DATA KONSENTRASI PLASMA CLOZAPINE

Waktu Konsentrasi Cp Terminal Cp Residual AUC

plasma Cp
(µg/ml)
0 0 14.9230000 14.923 1.575
0,5 6,3 14.7745137 8.474513669 5.6875
1 16,45 14.6275048 1.822495198 9.665
1,5 22,21 14.4819587 7.728041303 11.1275
2 22,3 14.3378608 7.9621392 21.9
3 21,5 14.0539521 7.446047865 162.45
12 14,6 11.7388476 2.861152429 77.55
18 11,25 10.4114238 0.838576186 42.62
22 10,06 9.6109555 0.449044488 239.415
55 4,45 4.9674352 0.517435182 89.7
78 3,35 3.1358606 0.214139409 167.5

Persamaan Farmakokinetika Clozapine

Y= 14,923e(-0,02.t) - 17,544e(-2,103.t)

Perhitungan Clozapine

 Cp terminal

1. Cp terminal = 14,923e-k.t

= 14,923e-0,02.0

= 14,923e-0

= 14,923 (mg/L)

2. Cp terminal = 14,923e-k.t

= 14,923e-0,02.0,5

= 14,923e-0,01
 = 14.7745137(mg/L)

3. Cp terminal = 14,923e-k.t

= 14,923e-0,02.1

= 14,923e-0,02

= 14.6275048 (mg/L)

4. Cp terminal = 14,923e-k.t

= 14,923e-0,02.1,5

= 14,923e-0,03

= 14,4819587 (mg/L)

5. Cp terminal = 14,923e-k.t

= 14,923e-0,02.2

= 14,923e-0,04

= 14.3378608 (mg/L)

6. Cp terminal = 14,923e-k.t

= 14,923e-0,02.3

= 14,923e-0,06

= 14,0539521 (mg/L)

7. Cp terminal = 14,923e-k.t

= 14,923e-0,02.12

= 14,923e-0,24

= 11,7388476 (mg/L)

8. Cp terminal = 14,923e-k.t
 = 14,923e-0,02.18

= 14,923e-0,36

= 10,4114238 (mg/L)

9. Cp terminal = 14,923e-k.t

= 14,923e-0,02.22

= 14,923e-0,44

= 9,6109555 (mg/L)

10. Cp terminal = 14,923e-k.t

= 14,923e-0,02.55

= 14,923e-1,1

= 4,9674352(mg/L)

11. Cp terminal = 14,923e-k.t

= 14,923e-0,02.78

= 14,923e-1,56

= 3,1358606 (mg/L)

 C Residual = ABS ( Cp – Cp terminal )

1. C residual = ABS (0 – 14.923)

= 14,923 (mg/L)

2. C residual = ABS (6,3 – 14,77451367)

= 8,47451367 (mg/L)
 3. C residual = ABS (16,45 – 14,6275048)

= 1,8224952 (mg/L)

4. C residual = ABS (22,21 – 14,4819587)

= 7,7280413 (mg/L)

5. C residual = ABS (22,3 – 14.3378608)

= 7,9621392 (mg/L)

6. C residual = ABS (21,5 – 14.0539521)

= 7,4460479 (mg/L)

7. C residual = ABS (14,6 – 11.7388476)

= 2,8611524 (mg/L)

8. C residual = ABS (11,25 – 10.4114238)

= 0,8385762 (mg/L)

9. C residual = ABS (10,06 – 9.6109555)

= 0,4490445 (mg/L)

10. C residual = ABS (4,45 – 4.9674352)

= 0,5174352 (mg/L)

11. C residual = ABS (3,35 – 3.1358606)

= 0,2141394 (mg/L)

 AUC
(Cp1 + Cp2) x (t2 − t1)
1. AUC 1 =
2
(0 + 6,3) x (0,5 −0)
= 2
6,3 x 0,5
= 2
 = 1,575 (mcg.jam/ml)
(Cp2 + Cp3) x (t3 − t2)
2. AUC 2 = 2
(6,3 + 16,45) x (1 −0,5)
= 2
22,75 x 0,5
= 2
= 5,6875 (mcg.jam/ml)

