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" <lha2...@snu.ac.kr
<mailto:lha2...@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: lha2...@snu.ac.kr <mailto:lha2...@snu.ac.kr> ;
hyu...@gmail.com <mailto:hyu...@gmail.com>
