From: "Sreenivasa Rao Vanapalli" <svanapal@blue.weeg.uiowa.edu>

Subject: Autoinduction

Date: Mon, 14 May 2001 17:33:55 -0500

 

Dear NMUsers

I'm trying to fit multiple oral dose data with autoinduction. The data fits well to a two compartment model with first order absorption. But when I'm trying to fit the data to a two compartment with hypothetical enzyme compartment, I'm getting error message 'floating-point error:divide by zero'

The control file I'm using is,

 

$PROBLEM MOXIDECTIN POOLED DATA

$INPUT ID DOSE=AMT TIME CP=DV WT CMT SEX EVID

$DATA MOXIMULTIEDIT

$SUBROUTINES ADVAN6 TOL=5

$MODEL NCOMPARTMENTS=4 COMP=(DEPOT,INITIALOFF,DEFDOSE)

COMP=(CENTRAL,DEFOBS,NOOFF) COMP=(ENZ) COMP=(PERIPH)

 

$PK

TVCLIN=THETA(1)

CLIN=TVCLIN*EXP(ETA(1))

KA=THETA(2)*EXP(ETA(2))

Q=THETA(3)*EXP(ETA(3))

TVVD=THETA(4)

V2=TVVD*EXP(ETA(4))

V3=THETA(5)*EXP(ETA(5))

KENZ=THETA(6)*EXP(ETA(6))

IC50=THETA(7)*EXP(ETA(7))

 

$DES

DADT(1)=-KA*A(1)

DADT(2)=KA*A(1)-CLIN*DV

DADT(3)=KENZ-KENZ*A(3)*(1-(CP/(CP+IC50)))

 

$ERROR

 

DEL=0

IF (F.EQ.0) DEL=1

W=F+DEL

Y=F*(1+ERR(1))+ERR(2)

IPRED=F

IRES=DV-IPRED

IWRES=IRES/W

CL=CLIN/A(3)

 

$THETA (0,.3,10) ;CLIN

(0,.8,100) ;ABSOR

(0,1.5,10) ;Q

(0,13,100) ;V2

(0,100,500);V3

(0,.001,100) ;KENZ

(0,500,1000) ;IC50

 

$OMEGA .002 .0001 .0001 .0001 .001 .001 .001

$SIGMA .05 .01

$ESTIMATION MAXEVAL=9999 POSTHOC

$COVARIANCE

$TABLE ID WT TIME V2 CL KA

$SCAT CP VS TIME

$SCAT PRED VS TIME

$SCAT (RES WRES) VS TIME

$SCAT WRES VS CP UNIT

$SCAT PRED VS CP UNIT

 

Any help would be appreciated.

 

Regards

 

Sreenivasa Rao Vanapalli, Ph.D,

Janssen Postdoctoral Research Scholar,

S411 PHAR, College of Pharmacy,

University of Iowa, Iowa City, IA-52242

319-353-5157 (Office)

319-337-2687 (Home)

 

*****

 

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

Subject: RE: Autoinduction

Date: Tue, 15 May 2001 09:00:19 +0200

 

Sreenivasa,

 

Very short look at your code: you have 3 diff eqs in the $DES block, but 4 compartments are declaired in the $MODEL block.

 

Best regards,

Vladimir

 

*****

 

From: "Ziad Hussein" <zhussein@medeval.com>

Subject: RE: Autoinduction

Date: Tue, 15 May 2001 09:32:58 +0100

 

Dear Sreenivasa,

 

Few years ago I have used a model with autoinduction for lamotrigine without the use of differential equation British Journal of Clinical Pharmacology 43: 457-465, 1997. The equation to describe autoinduction is:

 

TVCL=Theta(1)-Theta(2)*exp(-Theta(3)*Time)

 

in our case lamotrigine was dosed over 48 weeks. I hope that your data covers at least 2 weeks of dosing to able to model the autoinduction.

 

Kind regards,

Dr Ziad Hussein

Head of Pharmacokinetics

Medeval Ltd

Skelton House

Manchester Science Park

Lloyd Street North

Manchester, UK

 

Tel: xx-44-161-226 6525 (Ext 295)

 

*****

 

From: "Gibiansky, Ekaterina" <gibianskye@globomax.com>

Subject: RE: Autoinduction

Date: Tue, 15 May 2001 13:24:43 -0400

 

Sreenivasa,

 

another short look. You should not use observed values (DV, CP) in the $DES block, differential equations should be written in terms of predicted amounts in the compartments (A(2)/V2 in your case). Also, equation 3 does not seem right.

