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>: > 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 > > >
