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From: 이현아 <lha2000_at_snu.ac.kr>

Date: Thu, 1 Aug 2019 15:24:17 +0900

Received on Thu Aug 01 2019 - 02:24:17 EDT

Date: Thu, 1 Aug 2019 15:24:17 +0900

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 ; hyunal_at_gmail.com

Received on Thu Aug 01 2019 - 02:24:17 EDT