From: "nelamangala nagaraja" <nvnagaraj@hotmail.com>

Subject: INITIAL OBJ FUNCTION ERROR

Date: Wed, 05 Apr 2000 01:00:15 EDT

Dear NM Users,

I am fitting a dataset with parent drug (actually a prodrug) and its metabolite, both following a 2-compartment model and present in plasma and CSF. I am using ADVAN6 for modeling. When I started nonmem execution, it was immediately terminated with the following message in the output file:

MONITORING OF SEARCH:

0PROGRAM TERMINATED BY OBJ

ERROR IN CELS WITH INDIVIDUAL 5 ID= .50000000E+01

WEIGHTED SUM OF "SQUARED" INDIVIDUAL RESIDUALS IS INFINITE

MESSAGE ISSUED FROM ESTIMATION STEP

AT INITIAL OBJ. FUNCTION EVALUATION

The control file is as follows

$PROBLEM PRODRUG AND DRUG IN PLASMA AND CSF

$INPUT ID TIME AMT DV RATE CMT MDV

$DATA MPHSMPPC1.CSV IGNORE=C

$SUBROUTINE ADVAN6 TRANS 1 TOL=3

$MODEL

COMP=(CENTRAL1)

COMP=(PERIPH1)

COMP=(CENTRAL2)

COMP=(PERIPH2)

COMP=(CSF1)

COMP=(CSF2)

$PK

TVCL1 = THETA(1)

TVV1 = THETA(2)

K12A = THETA(3)

K21A = THETA(4)

TVCL2 = THETA(5)

TVV2 = THETA(6)

K34A = THETA(7)

K43A = THETA(8)

KF = THETA(9)

K12B = THETA(10)

K21B = THETA(11)

K34B = THETA(12)

K43B = THETA(13)

CL1=TVCL1*EXP(ETA(1))

V1=TVV1*EXP(ETA(2))

CL2=TVCL2*EXP(ETA(3))

V3=TVV2*EXP(ETA(4))

S1=V1

S3=V3

S5=0.125

S6=0.125

K1=CL1/V1

K2=CL2/V3

$DES

DADT(1)=-(K1-KF)*A(1)+ K21A*A(2)-K12A*A(1)-K12B*A(1)+K21B*A(5)

DADT(2)=-K21A*A(2)+K12A*A(1)

DADT(3)=KF*A(1)-K2*A(3)-K34A*A(3)+K43A*A(4)-K34B*A(3)+K43B*A(6)

DADT(4)=K34A*A(3)-K43A*A(4)

DADT(5)=K12B*A(1)-K21B*A(5)

DADT(6)=K34B*A(3)-K43B*A(6)

$THETA

(0.001, 18)

(0.001, 22)

(0.0001, 1.5)

(0.0001, 0.8)

(0.0001, 20)

(0.001, 30)

(0.001, 1.1)

(0.001, 1.2)

(0.0001, 0.45)

(0, 0.01)

(0, 0.012)

(0, 0.015)

(0, 0.011)

$OMEGA

0.1 ; FOR CL1

0.1 ; FOR V1

0.15; FOR CL2

0.12; FOR V3

$ERROR

R1=0

IF (CMT.EQ.1) R1=1

R2=0

IF (CMT.EQ.3) R2=1

R3=0

IF (CMT.EQ.5) R3=1

R4=0

IF (CMT.EQ.6) R4=0

Y1=F+EPS(1)

Y2=F+EPS(2)

Y3=F+EPS(3)

Y4=F+EPS(4)

Y=R1*Y1+R2*Y2+R3*Y3+R4*Y4

IPRED=F

IRES=DV-IPRED

$SIGMA 0.1 0.2 0.01 0.01

$ESTIMATION METHOD=0 MAXEVAL=9999 PRINT=5

$TABLE ID TIME AMT CL1 V1 K12A K21A CL2 V3 K34A K43A KF K12B K21B K34B K43B

NOPRINT ONEHEADER FILE=MPHSMPPC1B

I tried to use both additive and exponential error models Could you please suggest a solution for this.

Thanks

Raj

N.V. Nagaraja

Post Doc Res Assoc

Department of Pharmaceutics,

University of Florida,

Gainesville, FL-32610

Ph: 352-846-3257

Fax: 352-392-4447

From: "Piotrovskij, Vladimir [JanBe]" <VPIOTROV@janbe.jnj.com>

Subject: RE: INITIAL OBJ FUNCTION ERROR

Date: Wed, 5 Apr 2000 07:58:40 +0200

Dear Raj,

Recently, I and a colleague of mine had the same problem with a much simpler model. I have no explanation yet, but what we did to obviate the problem was log-transformation of concentrations and fitting the model to logarithms (F in the $ERR block was also log-transformed). The residual error model was additive. Contact me if you need more details on the implementation.

Best regards,

Vladimir

From: j.dejongh@lapp.nl

Date: Wed, 5 Apr 2000 09:43:25 +0200

Subject: RE: INITIAL OBJ FUNCTION ERROR

Dear Vladimir, Raj & other NM users,

I thought that this kind of error message might also be an indication for reconsideration of the initial theta values.

best regards,

Joost DeJongh

Dr. Joost DeJongh

Leiden Advanced Pharmacokinetics & Pharmacodynamics (LAP&P) Consultants

Archimedesweg 31

2333 CM Leiden

The Netherlands

Phone: + 71 568 6920

fax: + 71 568 6972

Date: Wed, 05 Apr 2000 09:49:11 +0200

From: Mats Karlsson <Mats.Karlsson@biof.uu.se>

Subject: Re: INITIAL OBJ FUNCTION ERROR

The reason for the problem is that for observations related to compartment 6, there model predicts that the residual error magnitude is zero (because of a typo, see below).

> R4=0

> IF (CMT.EQ.6) R4=0

Best regards,

Mats Karlsson

--

Mats Karlsson, PhD

Professor of Biopharmaceutics and Pharmacokinetics

Div. of Biopharmaceutics and Pharmacokinetics

Dept of Pharmacy

Faculty of Pharmacy

Uppsala University

Box 580

SE-751 23 Uppsala

Sweden

phone +46 18 471 4105

fax +46 18 471 4003

mats.karlsson@biof.uu.se