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: [email protected] ; [email protected]
$ERROR block for feedback mechanism
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" <[email protected]>:
> 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: [email protected] ; [email protected]
>
>
>
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
Quoted reply history
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" < [email protected] < mailto: [email protected] >>:
>
> 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: [email protected] <mailto:[email protected]> ;
> [email protected] <mailto:[email protected]>