(Cp3 + Cp4) x (t4 − t3)

3. AUC 3 = 2
(16,45 + 22,21) x (1,5 −1)
=
2
38,66 x 0,5
= 2
= 9,665 (mcg.jam/ml)

(Cp4 + Cp5) x (t5 − t4)

4. AUC 4 = 2
(22,21+ 22,3) x (2 −1,5)
= 2
44,51 x 0,5
= 2
= 11,1275 (mcg.jam/ml)

(Cp5 + Cp6) x (t6 − t5)

5. AUC 5 = 2
(22,3 + 21,5) x (3 −2)
= 2
43,8 x 1
= 2
= 21,9 (mcg.jam/ml)

(Cp6 + Cp7) x (t7 − t6)

6. AUC 6 = 2
( 21,5 +14,6) x (12 −3)
= 2
36,1 x 9
= 2
= 162,45 (mcg.jam/ml)

(Cp7 + Cp8) x (t8 − t7)

7. AUC 7 = 2
(14,6 + 11,25) x (18 − 12)
= 2
25,85 x 6
= 2
= 77,55 (mcg.jam/ml)
 (Cp8 + Cp9) x (t9 − t8)
8. AUC 8 = 2
(11,25 + 10,06) x (22 −18)
= 2
21,31 x 4
= 2
= 42,62 (mcg.jam/ml)

(Cp9 + Cp10) x (t10 − t9)

9. AUC 9 = 2
(10,06 + 4,45) x (55 −22)
= 2
14,51 x 33
= 2
= 239,415 (mcg.jam/ml)

(Cp10 + Cp11) x (t11 − t10)

10. AUC 10 = 2
(4,45 + 3,35) x (78 −55)
= 2
7,8 x 23
= 2
= 89,7 (mcg.jam/ml)

𝐶𝑝
11. AUC 11 = KE
3,35
= 0,02
= 167,5 (mcg.jam/ml)
 AUC Total = 1.575 + 5.6875 + 9.665 + 11.1275 + 21.9 + 162.45+
77.55 + 42.62 + 239.415 + 89.7 + 167.5
= 829,19 (mcg.jam/ml)

𝐴𝑈𝐶 𝑡𝑜𝑡𝑎𝑙+𝐶𝑝 𝑡𝑒𝑟𝑎ℎ𝑖𝑟

 AUC Takhingga = 𝑘𝑒

829,19 +3,35
= 0,02

= 41,627 (mcg.jam/ml)

 AUC Sisa = AUC Takhinga – AUC Total

= 41,627 – 829.19

= 40797.81 (mcg.jam/ml)
DATA KONSENTRASI PLASMA CLOZAPINE + FLUFOXAMIN

Waktu Konsentrasi Cp Terminal Cp Residual Cp Distribusi C2 Residual AUC

Cp
0 0 19.184 -19.184 51.604 70.788 3.37
0.5 13.48 19.10741727 - 43.34100519 48.96842245 8.87025
5.627417268
1 22.001 19.03114025 2.969859746 36.40110709 33.43124735 25.4445
2 28.888 18.87949851 10.00850149 25.67709088 15.66858939 87.981
5 29.766 18.4317846 11.3342154 9.012380011 2.321835389 26.453
6 23.14 18.28491857 4.855081429 6.357270947 1.502189518 124.14
12 18.24 17.42797368 0.812026316 0.783173667 0.028852649 206.16
24 16.12 15.83268697 0.287313035 0.01188592 0.275427115 346.68
48 12.77 13.0668253 - 2.737676x10- 0.296828037 279.96
06
0.296825299
72 10.56 10.78414067 - 6.3056765x10- 0.224140669 421.3872
10
0.224140669
120 6.9978 7.345417125 - 3.3452645x10- 0.347617125 874.725
17
0.347617125

