From: "James Bailey" <James_Bailey@Emory.org>

Subject: Different models for different age groups? Infinite objective functions

Date: Wed, 18 Jul 2001 11:04:41 -0500

To all:

Two questions.

#1

I am analyzing data from a study of a vasoactive intravenous drug in

pediatric patients. The majority of patients are neonates or infants.

Two previous, limited studies of this drug in pediatric patients used

were given, very quickly in the study that found a three compartment

model to be optimal and less quickly in the study using a two

compartment model. In the study I am analyzing, a loading dose was

given very slowly, followed by a constant rate infusion. For this data,

I find that the optimal model is one compartment. But when I analyze

subsets (neonates, infants, or chidren) I find that a two compartment

model works best for children and the one compartment model is optimal

for neonates and infants.

I am not satisfied using different models for somewhat arbitrarily

defined age groups. Does anyone know of a method to develop a unified

model? I have tried

using age as a covariate, with the following CONTROL file

(the model parameters are volumes and clearances)

TVV1=WT*THETA(1)

V1=TVV1*EXP(ETA(1))

TVV2 = WT*THETA(2)*EXP(THETA(5)*(AGE-8))

V2=TVV2*EXP(ETA(2))

TVCL=WT*THETA(3)

CL=TVCL*EXP(ETA(3))

TVQ=WT*THETA(4)

Q=TVQ*EXP(ETA(4))

(8 is the median age, in months, in the study). I have done something

similar for distribution clearance, Q. Any suggestions?

A second question relates to an error message I get frequently when

using conditional estimation. The error message is "Minimization

terminated due to proximity of last iteration estimate to a value at

which the objective function is infinite". I know the NONMEM Users

Manual says estimates from a minimization which is terminated due to

rounding errors may be useful, depending on the number of significant

digits, etc. Is there any useful information fom a minimization which

is terminated for the above reason?

Any help will be appreciated.

Jim Bailey

******

From: "Gobburu, Jogarao V" <GOBBURUJ@cder.fda.gov>

Subject: RE:Different models for different age groups? Infinite objective functions

Date: Wed, 18 Jul 2001 12:42:05 -0400

Dear Jim,

1. To a large extent, the approach depends on what you want to do with the

so developed model. You might want to comine data from adults and pediatrics

and then analyze.

2. You might also want to consider the use of allometric models for body

weight - CL(and Q) relationship. Further, there is evidence in literature

that age is an important parameter to describe the organ maturation process.

In general, liver and kidney reach comparable capacity to adults (after body

size adjustment) at about 2 years. Hence you might want to use an Emax or a

constant rate infusion type model (see below for a ref) to describe the

maturation process.

Anderson BJ, Woollard GA, Holford NH. A model for size and age changes in

the pharmacokinetics of paracetamol in neonates, infants and children. Br J

Clin Pharmacol. 2000 Aug;50(2):125-34.

Joga Gobburu,

Pharmacometrics,

CDER, FDA