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From: Leonid Gibiansky <lgibiansky_at_quantpharm.com>

Date: Fri, 16 Nov 2018 12:53:27 -0500

You should not expect dramatic differences between the model with

central binding and peripheral binding. So if the model failed

(completely failed ? or just not good enough?), this is for some other

reasons. You may want to start with the simple linear model, find

parameters, then add Michaelis-Menten part, and only then move to the

QSS model. On each stage, start with the parameters of the best model of

the previous stage.

To answer your specific question, equations and error block are two

independent parts of the model, so you just use

Y=A(1)/V1*(1+EPS) ; measured: free drug in central compartment

(if proportional error model is used).

Note that KM is not defined but used instead of KSS in some places,

could it be the reason for failure? TVKSS is not defined but used...

Regards,

Leonid

On 11/16/2018 12:17 PM, Amaranth Star wrote:

*> 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
*

*>
*

Received on Fri Nov 16 2018 - 12:53:27 EST

Date: Fri, 16 Nov 2018 12:53:27 -0500

You should not expect dramatic differences between the model with

central binding and peripheral binding. So if the model failed

(completely failed ? or just not good enough?), this is for some other

reasons. You may want to start with the simple linear model, find

parameters, then add Michaelis-Menten part, and only then move to the

QSS model. On each stage, start with the parameters of the best model of

the previous stage.

To answer your specific question, equations and error block are two

independent parts of the model, so you just use

Y=A(1)/V1*(1+EPS) ; measured: free drug in central compartment

(if proportional error model is used).

Note that KM is not defined but used instead of KSS in some places,

could it be the reason for failure? TVKSS is not defined but used...

Regards,

Leonid

On 11/16/2018 12:17 PM, Amaranth Star wrote:

Received on Fri Nov 16 2018 - 12:53:27 EST