[NMusers] $ERROR block TMDD

From: Amaranth Star <amaranthfan_at_gmail.com>
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

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