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 
_______________________________________________________

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
_______________________________________________________