Using covariates with positive and negative values
From: Garry Boswell
Subject:[NMusers] Using covariates with positive and negative values
Date: Mon, 5 May 2003 08:51:28 -0700
NONMEM GROUP,
I have data from a mouse TK study that I am attempting to analyze using NONMEM. Mice
were administered IP doses of a drug and single blood samples/animal were obtained at
serial time points. Both single dose and multiple dose (steady state) data were obtained. I
have LN transformed DV and have been successful at fitting the data using ADVAN2
TRANS2 and the control stream below:
$PROB ETA ON CL and V Sex on V
$INPUT ID DATE=DROP TIME ODV DV AMT MDV EVID CMT SS II Grp Sex Wt
$DATA COMBINED_LN_MOD.CSV IGNORE=c
$SUBROUTINES ADVAN2 TRANS2
$PK
TVCL = THETA(1)
TVV=THETA(2)+Sex*THETA(4)
TVKA = THETA(3)
CL=TVCL +EXP(ETA(1))
V=TVV + EXP(ETA(2))
KA=TVKA
K = CL/V
Half= (0.693/K)
S2 = V
$ERROR
PRD=F
IPRED=0
IF(F.GT.0) IPRED=LOG(F)
Y=IPRED + EPS(1)
IWRE=0
IRES=DV-IPRED
IF(IPRED.NE.0) IWRE=IRES/IPRED
$THETA (0, 2) (0, 30) (0, 6) (1) (1)
$OMEGA 0.6, 0.1
$SIGMA 0.1
$EST MAXEVALS = 3000
SIGDIGITS =4 PRINT = 10 POSTHOC
METHOD=CONDITIONAL
$COV CONDITIONAL
$TABLE NOPRINT
ID Grp Sex TIME CL V KA Half K
IPRED IRES IWRE PRD ODV PRED RES WRES
FILE=P129GBADVAN2TRAN2_CV17.PRN
However when I try to include a covariate for weight change on either V or CL, the
parameter goes negative and causes NONMEM to halt execution. This occurs with weight
change added as either an additive or portortional covariate. I did not LN transform
the weight data since both positive and negative changes were allowed. Would someone
with experience with this type of problem offer a suggestion?
Garry Boswell, Ph.D.
Senior Director, Pharmaceutical Development
Pharmacyclics, Inc.
995 Arques Avenue
Sunnyvale, CA 95085
(408) 328-3635
E-mail: gboswell@pcyc.com