From: "Panetta, Carl" Carl.Panetta@stjude.org
Subject: [NMusers] modeling interoccasion variability
Date: 11/18/2003 11:24 AM

I have a question on modeling interoccasion variability (IOV).
I have read through and used the method of handling IOV discussed
in Karlsson and Sheiner (JPP 1993) and it works fine when there
are 2 or 3 occasions per individual. But, in situations where there
are many more than 3 occasions per individual and each individual
does not necessarily have the same set of occasions, the method
becomes more difficult to implement and NONMEM does not always
converge successfully and/or give acceptable results. For example,
I am working with a set of data where there are 10 different occasions.
Not every individual has PK samples for each of the 10 occasions, but
each individual has about 3 to 5 occasions. Thus, while everybody has
an occasion 1 and most have an occasion 3 only a few have occasion 2.
Therefore, instead of having a measure of variability for each of the
10 occasions separately, I would like to have a single overall measure
of variability for the IOV for clearance (and other PK parameters) in
a similar manner as I can get a single measure of the interindividual
variability measure.

Does anybody have any suggestions, references, etc. on if and
how this can be done?

Thanks,

J. Carl Panetta, Ph.D.

Department of Pharmaceutical Sciences

St. Jude Children's Research Hospital

332 N. Lauderdale St.

Memphis, TN  38105

Phone: (901) 495-3172

Fax: (901) 525-6869

Carl.Panetta@stjude.org
_______________________________________________________

From: "Panetta, Carl" Carl.Panetta@stjude.org
Subject: RE: [NMusers] modeling interoccasion variability
Date: 11/18/2003 1:12 PM

After doing a bit more reading, I realized I was not using the
“SAME” option in the OMEGA block! This is what I was looking for.

While I think I have figured out my main problem, any other
comments or suggestions on working with IOV would be appreciated.

 

Thanks,

 

J. Carl Panetta, Ph.D.

Department of Pharmaceutical Sciences

St. Jude Children's Research Hospital

332 N. Lauderdale St.

Memphis, TN  38105

Phone: (901) 495-3172

Fax: (901) 525-6869

Carl.Panetta@stjude.org
_______________________________________________________

From: Nick Holford n.holford@auckland.ac.nz
Subject: RE: [NMusers] modeling interoccasion variability
Date: 11/18/2003 1:17 PM

Carl,

It sounds like you should be using the SAME option:

"instead of having a measure of variability for each of the 10
occasions separately, I would like to have a single overall measure
of variability for the IOV for clearance"

This means that you only estimate one OMEGA which is the same for
all occasions. The ETA for each occasion will be different because
they are sampled from a different distribution with the SAME variance.

I don't know of any intrinsic reason why having different numbers of
occasions for your subjects should make it hard to estimate BOV
(between occasion variability aka IOV). 

Here is an example showing how to code this for NM-TRAN:

$OMEGA .5 ; BSVCL
$OMEGA BLOCK(1)
.1 ; BOVCL1
$OMEGA BLOCK(1) SAME
;; BOVCL2
...
$OMEGA BLOCK(1) SAME
;; BOVCLn

$PK
IF (OCC.EQ.1) THEN
   BOVCL=ETA(2)
ENDIF
IF (OCC.EQ.2) THEN
   BOVCL=ETA(3)
ENDIF
...
IF (OCC.EQ.n) THEN
   BOVCL=ETA(n+1)
ENDIF
CL=POPCL*EXP(ETA(1) + BOVCL)
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford@auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
_______________________________________________________