Persamaan Farmakokinetika Clozapine + Flufoxamin

Y= 51,604e(-0,349.t) + 19,184e(-0,008.t) - 70,944e(-0,75.t)

Perhitungan Clozapine

 Cp terminal

1. Cp terminal = 19,184e-k.t

= 19,184e-0,008.0

= 19,184e-0

= 19,184 (mg/L)
2. Cp terminal = 19,184e-k.t

= 19,184e-0,008.0,5

= 19,184e-0,004

= 19,10741727 (mg/L)

3. Cp terminal = 19,184e-k.t

= 19,184e-0,008.1

= 19,184e-0,008

= 19,03114025 (mg/L)

4. Cp terminal = 19,184e-k.t

= 19,184e-0,008.2

= 19,184e-0,016

= 18,87949851 (mg/L)

5. Cp terminal = 19,184e-k.t

= 19,184e-0,008.5

= 19,184e-0,04

= 18,4317846 (mg/L)

6. Cp terminal = 19,184e-k.t

= 19,184e-0,008.6

= 19,184e-0,048

= 18,28491857 (mg/L)

7. Cp terminal = 19,184e-k.t

= 19,184e-0,008.12
 = 19,184e-0,096

= 17,42797368 (mg/L)

8. Cp terminal = 19,184e-k.t

= 19,184e-0,008.24

= 19,184e-0,192

= 15,83268697 (mg/L)

9. Cp terminal = 19,184e-k.t

= 19,184e-0,008.48

= 19,184e-0,384

= 13,0668253 (mg/L)

10. Cp terminal = 19,184e-k.t

= 19,184e-0,008.72

= 19,184e-0,576

= 10,78414067(mg/L)

11. Cp terminal = 19,184e-k.t

= 19,184e-0,008.120

= 19,184e-0,96

= 7,345417125 (mg/L)

 C Residual 1 = (Cp – Cp Terminal)

1. Cres = 0 – 19,184

= -19,184 (mg/L)

2. Cres = 13,48 – 19,10741727

 = -5,627417268 (mg/L)

3. Cres = 22,001 – 19,03114025

= 2,969859746 (mg/L)

4. Cres = 28,888 – 18,87949851

= 10,00850149 (mg/L)

5. Cres = 29,766 – 18,4317846

= 11,3342154 (mg/L)

6. Cres = 23,14 – 18,28491857

= 4,855081429 (mg/L)

7. Cres = 18,24 – 17,42797368

= 0,812026316 (mg/L)

8. Cres = 16,12 – 15,83268697

= 0,287313035 (mg/L)

9. Cres = 12,77 – 13,0668253

= -0,296825299 (mg/L)

10. Cres = 10,56 – 10,78414067

= -0,224140669 (mg/L)

11. Cres = 6,9978 – 7,345417125

= -0,347617125 (mg/L)

 Cp Distribusi

1. Cp Distribusi = 51,604e-0,349 . 0

= 51,604e-0
 = 51,604 (mg/L)

2. Cp Distribusi = 51,604e-0,349 . 0,5

= 51,604e-0,1745

= 43,34100519 (mg/L)

3. Cp Distribusi = 51,604e-0,349 . 1

= 51,604e-0,349

= 36,40110709 (mg/L)

4. Cp Distribusi = 51,604e-0,349 . 2

= 51,604e-0,698

= 25,67709088 (mg/L)

5. Cp Distribusi = 51,604e-0,349 .5

= 51,604e-1,745

= 9,012380011 (mg/L)

6. Cp Distribusi = 51,604e-0,349 . 6

= 51,604e-2,094

= 6,357270947 (mg/L)

7. Cp Distribusi = 51,604e-0,349 . 12

= 51,604e-4,188

= 0,783173667 (mg/L)

8. Cp Distribusi = 51,604e-0,349 . 24

= 51,604e-8,376

= 0,01188592 (mg/L)
 9. Cp Distribusi = 51,604e-0,349 . 48

= 51,604e-16,752

= 2,737676x10-06 (mg/L)

