULTAS FARMASI
UNIVERSITAS HASANUDDIN
MAKASSAR
2014
1. Using the repetitive dosing one compartment first order absorption
equations, estimate:
a. the maximum and minimum concentration for the 4th oral dose

ln [
t ' max=

( kk ) x ( 1e
a

) /(1ek )]

k ak

'

t max=

[( )

0.693
0.693
(
( 12 )
8.6 )
1e
1.3
ln
x
0.693
0.693

( 12 )
(
1.3 )
1e
8.6

0.693

( 0.693
1.3
8.6 )

ln ( 6.615 ) x
t ' max=

( 0.619
0.998 )]

0.452

t ' max=3.12hr

C 4,max =

( )[ (

FD k a
V k ak

( 0.77 )( 200 )
C 4,max =
( 2.4 )( 3 )

C 4,max =

((

0.693
)
1.3
0.693
0.693

1.3
8.6
(

)(

154 0.533
7.2 0.452

)]

1eNk k t
e
1ek

) ) [(

'

max

( 4)

1e

[(

( 12 )
(0.693
8.6 )

( 12 )
( 0.693
8.6 )

1e

)]

1eN k k
e
k
1e

)]

'

t max

( 3.12)
( 0.693
8.6 )

[(

( 4)

1e

( 12 )
( 0.693
1.3 )

1e

1
0.777[ (
0.189
)[[( 0.979
]
0.619 )]
0.998 )]

C 4,max =( 21.388 )( 1.179 ) ( 1.2280.189 )

C 4,max =26.199 mg/L

C 4,min =

( )[ [(

FD k a
V k ak

( 0.77 ) (200)
C 4,min =
(2.4)(3)

((

)] [(

1eNk
1eN k

k
1ek
1e

0.693
)
1.3
0.693
0.693

1.3
8.6
(

)(

) )[ (

( 4 )

1e

( 12 )
( 0.693
8.6 )

1e

)]

( 12 )
( 0.693
8.6 )

)] [(

( 4)

1e

( 12 )
( 0.693
1.3 )

1e

( 12 )
(0.693
1.3 )

( 12 )
(0.693
1.3 )

)]

)]

( 3.12)
( 0.693
1.3 )

C 4,min =

154 0.533
7.2 0.452

)[[( 0.979
)
(
0.619 ] [ 0.998 )]]

C 4,min =( 21.388 ) (1.179 )( 1.5811.002 )

C 4,min =14.600 mg/L

b. the number of days it should take to reach 99,9% of steady state

N=10 x t 1 /2,elim
N=10 x 8.6

N=86 hr=3.58 days

c. the maximum, minimum, and average plasma concentration at steady
state

C ss, max =

( )[ (

FD k a
V k ak

( 0.77 )( 200 )
C ss, max =
( 2.4 )( 3 )

C ss, max =

((

0.693
)
1.3
0.693
0.693

1.3
8.6
(

)(

154 0.533
7.2 0.452

)]

1
k t
e
k
1e

) )[ (

'

[(

max

1
( 12)
( 0.693
8.6 )

1e

)]

1
k
e
k
1e

)]

'

t max

( 3.12)
( 0.693
8.6 )

[(

1
1e

1
1
)[[( 0.619
)] 0.777[( 0.998
)] 0.189 ]

C ss, max =( 21.388 )( 1.179 )( 1.2550.189 )

C ss, max =26.880 mg/L

C ss, min =

( )[ [(

FD k a
V k ak

( 0.77 ) (200)
C ss, min =
(2.4)( 3)

((

)] [(

1
1

k
k
1e
1e

0.693
)
1.3
0.693
0.693

1.3
8.6
(

)(

) ) [(

)] ]

1
0.693

( 12 )
8.6

1e

)] [(

( 12 )
( 0.693
1.3 )

1e

( 12 )
( 0.693
1.3 )

)]

)]

( 3.12)
( 0.693
1.3 )

C ss, min =

154 0.533
7.2 0.452

1
1
)[[( 0.619
)][( 0.998
) ]]

C ss, min =( 21.388 ) (1.179 )( 1.6151.002 )

C ss, min =15.457 mg/ L
C ss. ave =
C ss, ave =

C ss. ave =

FD
Vk

( 0.77 ) (200)
0.693
( 2.4 ) ( 3 )
(12)
8.6

154
6.962

C ss. ave =22.120 mg/L

d. the plasma concentration at 6 hr and at 24 hr after the last dose if
dosing is stopped after steady state conditions have been reached

C ss, final=

( )[ (

FD k a
V k ak

)]

[(

1
1
k t
e
k
k
1e
1e
'

)]

k a t

'

Untuk t= 6 hr

( 0.77 ) ( 200 )
C ss, final=
( 2.4 )( 3 )

C ss, final=

((

0.693
)
1.3
0.693
0.693

1.3
8.6
(

154 0.533
7.2 0.452

)(

) [(

1
1e

( 12 )
( 0.693
8.6 )

)]

1
1
) [[( 0.619
)] 0.616[( 0.998
)] 0.040 ]

C ss, max =( 21.388 )( 1.179 )( 0.9950.040 )

C ss, max =24.081mg/ L
Untuk t= 24 hr

( 6)
( 0.693
8.6 )

[(

1
( 12 )
(0.693
1.3 )

1e

)]

(6 )
( 0.693
1.3 )

( 0.77 ) ( 200 )
C ss, final=
( 2.4 )( 3 )

C ss, final=

((

0.693
)
1.3
0.693
0.693

1.3
8.6
(

)(

154 0.533
7.2 0.452

))[ (

1e

( 12 )
(0.693
8.6 )

)]

( 24 )
( 0.693
8.6 )

