From:"Bonate, Peter" 
Subject:[NMusers] Metabolite kinetics help
Date:Fri, 28 Jun 2002 09:27:51 -0500

I was wondering if I could solicit some help from the group.  I'm trying to model parent and metabolite
kinetics.  Parent consists of 2-compartments and metabolite consists of 1-compartment.  The starting
values for parent are based on ADVAN3 results.  The starting values for metabolite parameters were
based on trial and error within SAAM II to give reasonable observed metabolite concentrations.  Sigma
is large due to some previous errors where it was suggested to raise the starting value of sigma.  Here
is my control stream:

$PROBLEM ADVAN9 P+M
$DATA PMCOV.DAT  IGNORE=C
$INPUT PTID=ID CYCL DAY HR TIME DV DOSE AMT RATE EVID MDV
    LYM WBC HO CMT TYPE L2=DROP
    AP HGB HCT NEUT PLAT=DROP RACE=DROP AGE=DROP
$SUBR ADVAN9 TRANS1  TOL=4
$MODEL NCOMP=3 COMP=(CENTRAL) COMP=(PERIP) COMP=(M)
$PK
    CL  = THETA(1)*EXP(ETA(1))
    V1  = THETA(2)*EXP(ETA(2))
    Q   = THETA(3)
    V2  = THETA(4)
    FM  = THETA(5)
    KELM = THETA(6)
    S1  = V1/1000
    S3 = 1

$ERROR
    IPRD = F
    IF (CMT .EQ. 1) THEN
        Y = F*EXP(EPS(1)) + EPS(2)
    ELSE
        Y = F*EXP(EPS(3)) + EPS(4)
    ENDIF
$THETA
    (0, 41.1, 600);        THETA(1) CL
    (0, 90.8, 1500);       THETA(2) Vc
    (0, 70.1, 1000);       THETA(3) CL
    (0, 232, 1500);        THETA(4) Vp
    (0, 0.001, 1);         THETA(5) FM
    (0, 0.2, 1);           THETA(6) KELM
$DES
    DADT(1) = -(CL + Q)*A(1)/V1 + Q/V2*A(2)
    DADT(2) = Q/V1*A(1) - Q/V2*A(2)
    DADT(3) = FM*CL/V1*A(1) - KELM*A(3)
$OMEGA 0.267
$OMEGA 0.211
$SIGMA 5 0.00001 FIXED
$SIGMA 5 0.00001 FIXED
$COV
$EST MAXEVAL=9999 SIGDIGITS=4 NOABORT METHOD=CONDITIONAL INTERACTION POSTHOC

I keep getting this error message:

0PRED EXIT CODE = 1
0INDIVIDUAL NO.    2   ID=0.20000000E+01   (WITHIN-INDIVIDUAL) DATA REC NO.   3
 THETA=
  4.11E+01   9.08E+01   7.01E+01   2.32E+02   1.00E-03   2.00E-01
 OCCURS DURING SEARCH FOR ETA AT A NONZERO VALUE OF ETA
 ERROR IN LSODI1: CODE 205
0END OF MESSAGES

Here is the data for individual 2.  I've ripped out the covariate columns
PTID    CYCLE   DAY     HR      TIME    DV      DOSE    AMT     RATE    EVID    MDV     CMT     TYPE
2       1       1       0       0       .       27      27      27      1       1       1       1
2       1       1       0       0       0       27      .       .       0       1       1       1
2       1       1       1       1       83.6    27      .       .       0       0       1       1
2       1       1       1       1       4512    27      .       .       0       0       3       2
2       1       1       2       2       37.1    27      .       .       0       0       1       1
2       1       1       2       2       5327.5  27      .       .       0       0       3       2
2       1       1       3       3       23.4    27      .       .       0       0       1       1
2       1       1       3       3       5979.8  27      .       .       0       0       3       2
2       1       1       4       4       0       27      .       .       0       1       1       1
2       1       1       4       4       5599.3  27      .       .       0       0       3       2
2       1       1       5       5       10.6    27      .       .       0       0       1       1
2       1       1       5       5       5599.3  27      .       .       0       0       3       2
2       1       1       24      24      3479.2  27      .       .       0       0       3       2
2       1       2       0       24      .       27      27      27      1       1       1       1
2       1       2       0       24      0       27      .       .       0       1       1       1
2       1       2       1       25      147.5   27      .       .       0       0       1       1
2       1       2       1       25      8426.1  27      .       .       0       0       3       2
2       1       3       0       48      .       27      27      27      1       1       1       1
2       1       4       0       72      .       27      27      27      1       1       1       1
2       1       5       0       96      .       27      27      27      1       1       1       1

Can someone tell me what I am doing wrong and what this error message means.  Thanks ALOT!

pete



Peter L. Bonate, PhD
Director, Pharmacokinetics
ILEX Oncology, Inc
4545 Horizon Hill Blvd
San Antonio, TX  78229
phone: 210-949-8662
fax: 210-949-8487
email: pbonate@ilexonc.com

*******

From:Alan Xiao 
Subject:Re: [NMusers] Metabolite kinetics help
Date:Mon, 01 Jul 2002 20:59:16 -0400

Peter, 

I do not know what this error message means.  But the following suggestion might 
help if you have not tried them yet: 

1). increase the initial FM values at least  to the order of the magnitude of 0.1 
	(Sam's simulation might mean  this); and/or 
2). move the term EXP(ETA(2))  from V2 to FM; 
  

Good luck. 
  

Alan. 

-- 
*****  Alan Xiao, Ph.D    ***************
*****  PK/PD Scientist    ***************
*****  Cognigen Corporation    **********
*****  Tel: 716-633-3463 ext 265   ******

*******


From:"Sam Liao" 
Subject:RE: [NMusers] Metabolite kinetics help
Date:Mon, 1 Jul 2002 17:34:21 -0400

Hi Peter:

When I tried this model in simulation mode, the metabolite concentrations
predicted were in the order of 10E-4, There could be some problems in your
model specification causing the ERROR IN LSODI1.

If the metabolite has the same concentration unit as the parent drug, S3
should be like this
    S1 = V1/1000
    S3 = 1/1000
Also check the FM initial estimate.

The initial estimates of EPS(1) and EPS(2) seems to be too large. However,
this may not be the cause of ERROR IN LSODI1.

Best regards,



Sam Liao, Ph.D.
PharMax Research
270 Kerry Lane,
Blue Bell, PA 19422
phone: 215-6541151
efax: 1-720-2946783