 

Regards,

Katya

--------------------------------------------------

Ekaterina Gibiansky, PhD

Senior Scientist

GloboMax LLC

7250 Parkway Drive, Suite 430

Hanover, MD 21076

Voice (410) 782-2234

FAX (410) 712-0737

E-mail: gibianskye@globomax.com

 

*****

 

From: "Sreenivasa Rao Vanapalli" <svanapal@blue.weeg.uiowa.edu>

Subject: Autoinduction

Date: Tue, 15 May 2001 19:24:51 -0500

 

hello NMUsers

I'm trying to fit multiple oral data to a two compartment model. This drug has very long half life (20 days). Plasma samples were collected for 28 days for single dose and every 28 days for multiple dose for six doses and for twelve doses. Declined Plasma concentrations were observed after administration of second dose, suggesting autoinduction. I'm wondering if my control stream to model this data is right or wrong. Can someone help me out. I'm getting floating point error messages.

 

$INPUT ID MDV DOSE=AMT TIME DV WT CMT SEX EVID

$DATA MOXIMULTIEDIT

$SUBROUTINES ADVAN8 TOL=5

$MODEL NCOMPARTMENTS=4 COMP=(DEPOT,INITIALOFF,DEFDOSE)

COMP=(CENTRAL,DEFOBS,NOOFF) COMP=(PERIPH) COMP=(ENZ)

 

$PK

TVCLIN=THETA(1)

CLIN=TVCLIN*EXP(ETA(1))

KA=THETA(2)*EXP(ETA(2))

K23=THETA(3)*EXP(ETA(3))

K32=THETA(4)*EXP(ETA(4))

TVVD=THETA(5)

V=TVVD*EXP(ETA(5))

KENZ=THETA(6)*EXP(ETA(6))

IC50=THETA(7)*EXP(ETA(7))

S2=V

 

$DES

CP=A(2)/V

C1=K23*A(2)

C2=K32*A(3)

CL=CLIN/A(4)

DADT(1)=-KA*A(1)

DADT(2)=KA*A(1)-C1+C2-CL*CP

DADT(3)=C1-C2

DADT(4)=KENZ-KENZ*A(4)*(1-(CP/(CP+IC50)))

 

$AESINITIAL

IF (TIME.EQ.0)THEN

A(4)=1

ENDIF

 

$ERROR

 

DEL=0

IF (F.EQ.0) DEL=1

W=F+DEL

Y=F*(1+ERR(1))+ERR(2)

IPRED=F

IRES=DV-IPRED

IWRES=IRES/W

 

 

$THETA (0,.3,10) ;CLIN apparent drug clearance

(0,.8,100) ;ABSOR

(0,.1,10) ;K23

(0,.01,100) ;K32

(0,13,500);V

(0,.001,100) ;KENZ rate constant for enzyme degradation/inactivation

(0,200,1000) ;IC50 Drug conc at 50% of the max inhibition of enzyme

degradation

 

$OMEGA .002 .0001 .0001 .0001 .001 .001 .001

$SIGMA .05 .01

$ESTIMATION MAXEVAL=9999 POSTHOC

$COVARIANCE

 

Best regards

 

Sreenivasa Rao Vanapalli, Ph.D,

Janssen Postdoctoral Research Scholar,

S411 PHAR, College of Pharmacy,

University of Iowa, Iowa City, IA-52242

319-353-5157 (Office)

319-337-2687 (Home)

 

*****

 

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

Subject: RE: Autoinduction

Date: Wed, 16 May 2001 08:48:37 +0200

 

Sreenivasa,

 

You modified already your control compared to the yesterday version, particularly, you excluded DV from $DES block. There are still a few issues that may cause problems:

1. An enzyme submodel. I prezume the enzyme should have some steady-state level which is altered by the drug. There should be a formation rate for the enzyme not equal to KENZ, say KIN. The baseline amount of enzyme is then KIN/KENZ.

2. Initialization of compartment 4. I think you do not need $AESINITIAL. You have to introduce a unit amount into COMP 4 at TIME=0 using an extra dose record in your data set.

3. In your model, the enzyme has no impact on the drug elimination. In the framework of the autoinduction model CL should depend on the enzyme amount.

 

Have a look at the following recent publications:

1. Hassan M. Svensson USH. Ljungman P. Bjorkstrand B. Olsson H. Bielenstein M. Abdel-Rehim M. Nilsson C. Johansson M. Karlsson MO. A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients. British Journal of Clinical Pharmacology. 1999; 48(5):669-677.

2. Kerbusch T. Huitema ADR. Ouwerkerk J. Keizer HJ. Mathot RAA. Schellens JHM. Beijnen JH. Evaluation of the autoinduction of ifosfamide metabolism by a population pharmacokinetic approach using NONMEM. British Journal of Clinical Pharmacology. 2000; 49(6):555-561.

 

Best regards,

Vladimir