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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

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:

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