2-compartment model: V2 doesn't vary
From: "Stefan Wilde" <stefanwilde@hotmail.com>
Subject: 2-compartment model: V2 doesn't vary
Date: Fri, 28 Sep 2001 19:41:46 +0200
Dear nonmem users,
I'm analysing a dataset in a sparse data situation:
30 subjects, 3 visits per subject, 3 samples per visit (1st: 5-200 min post
infusion, 2nd sample 60 min. later, 3rd sample approx. 16h p.i.)
2 different drugs are studied, both of them known to follow 2-compartment
kinetics.
Analysing these data with NONMEM (NMTran, Advan3, Trans4) gives reasonable
estimates for all kinetic parameters and for variability of all parameters
but V2.
The peripheral Vd doesn't vary beetwen subjects
(Est. of eta = 1EXP-11).
Even when fixing intercompartment clearance V2 doesn't vary.
Estimating 2-compartment kinetics of the 2nd drug given (slightly different
post-infusion times) the results are the same: no variability of V2.
We are quite concerned about these findigs that don't sound reasonable to
us. Any explanations or suggestions of how to solve this problem are
appreciated.
Below you find excerpts of the nonmem control stream and the dataset.
Thanks in advance,
Stefan
Control stream excerpt:
$INPUT ID CY TIME AMT RATE DV MDV EVID
$SUBROUTINE ADVAN=ADVAN3 TRANS=TRANS4
$PK
CALLFL=1
CL = THETA(1)*EXP(ETA(1))
V1 = THETA(2)*EXP(ETA(2))
Q = THETA(3)*EXP(ETA(3))
V2 = THETA(4)*EXP(ETA(4))
S1 = V1/1000
$ERROR
Y = F*(1+ERR(1)) ;Multiplikatives Modell
$THETA
(0,1.3,10000)
(0,30,10000)
(0,.9,10000)
(0,500,10000)
$OMEGA DIAGONAL(4) .01 .1 .1 .01
$SIGMA .8
$ESTIMATION METHOD=COND NOABORT PRINT=5 MAXEVAL=9999 SIGDIGIT=7
Dataset excerpt:
ID Cycle Time Amt Rate DV MDV EVID
3 1 0 50 3.33333 0 1 4
3 1 15 0 0 0 1 0
3 1 130 0 0 8.41 0 0
3 1 345 0 0 6.98 0 0
3 1 1195 0 0 3.88 0 0
3 2 0 50 2.5 0 1 4
3 2 20 0 0 0 1 0
3 2 150 0 0 8.1 0 0
3 2 990 0 0 4.02 0 0
3 3 0 50 0.625 0 1 4
3 3 80 0 0 0 1 0
3 3 95 0 0 12.3 0 0
3 3 405 0 0 6.59 0 0
3 3 1245 0 0 4.59 0 0
9 1 0 48 1.29729 0 1 4
9 1 37 0 0 0 1 0
9 1 41 0 0 222 0 0
9 1 165 0 0 6.89 0 0
9 1 1277 0 0 2.24 0 0
--
Stefan Wilde
Institute of Pharmacology
Clinical Pharmacology
University of Cologne
Germany