QUESTION ABOUT MIXTURE MODEL
From: "Annick Rousseau" annick.rousseau@unilim.fr
Subject: [NMusers] QUESTION ABOUT MIXTURE MODEL
Date: Wed, 20 Jul 2005 15:48:51 +0200
Dear NMUsers
We are trying to model pharmacokinetic profiles after oral administration. Some profiles
(nearly 50%) exhibit two concentration peaks while others show only a single peak. So we
have tested a mixture model in order to describe the profiles either with a simple model
(with first order absorption and lagtime) or a double first-order absorption model. It is
noteworthy that when we tested independently these models, both minimize successfully
with the same obj function value.
The control file we are using is:
$SUBROUTINES TOL=4 ADVAN6
$MODEL
COMP=(1); DOSE, 1
COMP=(2); DOSE, 2
COMP=(3);GA
COMP=(4); CENTRAL
COMP=(5);PERIPH
$PK
EST=MIXEST
TTT=0
PP=2
IF (MIXNUM .EQ.1) THEN
PP=1
K13=THETA(1)*EXP(ETA(1))
K23=THETA(2)*EXP(ETA(2))
CL=THETA(3)*EXP(ETA(3))
K14=0
K34=THETA(9)*EXP(ETA(9)) ;GA
F1=THETA(10)*EXP(ETA(10))
ALAG2=THETA(7)*EXP(ETA(7))
K45=0
K54=0
F2=1-F1
ELSE
F1=1
K13=0
K23=0
K14=THETA(4)*EXP(ETA(4))
CL=THETA(5)*EXP(ETA(5))
ALAG2=0
K34=0
K45=THETA(12)*EXP(ETA(11))
K54=THETA(13)*EXP(ETA(12))
ENDIF
ALAG1=THETA(6)*EXP(ETA(6))
V4=THETA(8)*EXP(ETA(8))
K40=CL/V4
S4=V4
IF (TIME .GT. THETA(7)) TTT=1
$MIX
NSPOP=2
P(1)=THETA(11)
P(2)=1-P(1)
$DES
DADT(1)=-K13*A(1)-K14*A(1)
DADT(2)=-K23*A(2)
DADT(3)=K13*A(1)+TTT*K23*A(2)-K34*A(3)
DADT(4)=K34*A(3)-A(4)*K40+K14*A(1)-K45*A(4)+K54*A(5)
DADT(5)=K45*A(4)-K54*A(5)
$ERROR
...
$THETA
....
$OMEGA
......
$SIGMA
......
We obtain something we did not explain: (i) the following message :
0MINIMIZATION SUCCESSFUL
NO. OF FUNCTION EVALUATIONS USED: 2053
NO. OF SIG. DIGITS IN FINAL EST.: 3.3
(ii) no estimation of neither pharmacokinetic population parameters nor variability. The run
minimizes successfully at a lower obj function value (-300) than with
the two tested models but unable to run estimation.
We have tried several parameter initial values without success.
Any help would be appreciated.
Regards
Aurelie Premaud
Annick Rousseau
Service de Pharmacologie et Toxicologie
CHU Dupuytren
2 Rue Martin Luther King
87042 Limoges
tel +33 (0) 5 55 05 61 40
fax +33)(0) 5 55 05 61 62