**From: "David Nix" <nix@pharmacy.arizona.edu>
**

Date: 19 Dec 1997 15:43:52 -0500

In using Advan3/ Trans3 routines, it has been common to obtain the error V>Vss. This model is parameterized by:

CL

V

Q - distributional clearance

Vss

with the following relationships:

k10 = CL/V

k12 = Q/V

k21 = Q (Vss-V)

The population estimates come out reasonable, but V>Vss for some individuals. As a result, the, the post hoc eta's are not obtained for anyone. I have got around this problem previously by parameterizing the model differently.

Does anyone have and error trap or other method to avoid this problem which makes it possible to parameterize using Vss.

******
**

**From: "Harnisch, Lutz, HMR/DE" <Lutz.Harnisch@hmrag.com>
**

we use these alternatives:

ADVAN3 TRANS4

CL = THETA(1)

V1 = THETA(2)

V2 = THETA(3)

VSS = V1+V2

DVZ = THETA(4)

VZ = V1 + V2 + DVZ

Q = CL*(V2/DVZ) * (V2+DVZ)/VZ

or

...

V1 = THETA(2)

VSS = THETA(3)

V2 = VSS-V1 ...

or if (V1<V2)

...

V1 = THETA(2)

DV2 = THETA(3)

V2 = V1+DV2

VSS=V1+V2 ...

but only the first and last one give always POSTHOC estimates. But therefore you have to recalculate the error/omega of VSS. The second method has the same difficulties with V1>VSS, its only for completeness. That's what we use, also to avoid the interpretation of Q itself, because Vz is more meaningful for our understanding.

Best regards

Lutz

______________________________

Lutz Harnisch

Hoechst Marion Roussel

Preclinical Development

Pharmacokinetics

Population Analysis an Modelling

Building H840, Room 449

D-65926 Frankfurt/Main

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

phone: +49 (69) 305-16481

fax: +49 (69) 305-81990

mailto:Lutz.Harnisch@hmrag.com

______________________________

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**

**From: alison@c255.ucsf.EDU (ABoeckmann)
**

If you really do not want to reparameterize, there is a way to tell NONMEM that a given set of thetas and etas are unacceptable: the EXIT statement. (See Guide IV, Chapt 4, G.2 Implementation). In your case, you might have code that looks like this:

V=TV*EXP(ETA(1))

VSS=TVSS*EXP(ETA(2))

IF (VSS.LE.V) EXIT 1 100

During the posthoc step, NONMEM will try to avoid etas that give rise to this condition.

The second integer that follows EXIT, 100, identifies it in error messages such as

PK SUBROUTINE: USER ERROR CODE = 100