non-linear PK
From: "Jing Li" jli29@jhmi.edu
Subject: [NMusers] non-linear PK
Date: Thu, 06 Oct 2005 11:47:14 -0400
Hi,
I am trying to fit a population PK model with nonlinear elimination (Michaelis-Menten)
with NONMEM. The drug was given to 15 patients by 20-min infusion weekly. Each patient
received 6 different doses each week for 6 weeks, and intense PK sampling was drawn after
each dose. The drug shows apparent non-linear clearance.
The following is the model control file. The model did not converge no matter how I changed
the initial estimates. Is there any problem with the control file? Any thoughts
would be appreciate!
Best regards.
Jing
$PROB 20-MIN IV INFUSION MULTIPLE DOSE WITHOUT COVARIATES
$INPUT ID WEEK AMT RATE TIME XDV DV MDV EVID
;XDV, observations, DV, log-transformed concentrations
$DATA ANTISOMA_DART_3.csv IGNORE=@
$SUBROUTINES ADVAN9 TRANS1 TOL=3
$MODEL NPAR=9, NCOMP=3, COMP=(CENTRAL,DEFOBS),
COMP=(PERIPH1), COMP=(PERIPH2)
;$ABB DERIV2=NO
$PK
VM = THETA(1) *EXP(ETA(1))
KM = THETA(7)*EXP(ETA(7))
V1 = THETA(2)*EXP(ETA(2))
V2 = THETA(3)*EXP(ETA(3))
V3 = THETA(4)*EXP(ETA(4))
Q2 = THETA(5)*EXP(ETA(5))
Q3 = THETA(6)*EXP(ETA(6))
SC = V1
K12 = Q2/V1
K21 = Q2/V2
K23 = Q3/V2
K32 = Q3/V3
OBS = XDV ;non-transformed observations
$ERROR (ONLY OBSERVATION)
DEL = 0
IF(F.EQ.0) DEL = .000001
IPRED = F + DEL
W = SQRT(THETA(8)**2+THETA(9)**2*F*F)
IPRED = LOG(IPRED)
IRES = DV-IPRED
IWRES = IRES/W
Y = IPRED+ERR(1)*W
$DES
C1 = A(1)/V1
DADT(1) = - K12*A(1) - A(1)*VM/(KM+C1)
DADT(2) = K12*A(1) - K21*A(2) + K32*A(3) - K23*A(2)
DADT(3) = K23*A(2) - K32*A(3)
$THETA (0,1) ;1 VM (uM/h)
$THETA (0,3,10) ;2 V1
$THETA (0,5,20) ;3 V2
$THETA (.5,2,10) ;4 V3
$THETA (0,.2,5) ;5 Q2
$THETA (0,1,5) ;6 Q3
$THETA (10,200) ;7 KM (uM)
$THETA (0,.5) ;8 SD ADD ERROR
$THETA (0,.1) ;9 CV PROP ERROR
$OMEGA .1 ;1 VM
$OMEGA .1 ;2 V1
$OMEGA .3 ;3 V2
$OMEGA .1 ;4 V3
$OMEGA .1 ;5 Q2
$OMEGA .1 ;6 Q3
$OMEGA .1 ;7 KM
$SIGMA 1 FIX
$EST MAXEVALS=9990 PRINT=2 POSTHOC MSFO=msfb40 POSTHOC ;METH=1 INTER
$COV
$TAB ID ID WEEK AMT RATE ONEHEADER NOPRINT FILE=mytab40
$TAB ID TIME DV IPRED IWRES ONEHEADER NOPRINT FILE=sdtab40
$TAB ID VM KM V1 V2 V3 Q2 Q3 ETA1 ETA2 ETA3 ETA4 ETA5 ETA6
ONEHEADER NOPRINT FILE=patab40