Re: [NMusers] $ERROR block for feedback mechanism

From: Leonid Gibiansky <lgibiansky_at_quantpharm.com>
Date: Thu, 1 Aug 2019 10:41:16 -0400

Alternatively, if OMEGA block is placed before the $PK block, A()
variables can be used in the PK block, so F1=function(A4) can be defined
there. Results will be different, as this procedure will use A(4) at
dose time to reduce the dose while the $DES block version will use
current A(4) to reduce amount transferred to the second compartment.
Regards
Leonid

On 8/1/2019 3:19 AM, Sven Mensing wrote:
> 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 "이현아" <lha2000_at_snu.ac.kr
> <mailto:lha2000_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. Base 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 absorption model
> and sigmoid Emax model linked with an effect compartment. To address
> changes in intragastric pH over time affecting the relative
> bioavailability (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
> maximal 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 for the feedback by pH for plasma concentration of YH4808, 7
> is a maximum intagastric pH by drug X treatment.____
>
> F1=THETA(PH) <-I’d like to estimate F1 by changing intragastric 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 <mailto:lha2000_at_snu.ac.kr> ;
> hyunal_at_gmail.com <mailto:hyunal_at_gmail.com>
>
>

Received on Thu Aug 01 2019 - 10:41:16 EDT

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