- On 6 Oct 2005 at 11:47:14, "Jing Li" (jli29.at.jhmi.edu) sent the message

Back to the Top

Hi,

I am trying to fit a population PK model with nonlinear elimination

(Michaelis-Menten) with NONMEM. The drug was given to 15 patients by

20-min infusion weekly. Each patient received 6 different doses each

week for 6 weeks, and intense PK sampling was drawn after each dose.

The drug shows apparent non-linear clearance.

The following is the model control file. The model did not converge

no matter how I changed the initial estimates. Is there any problem

with the control file? Any thoughts would be appreciate!

Best regards.

Jing

$PROB 20-MIN IV INFUSION MULTIPLE DOSE WITHOUT COVARIATES

$INPUT ID WEEK AMT RATE TIME XDV DV MDV EVID

;XDV, observations, DV, log-transformed concentrations

$DATA ANTISOMA_DART_3.csv IGNORE=.-at-.

$SUBROUTINES ADVAN9 TRANS1 TOL=3

$MODEL NPAR=9, NCOMP=3, COMP=(CENTRAL,DEFOBS),

COMP=(PERIPH1), COMP=(PERIPH2)

;$ABB DERIV2=NO

$PK

VM = THETA(1) *EXP(ETA(1))

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

V1 = THETA(2)*EXP(ETA(2))

V2 = THETA(3)*EXP(ETA(3))

V3 = THETA(4)*EXP(ETA(4))

Q2 = THETA(5)*EXP(ETA(5))

Q3 = THETA(6)*EXP(ETA(6))

SC = V1

K12 = Q2/V1

K21 = Q2/V2

K23 = Q3/V2

K32 = Q3/V3

OBS = XDV ;non-transformed

observations

$ERROR (ONLY OBSERVATION)

DEL = 0

IF(F.EQ.0) DEL = .000001

IPRED = F + DEL

W = SQRT(THETA(8)**2+THETA(9)**2*F*F)

IPRED = LOG(IPRED)

IRES = DV-IPRED

IWRES = IRES/W

Y = IPRED+ERR(1)*W

$DES

C1 = A(1)/V1

DADT(1) = - K12*A(1) - A(1)*VM/(KM+C1)

DADT(2) = K12*A(1) - K21*A(2) + K32*A(3) - K23*A(2)

DADT(3) = K23*A(2) - K32*A(3)

$THETA (0,1) ;1 VM (uM/h)

$THETA (0,3,10) ;2 V1

$THETA (0,5,20) ;3 V2

$THETA (.5,2,10) ;4 V3

$THETA (0,.2,5) ;5 Q2

$THETA (0,1,5) ;6 Q3

$THETA (10,200) ;7 KM (uM)

$THETA (0,.5) ;8 SD ADD ERROR

$THETA (0,.1) ;9 CV PROP ERROR

$OMEGA .1 ;1 VM

$OMEGA .1 ;2 V1

$OMEGA .3 ;3 V2

$OMEGA .1 ;4 V3

$OMEGA .1 ;5 Q2

$OMEGA .1 ;6 Q3

$OMEGA .1 ;7 KM

$SIGMA 1 FIX

$EST MAXEVALS=9990 PRINT=2 POSTHOC MSFO=msfb40 POSTHOC ;METH=1 INTER

$COV

$TAB ID ID WEEK AMT RATE ONEHEADER NOPRINT FILE=mytab40

$TAB ID TIME DV IPRED IWRES ONEHEADER NOPRINT FILE=sdtab40

$TAB ID VM KM V1 V2 V3 Q2 Q3 ETA1 ETA2 ETA3 ETA4 ETA5 ETA6

ONEHEADER NOPRINT FILE=patab40 - On 6 Oct 2005 at 12:29:45, Brenda Cirincione (Brenda.Cirincione.aaa.cognigencorp.com) sent the message

Back to the Top

The following message was posted to: PharmPK

Hi,

At a quick glance and without knowing more about your specific PK

model, one of the things that I noticed in your control stream is

that the differential equation for compartment 2, Dadt(2), you

include a term -K21*A(2), but a corresponding term +K21*A(2) is not

included in the Dadt(1) differential equation. This may contribute

to the difficulties that you are seeing.

Regards,

Brenda - On 6 Oct 2005 at 12:27:16, Leonid Gibiansky (leonidg.aaa.metrumrg.com) sent the message

Back to the Top

The following message was posted to: PharmPK

Hi Jing,

1. You have way too many eta effects. Start with CL, central volume

only, fix the rest to zero, at least to define the range of parameter

values. You may add more later if needed.

2. This is an error:

W = SQRT(THETA(8)**2+THETA(9)**2*F*F)

you should use

W = SQRT(THETA(8)**2+THETA(9)**2/F/F)

3. This is an error as well:

DADT(1) = - K12*A(1) - A(1)*VM/(KM+C1)

DADT(2) = K12*A(1) - K21*A(2) + K32*A(3) - K23*A(2)

you are missing K21*A(2) in

DADT(1) = - K12*A(1) - A(1)*VM/(KM+C1)+ K21*A(2)

Leonid

[F/F = 1? - db] - On 6 Oct 2005 at 18:51:56, "Perez Ruixo, Juan Jose [PRDBE]" (JPEREZRU.aaa.PRDBE.jnj.com) sent the message

Back to the Top

The following message was posted to: PharmPK

Dear Jing,

The input from the second compartment to the first compartment is

missing.