10. Cp Distribusi = 51,604e-0,349 . 72

= 51,604e-25,128

= 6,3056765x10-10 (mg/L)

11. Cp Distribusi = 51,604e-0,349 . 120

= 51,604e-41,88

= 3,3452645x10-17 (mg/L)

 C Residual 2 = ABS (Cres 1 – Cp distribusi)

1. Cres = ABS (-19,184 – 51,604)

= 70,788 (mg/mL)

2. Cres = ABS (-5,627417268 – 43,34100519)

= 48,96842245 (mg/mL)

3. Cres = ABS (2.96985974 – 36,40110709)

= 33,43124735 (mg/mL)

4. Cres = ABS (10,00850149 – 25,67709088 )

= 15,66858939 (mg/mL)

5. Cres = ABS (11,3342154 – 9,012380011)

= 2,321835389 (mg/mL)

6. Cres = ABS (4,855081429 – 6,357270947)

= 1,502189518 (mg/mL)

7. Cres = ABS (0,812026316 – 0,783173667)

 = 0,028852649 (mg/mL)

8. Cres = ABS (0,287313035 – 0,01188592)

= 0,275427115 (mg/mL)

9. Cres = ABS (-0,296825299 – 2,737676x10-06 )

= 0,296828037 (mg/mL)

10. Cres = ABS (-0,224140669 – 6,3056765x10-10)

= 0,224140669 (mg/mL)

11. Cres = ABS (-0,347617125 – 3,3452645x10-17)

= 0,347617125 (mg/mL)

 AUC
(Cp1 + Cp2) x (t2 − t1)
1. AUC 1 =
2
(0 + 13,48) x (0,5 −0)
= 2
13,48 x 0,5
= 2
= 3,37 (mcg.jam/ml)
(Cp2 + Cp3) x (t3 − t2)
2. AUC 2 = 2
(13,48 + 22,001) x (1 −0,5)
= 2
35,481 x 0,5
= 2
= 8,87025 (mcg.jam/ml)

(Cp3 + Cp4) x (t4 − t3)

3. AUC 3 = 2
(22,001 + 28,888) x (2 −1)
=
2
50,889 x 1
= 2
= 25,4445 (mcg.jam/ml)

(Cp4 + Cp5) x (t5 − t4)

4. AUC 4 = 2
(28,888+ 29,766) x (5 −2)
= 2
58,654 x 3
= 2
 = 87,981 (mcg.jam/ml)

(Cp5 + Cp6) x (t6 − t5)

5. AUC 5 = 2
(29,766 + 23,14) x (6 −5)
= 2
52,906 x 1
= 2
= 26,453 (mcg.jam/ml)

(Cp6 + Cp7) x (t7 − t6)

6. AUC 6 = 2
( 23,14 +18,24) x (12 −6)
= 2
41,38 x 6
=
2
= 124,14 (mcg.jam/ml)

(Cp7 + Cp8) x (t8 − t7)

7. AUC 7 = 2
(18,24 + 16,12) x (24 − 12)
= 2
34,36 x 12
= 2
= 206,16 (mcg.jam/ml)
(Cp8 + Cp9) x (t9 − t8)
8. AUC 8 = 2
(16,2 + 12,77) x (48 −24)
= 2
28,89 x 24
= 2
= 346,68 (mcg.jam/ml)

(Cp9 + Cp10) x (t10 − t9)

9. AUC 9 = 2
(12,77 + 10,56) x (72 −48)
= 2
23,33 x 24
= 2
= 279,96 (mcg.jam/ml)

(Cp10 + Cp11) x (t11 − t10)

10. AUC 10 = 2
(10,56 + 6,9978) x ( 120 −72)
= 2
17,5578 x 48
= 2
= 421,3872 (mcg.jam/ml)
 𝐶𝑝
11. AUC 11 = KE
6,9978
= 0,008
= 874,725 (mcg.jam/ml)

