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 ; hyu...@gmail.com
