Cone shaped DV-PRED
From: majid.vakily@tap.com
Subject: [NMusers] Cone shaped DV-PRED
Date: Wed, April 20, 2005 4:58 pm
I have been working on a drug with a complex absorption profile. I have
used 2 compartment model with first order input and output (ADVAN4,TRANS1)
and the estimated population parameters, individual estimates, and
estimates of interindividual and residual variability values are
reasonable. However, the population DVs often go as high as
~120 ng/L, population predictions never exceeds 35-45 ng/mL, resulting in a
truncated, cone-shaped DV vs PRED plot. As I indicated the DV vs IPRED
values appear to be fine. I have approximately 5 samples/patient (over 300
patients in the index set). Considering the complex nature of absorption
for this drug with a slow early phase (0.25 to 0.5 hour postdose) and a
rapid phase, I decided to use series of absorption compartments to mimic
the shape of the plasma concentration-time curve during the absorption
phase and capture the Cmax. However, the program is running very slow and
I am not sure this is expected or I have a fundamental error in my codes. I
appreciate input about this issue or any other suggestions which may
improve the fit.
$PROB RUN# 1 OUR TEXT
$INPUT C STDY=DROP SOUD=DROP ID CMT=DROP DATE TIME AMT DV TYPE=DROP EVID SS
II
UT=DROP AGE=DROP BMI=DROP RACE=DROP ALC=DROP SMK=DROP HTEN=DROP DBET=DROP
CAD=DROP DOSE=DROP ALB=DROP ALT=DROP BIL=DROP CRCL=DROP ACEI=DROP ACT=DROP
ASA=DROP DRTC=DROP STER=DROP IRON=DROP NSDS=DROP PPI=DROP SSRI=DROP
DCDT=DROP RSND=DROP COM1=DROP
$DATA POPPKASO1.csv IGNORE=C
$SUBROUTINES ADVAN6 TRANS1 TOL=3
$MODEL
NCOMP=5 NPAR=14
COMP=(DEPOT DEFDOSE) ;GUT COMPARTMENT FOR PARENT DRUG
COMP=(GUT NODOSE);GI COMPARTMENT 2 FOR PARENT DRUG
COMP=(GUT NODOSE);GI COMPARTMENT 3 FOR PARENT DRUG
COMP=(CENTRAL DEFOBS NODOSE);CENTRAL COMPARTMENT FOR PARENT DRUG
COMP=(PERIPH NODOSE) ;PERIPHERAL COMPARTMENT FOR PARENT DRUG
$PK
TVCL=THETA(1)
CL=TVCL*EXP(ETA(1))
TVV4=THETA(2)
V4=TVV4*EXP(ETA(2))
TVKA=THETA(3)
KA=TVKA*EXP(ETA(3))
TVV5=THETA(4)
V5=TVV5*EXP(ETA(4))
TVQ=THETA(5)
Q=TVQ*EXP(ETA(5))
TVMT=THETA(6)
MT=TVMT*EXP(ETA(6))
Kel=CL/V4
K45=Q/V4
K54=Q/V5
KT=3/MT
S4=V4/1000
$DES
DADT(1)=-KT*A(1)
DADT(2)=KT*A(1)-KT*A(2)
DADT(3)=KT*A(2)-KA*A(3)
DADT(4)=KA*A(3)+K54*A(5)-Kel*A(4)-K45*A(4)
DADT(5)=K45*A(4)-K54*A(5)
$ERROR
Y=(A(4)/V4)*(1+ERR(1))+ERR(2)
DEL=0
IF (F.EQ.0) DEL=1
IPRED=F
W=IPRED+DEL
IRES=DV-IPRED
IWRES=IRES/W
$THETA
(15, 150, 1500) ;[CL]
(3, 200, 2000) ;[V4]
(0.1, 1, 100) ;[KA]
(3, 800, 8000) ;[V5]
(10, 100, 3000) ;[Q]
(0.01, 0.25, 2.5) ;[MT]
$OMEGA
0.5 ;[CL]
1 ;[V4]
0.5 ;[KA]
1 ;[V5]
1 ;[Q]
0.4 ;[MT]
$SIGMA
0.4 ;[PROPORTIONAL]
4 ;[ADDITIVE]
$EST MAXEVAL=9999 MSF=1.msf PRINT=5 NOABORT METHOD=0 POSTHOC
$COVARIANCE
$TABLE ID TIME IPRED CL V4 Q V5 KA MT AUC T50 NOPRINT ONEHEADER FILE=1.TAB
Thanks,
Majid Vakily, Ph.D.
Senior Research Investigator
Department of Drug Metabolism & Pharmacokinetics
Phone: (847) 582-2198
Fax; (847) 582-2388