 AUC Total = 3,37 + 8,87025 + 25,4445 + 87,981 + 26,453 +

124,14 + 206,16 + 346,68 + 279,96 + 421,3872 +
874,725
= 2405,17095 (mcg.jam/ml)

𝐴𝑈𝐶 𝑡𝑜𝑡𝑎𝑙+𝐶𝑝 𝑡𝑒𝑟𝑎ℎ𝑖𝑟

 AUC Takhingga = 𝑘𝑒

2405,17095 +6,9978
= 0,008

= 301521.0938 (mcg.jam/ml)

 AUC Sisa = AUC Takhinga – AUC Total

=301521.0938 – 2405,17095

= 299115.9228 (mcg.jam/ml)

Parameter Clozapine

 Ka = 2,103 jam

 Ke = 0,02 jam

 Kd =-

 F = 0,5 %

ln 2
 T ½ eliminasi = 𝑘𝑒

ln 2
= 0,02

= 34,65735903 jam
 ln 2
 T ½ absorpsi = 𝑘𝑒

ln 2
= 2,103

= 0,329599229 jam

2,3 𝑘𝑎
 T max = (𝑘𝑎−𝑘𝑒) . log ( 𝑘𝑒 )

2,3 2,103
= (2,103−0,02) . log ( 0,02 )

2,3
= 2,083 . log (105,15)

= 1,104176668 . 2,021809277

= 2,232434631 jam

 C max = y = Be-ket.t – Ce-kat.t

= 14,923e-0,02.2,232434631 – 17,544e-2,103. 2,232434631

= 14,923e-0,044648692 – 17,544e-4,694810029

= 14,27136318 – 0,160397845

= 14,11096534 mcg/ml

𝐹𝑥𝐷
 Vd = 𝐾𝑒 𝑥 𝐴𝑈𝐶

0,5 𝑥 10000
= 0,02 𝑥 829,19

5000
= 16,5838

= 301.4990533 L
𝐹𝑥𝐷
 CL = 𝐴𝑈𝐶

0,5 𝑥 10000
= 829,19
 5000
= 829,19

= 6.029981066 ml/jam

𝐴𝑈𝐶
 AUC IV = 𝐹

829,19
= 0,5

= 1658.38 mcg.jam/ml

Parameter Clozapine + Flufoxamin

 Ka = 0,75 jam

 Ke = 0,008 jam

 Kd = 0,349

 F = 6,89988x10-05 %

 AUC = 2405,17095 mcg.jam/ml

ln 2
 T ½ eliminasi = 𝑘𝑒

ln 2
= 0,008

= 86,64339757 jam

ln 2
 T ½ absorpsi = 𝑘𝑒

ln 2
= 0,75

= 0,924196241jam

2,3 𝑘𝑎
 T max = . log ( )
(𝑘𝑎−𝑘𝑒) 𝑘𝑒

2,3 0,75
= (0,75−0,008) . log (0,008)
 2,3
= 0,742 . log 93,75

= 3,099730458 . 1,971971276

= 6.112579428 jam

 C max = y = Be-kdt.t + Be-ket.t– Ce-kat.t

= 51,604e-0,349.6,112579428 + 19,184e-0,008. 6,112579428 –

70,94e-0,75. 6,112579428

= 51,604e-2,13329022 + 19,184e-0,048900635 – 70,,94e-4,584434571

= 6,112335662 + 18,26845795 – 0,724263413

= 23.656489 mcg/ml

𝐹𝑥𝐷
 Vd = 𝐾𝑒 𝑥 𝐴𝑈𝐶

6,89988x10−05 𝑥 100000
= 0,008 𝑥 2405,17095

6,89988
= 19,2413676

= 0.358596132 L

𝐹𝑥𝐷
 CL = 𝐴𝑈𝐶

6,89988x10−05 𝑥 100000
= 2405,17095

6,89988
= 2405,17095

= 0.002868769 ml/jam

𝐴𝑈𝐶
 AUC IV = 𝐹

2405,17095
= 0,5

= 4810.3419 mcg.jam/ml