Probably what you want to fit is a system of DE as follows

DADT(1) = - K12*A(1) + K21*A(2) -

A(1)*VM/(KM+C1)

DADT(2) = K12*A(1) - K21*A(2) - K23*A(2) + K32*A(3)

DADT(3) = + K23*A(2) - K32*A(3)

However, I'm not sure you want to start with a catenary model,

instead of a

mamillary model. If you like to test a mamillary model, it should be as

follows:

DADT(1) = - K12*A(1) + K21*A(2) - K13*A(1) + K31*A(3) -

A(1)*VM/(KM+C1)

DADT(2) = K12*A(1) - K21*A(2)

DADT(3) = + K13*A(1) - K31*A(3)

Regards,

Juan Jose Perez Ruixo, PhD.

Principal Scientist. Advanced PK/PD Modelling & Simulation,

Global Clinical Pharmacokinetic and Clinical Pharmacology,

Johnson & Johnson Pharmaceutical Research & Development,

a Division of Janssen Pharmaceutica, NV.

Email: jperezru.aaa.prdbe.jnj.com - On 6 Oct 2005 at 13:05:35, "Kowalski, Ken" (Ken.Kowalski.-at-.pfizer.com) sent the message

Back to the Top

The following message was posted to: PharmPK

Leonid,

I think W is correctly specified in Jing's control stream below. As

she has

coded it, W is the residual standard deviation (given the ETAs) for the

combined proportional and additive error model. That is,

Var(Y | ETAs) = (W^2)Var(ERR(1)) = W^2 = THETA(8)**2 + (THETA(9)**2)*F*F

where THETA(8) is the residual SD for the additive component and THETA

(9) is

the residual CV for the proportional component.

Ken - On 6 Oct 2005 at 12:20:29, Paul Hutson (prhutson.-a-.pharmacy.wisc.edu) sent the message

Back to the Top

Jing:

From a first look:

1) your central compartment (1) does not appear to reflect the return

from compartment 2

DADT(1) = - K12*A(1) - A(1)*VM/(KM+C1)+ K21*A(2)

2) your saturable term should use C1 instead of A(1) in order to

yield units of mass/time.

3) Is there a reason you are setting this up to have no exchange

between compartment 1 and 3?

Paul

> $DES

> C1 = A(1)/V1

> DADT(1) = - K12*A(1) - A(1)*VM/(KM+C1)

> DADT(2) = K12*A(1) - K21*A(2) + K32*A(3) - K23*A(2)

> DADT(3) = K23*A(2) - K32*A(3)

--

Paul R. Hutson, Pharm.D.

Associate Professor

UW School of Pharmacy

777 Highland Avenue

Madison WI 53705-2222

Tel 608.263.2496

Fax 608.265.5421 - On 6 Oct 2005 at 12:20:29, Paul Hutson (prhutson.-a-.pharmacy.wisc.edu) sent the message

Back to the Top

Jing:

From a first look:

1) your central compartment (1) does not appear to reflect the return

from compartment 2

DADT(1) = - K12*A(1) - A(1)*VM/(KM+C1)+ K21*A(2)

2) your saturable term should use C1 instead of A(1) in order to

yield units of mass/time.

3) Is there a reason you are setting this up to have no exchange

between compartment 1 and 3?

Paul

> $DES

> C1 = A(1)/V1

> DADT(1) = - K12*A(1) - A(1)*VM/(KM+C1)

> DADT(2) = K12*A(1) - K21*A(2) + K32*A(3) - K23*A(2)

> DADT(3) = K23*A(2) - K32*A(3)

--

Paul R. Hutson, Pharm.D.

Associate Professor

UW School of Pharmacy

777 Highland Avenue

Madison WI 53705-2222

Tel 608.263.2496

Fax 608.265.5421 - On 6 Oct 2005 at 13:20:13, Leonid Gibiansky (leonidg.-a-.metrumrg.com) sent the message

Back to the Top

The following message was posted to: PharmPK

Ken,

Note that data are log-transformed. See

http://www.cognigencorp.com/nonmem/nm/99apr232002.html

for Mats Karlsson explanation how to apply combined error in the log-

transformed case.

--cut here --

To get the same error structure for log-transformed data as the

additive+proportional on the normal scale, I use

Y=LOG(F)+SQRT(THETA(x)**2+THETA(y)**2/F**2)*EPS(1)

with

$SIGMA 1 FIX

THETA(x) and THETA(y) will have the same meaning as on the

untransformed scale

with

Y=F+SQRT(THETA(y)**2+THETA(x)**2*F**2)*EPS(1)

with

$SIGMA 1 FIX

-- cut here --

Leonid - On 6 Oct 2005 at 13:51:15, "Peter Moate" (moate.at.vet.upenn.edu) sent the message

Back to the Top

The following message was posted to: PharmPK

To Jing,

Jing, I have not used NONMEM, but are you sure your equations are

correct?

It looks to me as if equation 1 should read:

DADT(1) = K21*A(2) - K12*A(1) - A(1)*VM/(KM+C1)

Regards, Peter Moate

Want to post a follow-up message on this topic? If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Non-linear PK" as the subject

PharmPK Discussion List Archive Index page

Copyright 1995-2010 David W. A. Bourne (david@boomer.org)