From: David Foster - david.foster@adelaide.edu.au
Subject: [NMusers] ERROR: ABSORPTION LAG IS GREATER THAN OR EQUAL TO STEADY STATE DOSE INTERVAL
Date: 12/23/2003 1:21 AM
Hello all,
I seem to be having a few problems with coding/modeling steady-state PK data.
Briefly, the subjects are at steady-state with 48 hourly inter-dosing interval,
they come in about 47.5 hours (T=47.5) after the previous dose (T=0) and a blood
gets taken. Then at 48 hours, they take the "study" dose (same dose/formulation etc
as their usual medication) and an intensive blood sampling schedule follows over the
subsequent 48 hours (T=48-96 hr). The data are (surprisingly) nice looking, and clearly
2 compartment and it looks like a lag might be there in many subjects. I have about 20
subjects, with about 15 bloods per subject (see below). It runs okay, but when I try
to incorporate a LAG, then I get early terminations with error messages that say:
PK PARAMETER FOR ABSORPTION LAG IS GREATER THAN OR EQUAL TO STEADY STATE DOSE INTERVAL
Considering my initial estimate is 0.25 hours, and II=48, I find this hard to believe...
I have tried constraining ALAG1 to <2 hours, but I still get terminations like this:
0PRED EXIT CODE = 1
0INDIVIDUAL NO. 2 ID=0.20000000E+01 (WITHIN-INDIVIDUAL) DATA REC NO. 1
THETA=
3.93E-01 5.02E+01 4.04E+01 4.01E+02 2.01E+01 1.86E-01
OCCURS DURING SEARCH FOR ETA AT A NONZERO VALUE OF ETA
PK PARAMETER FOR ABSORPTION LAG IS GREATER THAN OR EQUAL TO STEADY STATE DOSE I
NTERVAL
0ITERATION NO.: 5 OBJECTIVE VALUE: 0.2712E+04 NO. OF FUNC. EVALS.:35
CUMULATIVE NO. OF FUNC. EVALS.: 132
PARAMETER: 0.9915E-01 0.1002E+00 0.1005E+00 0.1001E+00 0.9998E-01 0.8578E
-01 0.1000E+00 0.1000E+00 0.1000E+00 0.1000E+00
0.1000E+00 0.1000E+00 0.1002E+00
GRADIENT: 0.1056E+07 -0.3596E+05 -0.4356E+07 0.1374E+08 -0.2798E+05 0.4382E
+06 -0.8636E+03 -0.1988E+04 -0.1510E+04 -0.4564E+04
-0.5046E+04 -0.1614E+04 -0.1934E+06
THETA: KA CL V2 V3 Q ALAG
ETA:
ERR: CCV
XXXXX.lst 2712.412 eval=132 sig=. sub=17 obs=252 CCIL=YNYN NV1.1 PIV1.1
THETA = 0.393 50.2 40.4 401 20 0.186
ETASD = 0.3 0.3 0.3 0.3 0.3 0.3
ERRSD = 0.0500999
MINIMIZATION TERMINATED
DUE TO PROXIMITY OF NEXT ITERATION EST. TO A VALUE
AT WHICH THE OBJ. FUNC. IS INFINITE
AT THE LAST COMPUTED INFINITE VALUE OF THE OBJ. FUNCT.:
PRED EXIT CODE = 1
INDIVIDUAL NO. 2 ID=0.20000000E+01 (WITHIN-INDIVIDUAL) DATA REC NO. 1
THETA=
3.93E-01 5.02E+01 4.04E+01 4.01E+02 2.00E+01 1.86E-01
PK PARAMETER FOR ABSORPTION LAG IS GREATER THAN OR EQUAL TO STEADY STATE DOSE IN
TERVAL
Any suggestions? Thnaks,
David
I have coded the data as follows:
# Example.dat
# SS with 2 dose data
# ID,AMT,TIME,SS,II,RATE,DV,MDV
1,99705,0.00,1,48,0,.,1
1,.,47.75,.,.,.,42.56,0
1,99705,48.00,0,.,0,.,1,
1,.,48.25,.,.,.,61.87,0
1,.,48.50,.,.,.,133.04,0
1,.,49.00,.,.,.,254.87,0
1,.,49.58,.,.,.,236.67,0
1,.,50.17,.,.,.,237.82,0
1,.,50.58,.,.,.,246.74,0
1,.,51.25,.,.,.,184.27,0
1,.,52.25,.,.,.,169.88,0