1
1
) [[( 0.619
)] 0.144[( 0.998
)] 2.777 x 10

[(

1e

( 12 )
(0.693
1.3 )

)]

( 24 )
( 0.693
1.3 )

C ss, max =( 21.388 )( 1.179 ) ( 0.2322.782 x 106 )

C ss, max =5.850 mg/L
Since the absorption and elimination half-lives indicate this additive may
approximately follow pseudo-instantaneous absorption, use the repetitive
dosing one compartment instantaneous absorption equation to estimate
e. the maximum and minimum concentration for the 4th oral dose
Nk

C 4,max =

FD 1e
V 1ek

C 4,max =

( 0.77 ) (200) 1e
0.693
( 2.4 ) (3)
(
)(12)
1e 8.6

C 4,max =

154 0.979
7.2 0.619

( 4)

( 12 )
(0.693
8.6 )

C 4,max =33.828 mg/L

Nk

FD 1e
C 4,min =
ek
k
V 1e
C 4,min =C 4,max ek
( 12 )
( 0.693
8.6 )

C 4,min =(33.828)e

C 4,min =( 33.828 ) ( 0.380 )

C 4,min =12.854 mg/ L
f.

the maximum, minimum, and average plasma concentration at steady

state

C ss, max =

FD
1
V 1ek

C ss, max =

( 0.77 ) (200)
( 2.4 ) (3)

C ss, max =

154
1
7.2 0.619

1
( 12)
(0.693
8.6 )

1e

C ss, max =34.553 mg/L

C ss, min =

FD 1eNk k
e
V 1ek

C ss, min =C ss, max ek

( 12)
( 0.693
8.6 )

C ss, min =(34.553)e

C ss, min =( 34.553 ) (0.380)

C ss, min =13.130 mg/L
C ss. ave =
C ss, ave =

C ss. ave =

FD
Vk

( 0.77 ) (200)
0.693
( 2.4 ) ( 3 )
(12)
8.6

154
6.962

C ss. ave =22.120 mg/L

g. the plasma concentration at 6 hr and at 24 hr after the last dose if
dosing is stopped after steady state conditions have been reached

C ss, final=

FD
V

[ [(

)]

1
ek t
k
1e

'

C ss, final=C ss ,max ek t

'

Untuk t= 6 hr
(6 )
( 0.693
8.6 )

C ss, final =( 34.553 ) e

C ss, final=( 34.553 )( 0.616)
C ss, final=21.284 mg/L

Untuk t= 24 hr
( 24 )
( 0.693
8.6 )

C ss, final =( 34.553 ) e

C ss, final=( 34.553 )(0.144)

C ss, final=4.975 mg/L

2. Estimate the following for a standard 8 hr work shift 5 days per week
(Monday-Friday, assume concentration start at zero on the first day)
a. The maximum concentration on Friday

C5, max=

C5, max=

C5, max=

ko
1eNk
(1ekT )
Vk
1ek

(10)
(1e
0.693
( 3.2 ) (74 ) (
)
11.4

10
0.992
(0.385)
14.395
0.622

0.693
(8)
11.4

( 5)

1e

(16 )
( 0.693
11.4 )

(16)
( 0.693
11.4 )

1e

C5, max=0.426 mg/L

b. The concentration at the start of his shift on the following Monday
(exactly 3 days after the start of the previous Fridays exposure)
Nk
ko
1e
kT
C5, final= (1e )
ek(t T )
k
Vk
1e

C5, final=

C5, final=

(10)
(1e
0.693
( 3.2 )( 74 ) (
)
11.4

'

0.693
(8 )
11.4

( 5 )

1e

(16)
( 0.693
11.4 )

(16)
( 0.693
11.4 )

1e

(648 )
( 0.693
11.4 )

( 10 )
0.992
( 0.385 )
(0.033)
0.622
( 14.395 )

C5, final=0.014 mg/L

Estimate the following for an alternative 10 hr work shift, 4 days per week
(Monday-Thursday, assume concentration start at zero on the first day)
c. The maximum concentration on Thursday

C 4,max =

ko
1eNk
(1ekT )
Vk
1ek

)
0.693

( 4 )

( 0.693 )(14)

(
(10)
) (10)) 1e 11.4
C 4,max =
(1e 11.4
0.693
0.693
(
(14 )
11.4 )
( 3.2 ) ( 74 ) (
)
1e
11.4

C 4,max =

10
0.966
(0.455)
14.395
0.573

C 4,max =0.532 mg/ L

d. The concentration at the start of his shift on the following Monday
(exactly 4 days after the start of the previous Thursdays exposure)

C 4,final=

ko
1eNk k (t T )
( 1ekT )
e
Vk
1ek

'

0.693

( 4)

(0.693 )(14)

0.693

(
(
(8610)
(10)
)(10 )) 1e 11.4
11.4 )
C 4,final=
(1e 11.4
e
0.693
0.693
(
(14)
11.4 )
( 3.2 ) (74 ) (
)
1e
11.4

C 4,final=

( 10 )
0.966
( 0.455 )
(0.0098)
0.573
( 14.395 )

C5, final=0.00522 mg/ L

Estimate the following for an alternative 8 hr work shift, 7 days per week
without any days of
e. The number of days it will take to reach 99,9% of steady state

N=10 x t 1 /2,elim
N=10 x 11.4

N=114 hh hr=4.75 days

f.

The maximum steady state concentration

C ss, max =

ko
1
(1ekT )
k
Vk
1e

)
0.693

(
(10)
)(8)
1
C ss, max =
(1e 11.4 )
0.693

(
)(16)
( 3.2 ) ( 74 ) ( 0.693 )
1e 11.4
11.4

C ss, max =

10
1
(0.385)
14.395
0.622

C ss, max =0.429 mg/L