- Contemporary messages sorted: [ by date ] [ by thread ] [ by subject ] [ by author ] [ by messages with attachments ]

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“ķģ" <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) <- Iād 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

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“ķģ" <lh=

a2000_at_snu.ac.kr>:

se

on

s

ty

-----------

---------------

l

or

c pH in my

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