indirect PK-PD model and lag-time
From: Silvy Laporte <laporte_s@univ-st-etienne.fr>
Subject: indirect PK-PD model and lag-time
Date: 23 Sep 1998 11:41:34 -0400
Dear NM users,
We are trying to use ADVAN6 to model an indirect response model for an oral anticoagulant. The PD marker is the Prothrombin time ratio. Using a code as following, the effect is too early modified. We want to include a lag-time for this PD marker to take into account the fact the first effect is measured 10 hours after administration of the drug. Must we use an ALAG parameter and which one ? Or is there another solution?
Any advice would be very appreciated.
Thank you in advance.
Silvy Laporte and Patrick Mismetti.
Thrombosis Research Group St-Etienne FRANCE
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$PROBLEM mod=E8le PKPD PTR ACENOC PK 2 cpt
$DATA tp2.dat
$INPUT ID TIME AMT DV EVID MDV CMT
$SUBROUTINE ADVAN6 TOL=3 ; IV two-CMT
$MODEL
COMP=(CENTRAL,DEFDOSE,DEFOBS)
COMP=PERIPH
COMP=EFFECT
$PK
K=THETA(1)*EXP(ETA(1))
V1 =THETA(2)*EXP(ETA(2))
CL=V1*K
K12=THETA(3)
K21=THETA(4)
Q=K12*V1
V2=Q/K21
S1=V1/1000
KIN=THETA(5)*EXP(ETA(3))
KOUT=KIN
C50=THETA(6)*EXP(ETA(4))
$DES
DADT(1)=-(K12+K)*A(1) ; PK model 1st cpt
DADT(2)= K12*A(1)-K21*A(2) ; PK model 2nd cpt
EFF=C50/(C50+A(1)/S1)
DADT(3)=KIN*EFF-KOUT*A(3) ; PTR model
$ERROR
Y1=F*EXP(ERR(1))+ERR(2)
PTR=THETA(7)*F/(THETA(8)+F)
Y2=PTR*EXP(ERR(3))
BIN=1
IF (CMT.EQ.3) BIN=0
Y=BIN*Y1 + (1-BIN)*Y2
$THETA (0,0.05,10) (1,5,100) ; K and V1
(0.001,0.05,2) (0.001,0.2,5) ; K12 and K21
(0.001,0.02) (0.005,0.1) ; KIN and C50
(100 FIX)
(0.01,0.1)
$OMEGA (0.0271 FIX) (0.0185 FIX)
0.16 0.16
$SIGMA (0.0270 FIX) (57.9 FIX) 0.16
$ESTIMATION PRINT=5 MAXEVAL=3000
$SCATTER PRED VS TIME BY BIN
$SCATTER PRED VS DV UNIT BY BIN