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Re: [NMusers] $ERROR block for feedback mechanism

From: Sven Mensing <sv.mensing_at_gmail.com>
Date: Thu, 1 Aug 2019 09:19:09 +0200

Dear Hyun,

my first idea is to add F to the differential equations.

DADT(1) = -KA*A(1)

DADT(2) = -K23*A(2)-K20*A(2)+K32*A(3)+KA*A(1)* BioaPH


where only a fraction of the drug (BioaPH) is absorbed to your second
compartment.


Kind regards


Sven Mensing

Am Do., 1. Aug. 2019 um 08:34 Uhr schrieb "ģ“ķ˜„ģ•„" <lh=
a2000_at_snu.ac.kr>:

> Hello, NMusers.
>
>
> I have a question about a feedback mechanism in a PK/PD model.
>
> Drug X is an acid reducing agent, and after multiple oral administration,
> the systemic exposure to drug X decreased. Our previous result suggested
> that the main cause of the reduced exposure was the reduced solubility of
> drug X caused by elevated intragastric pH after treatment with drug X. Ba=
se
> on this result, we developed a PK/PD model. The PK/PD profile was best
> described using a 2 compartment PK model with lagged first-order absorpti=
on
> model and sigmoid Emax model linked with an effect compartment. To addres=
s
> changes in intragastric pH over time affecting the relative bioavailabili=
ty
> (F1), we introduced a feedback path such that increased intragastric pH
> decreases the F1 of drug X.
>
> I have tried to add feedback path in our NONMEM code, but I need help
> writing code.
>
> Here is the control stream that I have used:
>
>
> $SUBROUTINE ADVAN13 TOL=6
>
> $MODEL
>
> COMP=(DEPOT)
>
> COMP=(CENTRAL)
>
> COMP=(PERIPH)
>
> COMP=(EFFECT)
>
>
> -------------------------------------------------------------------------=
-----------
>
> $PK
>
> CL = THETA(1)*EXP(ETA(1))*(WT/70)**THETA(22)
>
> V2 = THETA(2)*EXP(ETA(2))
>
> Q = THETA(3)*EXP(ETA(3))
>
> V3 = THETA(4)*EXP(ETA(4))
>
> KA = THETA(5)*EXP(ETA(5))
>
> ALAG1 = THETA(6)*EXP(ETA(6))
>
>
> -------------------------------------------------------------------------=
---------------
>
> EMAX = THETA(17)*EXP(ETA(8))
>
> EC50 = THETA(18)*EXP(ETA(9))
>
> KE0 = THETA(19)*EXP(ETA(10))
>
> EDMAX = THETA(20)*EXP(ETA(11)) ; maximal reduction of F1
>
> ED50 = THETA(21)*EXP(ETA(12)) ; intragastric pH producing 50% of maxima=
l
> reduction of F1
>
>
>
> $DES
>
> DCP = A(2)/V2
>
> DCE = A(4)
>
> DADT(1) = -KA*A(1)
>
> DADT(2) = -K23*A(2)-K20*A(2)+K32*A(3)+KA*A(1)
>
> DADT(3) = -K32*A(3)+K23*A(2)
>
> DADT(4) = KE0*(DCP-DCE)
>
>
>
> $ERROR
>
> CP = A(2)/V2
>
> CE = A(4)
>
>
>
> Q1 = 1 ; dummy indicator for compartment 2
>
>
>
> IF (CMT .EQ. 4) Q1=0
>
> PH = E0*(1+(EMAX*CE)/(EC50+CE)) ; Emax model for pH driven by effect
> compartment concentration
>
> PHPK = CP*(1-(EDMAX*(PH-7))/(ED50+(PH-7))) ; Inhibitory effect model f=
or
> the feedback by pH for plasma concentration of YH4808, 7 is a maximum
> intagastric pH by drug X treatment.
>
>
>
> F1=THETA(PH) <- Iā€™d like to estimate F1 by changing intragastri=
c pH in my
> $ERROR block.
>
>
>
>
>
> My question is that how can I make NONMEM code to address changes in
> intragastric pH affecting the F1 (feedback mechanism to describe a
> phenomenon that PD (intragastric pH) affects PK (F1)) in my $ERROR block?
>
>
>
> Thanks in advance.
>
>
>
>
> *Hyun A Lee*
>
> Department of Clinical Pharmacology and Therapeutics,
>
> Seoul National University College of Medicine and Hospital
>
> 101 Daehak-ro, Jongno-gu,
>
> Seoul 03080, Korea
>
> Tel: +82-31-888-9574, Fax: +82-31-888-9575
>
> Mobile: +82-10-8629-5014
>
> E-mail: lha2000_at_snu.ac.kr ; hyunal_at_gmail.com
>
>
>


Received on Thu Aug 01 2019 - 03:19:09 EDT

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