From: Amaranth Star <*amaranthfan*>

Date: Fri, 16 Nov 2018 12:17:22 -0500

Hello NONMEM Users,

I’m relatively new NONMEM user. I have a drug which has showed TMDD

(QSS) elimination in a previous study. In that study the drug binds to

its target in central compartment. I only have the time course of the

drug concentration. I tried to test the same model as well as

Michaelis-Menten(MM)approach in my study but I failed.

Reading some papers (Wan-Su Park et al, 2017Doi: 10.1111/bcpt.12675; P

Dua et al, 2015 doi:10.1002/psp4.41 ), I found that the drug can only

binds to its target in peripheral compartment or in both compartments

at the same time. I want to try these models but I have trouble

writing the $ERROR block. The code I have written for the model in

which the drug binds to its target in peripheral compartment is given

as following:

$INPUT ID TIME AMT TINF RATE DV TAD MDV EVID

$DATA ADPKD_100918.csv

$SUBROUTINE ADVAN13 TOL=9

$MODEL COMP=(CENTRAL) COMP=(PERIPH1) COMP(PERIPH2)

$PK

TVCL=THETA (1) ;Linear elimination constant from the central=

Comp

TVV1=THETA(2) ; Volume of Central Comp

TVQ = THETA(3) ; Distributional clearance

TVV2 = THETA(4) ; tissue distribution volumes

TVKM= THETA (5) ; MM constant

TVVM= THETA(6) ; Vmax

TVKINT = THETA (7) ; Internalization constant

TVKSYN = THETA(8) ; Synthesis rate constant

TVKDEG = THETA(9) ; Degradation rate constant

CL = TVCL*EXP(ETA(1))

V1 = TVV1*EXP(ETA(2))

Q = TVQ ;*EXP(ETA(3))

V2 = TVV2;*EXP(ETA(4))

KSS = TVKSS;*EXP(ETA(5))

KINT = TVKINT

KSYN = TVKSYN

KDEG = TVKDEG

K = CL/V1 ; elimination rate constant

K12 = Q/V1 ; central-tissue rate constant

K21 = Q/V2 ;tissue-central rate constant

S1 = V1

BASE = KSYN/KDEG ; baseline for target

A_0(3) = BASE

$DES

CONC=0.5*(A(2)/V2-A(3)-KM)+0.5*SQRT((A(2)/V2-A(3)-KM)**2+4*KSS*A(2)/V2)

DADT(1) = -(K+K12)*A(1)+K21*CONC*V2

DADT(2) = K12*A(1)- K21*CONC*V2 - KINT*A(3)*CONC*V2/(KSS+CONC)

DADT(3) = KSYN - KDEG*A(3) - (KINT-KDEG)*CONC*A(3)/(KSS+CONC)

; CONC = Concentration of free drug in peripheral comp (not measured)

; A1 = Free drug in Central Compart (not measured)

;A2 = Free Drug second compartment amount (not measured)

; A3 = Target (not measured)

Although I have written a differential equation for the total drug in

peripheral compartment, but I have only measured the free drug

concentration in central compartment. I’m not sure how can I write

that in the $ERROR block.

Any suggestion or help will be gratefully received

Regards,

Niurys de Castro Suárez

--

MSc Niurys de Castro Suárez

Profesor Asistente Farmacocinética/Biofarmacia

Investigador Agregado

Departamento Farmacia

Instituto de Farmacia y Alimentos, Universidad de La Habana

Cuba

"Una estrella brilla en la hora de nuestro encuentro"

Received on Fri Nov 16 2018 - 12:17:22 EST

Date: Fri, 16 Nov 2018 12:17:22 -0500

Hello NONMEM Users,

I’m relatively new NONMEM user. I have a drug which has showed TMDD

(QSS) elimination in a previous study. In that study the drug binds to

its target in central compartment. I only have the time course of the

drug concentration. I tried to test the same model as well as

Michaelis-Menten(MM)approach in my study but I failed.

Reading some papers (Wan-Su Park et al, 2017Doi: 10.1111/bcpt.12675; P

Dua et al, 2015 doi:10.1002/psp4.41 ), I found that the drug can only

binds to its target in peripheral compartment or in both compartments

at the same time. I want to try these models but I have trouble

writing the $ERROR block. The code I have written for the model in

which the drug binds to its target in peripheral compartment is given

as following:

$INPUT ID TIME AMT TINF RATE DV TAD MDV EVID

$DATA ADPKD_100918.csv

$SUBROUTINE ADVAN13 TOL=9

$MODEL COMP=(CENTRAL) COMP=(PERIPH1) COMP(PERIPH2)

$PK

TVCL=THETA (1) ;Linear elimination constant from the central=

Comp

TVV1=THETA(2) ; Volume of Central Comp

TVQ = THETA(3) ; Distributional clearance

TVV2 = THETA(4) ; tissue distribution volumes

TVKM= THETA (5) ; MM constant

TVVM= THETA(6) ; Vmax

TVKINT = THETA (7) ; Internalization constant

TVKSYN = THETA(8) ; Synthesis rate constant

TVKDEG = THETA(9) ; Degradation rate constant

CL = TVCL*EXP(ETA(1))

V1 = TVV1*EXP(ETA(2))

Q = TVQ ;*EXP(ETA(3))

V2 = TVV2;*EXP(ETA(4))

KSS = TVKSS;*EXP(ETA(5))

KINT = TVKINT

KSYN = TVKSYN

KDEG = TVKDEG

K = CL/V1 ; elimination rate constant

K12 = Q/V1 ; central-tissue rate constant

K21 = Q/V2 ;tissue-central rate constant

S1 = V1

BASE = KSYN/KDEG ; baseline for target

A_0(3) = BASE

$DES

CONC=0.5*(A(2)/V2-A(3)-KM)+0.5*SQRT((A(2)/V2-A(3)-KM)**2+4*KSS*A(2)/V2)

DADT(1) = -(K+K12)*A(1)+K21*CONC*V2

DADT(2) = K12*A(1)- K21*CONC*V2 - KINT*A(3)*CONC*V2/(KSS+CONC)

DADT(3) = KSYN - KDEG*A(3) - (KINT-KDEG)*CONC*A(3)/(KSS+CONC)

; CONC = Concentration of free drug in peripheral comp (not measured)

; A1 = Free drug in Central Compart (not measured)

;A2 = Free Drug second compartment amount (not measured)

; A3 = Target (not measured)

Although I have written a differential equation for the total drug in

peripheral compartment, but I have only measured the free drug

concentration in central compartment. I’m not sure how can I write

that in the $ERROR block.

Any suggestion or help will be gratefully received

Regards,

Niurys de Castro Suárez

--

MSc Niurys de Castro Suárez

Profesor Asistente Farmacocinética/Biofarmacia

Investigador Agregado

Departamento Farmacia

Instituto de Farmacia y Alimentos, Universidad de La Habana

Cuba

"Una estrella brilla en la hora de nuestro encuentro"

Received on Fri Nov 16 2018 - 12:17:22 EST