1,.,54.25,.,.,.,152.63,0
1,.,57.08,.,.,.,124.84,0
1,.,60.00,.,.,.,104.2,0
1,.,72.08,.,.,.,57.83,0
1,.,83.83,.,.,.,55.07,0
1,.,94.83,.,.,.,52.4,0
The control stream looks like this:
$PROBLEM Example control stream
$INPUT ID,AMT,TIME,SS,II,RATE,DV,MDV
$DATA Example.dat
$SUBROUTINES ADVAN4 SS=SS4 TRANS4
$PK
KA = THETA(1)*EXP(ETA(1))
CL = THETA(2)*EXP(ETA(2))
V2 = THETA(3)*EXP(ETA(3))
V3 = THETA(4)*EXP(ETA(4))
Q = THETA(5)*EXP(ETA(5))
ALAG1 = THETA(6)*EXP(ETA(6))
K = CL/V2
K23 = Q/V2
K32 = Q/V3
S2 = V2
S3 = V3
$THETA (0,0.4,) ; KA
$THETA (0,50,) ; CL
$THETA (0,40,) ; V2
$THETA (0,400,) ; V3
$THETA (0,20,) ; Q
$THETA (0,0.25,) ; ALAG
$OMEGA
0.09
0.09
0.09
0.09
0.09
0.09
$ERROR
;CCV ERROR
DEL=0
IF (F.EQ.0) DEL=1
IPRED=F
IRES=DV-IPRED
IWRES=IRES/(F+DEL)
Y = F*(1+ERR(1))
$SIGMA (0.0025) ;CCV ERR(1)
$ESTIMATION MAXEVALS=9000 METHOD=1 INTERACTION POSTHOC NOABORT SIG=3
$COVARIANCE PRINT=E
$SCATTER DV VS PRED UNIT
$SCATTER WRES VS PRED
$TABLE ID,AMT,TIME,DV,KA, CL, V2, V3, Q, IPRED,IRES,IWRES
NOPRINT ONEHEADER FILE=Example.fit
--
David Foster, PhD
NHMRC Research Officer
Department of Clinical and Experimental Pharmacology
Faculty of Health Sciences
The University of Adelaide
Adelaide, South Australia 5005
Tel: +61 08 8303 5985
Fax: +61 08 8224 0685
Email: david.foster@adelaide.edu.au
http://www.adelaide.edu.au/Pharm/index.htm
ERROR: ABSORPTION LAG IS GREATER THAN OR EQUAL TO STEADY STATE DOSE INTERVAL
From: "Bachman, William (MYD)" - bachmanw@iconus.com
Subject: RE: [NMusers] ERROR: ABSORPTION LAG IS GREATER THAN OR EQUAL TO STEADY STATE DOSE INTERVAL
Date: 12/23/2003 9:15 AM
David,
Just an empirical suggestion (I haven't really thoroughly looked over your
control stream and data snippet), but, I would try using an additive
variance model on the ALAG1 (and possibly the KA, as well). In my
experience, they tend not to be log normally distributed.
Bill
William J. Bachman, Ph.D.
Manager, Pharmacometrics Research and Development
GloboMax
The Strategic Pharmaceutical Development Division of ICON plc
7250 Parkway Drive, Suite 430
Hanover, MD 21076
410-782-2212
bachmanw@iconus.com
From: VPIOTROV@PRDBE.jnj.com
Subject: RE: [NMusers] ERROR: ABSORPTION LAG IS GREATER THAN OR EQUAL TO STEADY STATE DOSE INTERVAL
Date: 1/6/2004 10:49 AM
David,
You may try constraining individual ALAG using logit-logistic
transformation. I think in your case individual ALAG can hardly exceed 1 hr,
so the following may work:
..
TALAG = THETA(.)
LOGIT = LOG(TALAG/(1-TALAG))
ALAG1 = EXP(TALAG+ETA(.))/(1+EXP(TALAG+ETA(.)))
..
THETA(.) should have boundaries like (0,.1,1)
Hope this helps.
Vladimir
-----------------------------------------------------------------
Vladimir Piotrovsky, Ph.D.
Research Fellow, Advanced PK-PD Modeling & Simulation
Global Clinical Pharmacokinetics and Clinical Pharmacology
Johnson & Johnson Pharmaceutical Research & Development
B-2340 Beerse
Belgium
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