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Re: ETA on ALAG1

From: Jurgen Bulitta <jbulitta>
Date: Sat, 13 Dec 2008 08:02:44 +0100

Dear Nidal, Dear All,

It is good that there are various options in NONMEM to
resolve the difficulty of estimating variability in lag-time.

I think there are two additional points:
1) Do we believe that there truly is a notable variability
in lag-time?
2) Is it really important to precisely describe the absorption
process for the drug / task of interest?
Or: Do the other parameter estimates change notably,
if the absorption process is in part misspecified?

From my experience:
For 1), to the best of my memory, all frequently sampled
PK studies I ever modeled benefitted from inclusion of
lag time and associated BSV.
I would consider gastrointestinal transit as one of the more
variable processes in PK, so inclusion of BSV is justified.

For 2), Sometimes, estimates for CL and V1 differ between
more sophisticated and basic absorption models. (Rada
Savic et al. have generated hard data on this). If CL
is not affected and one only likes to predict AUC, then it
may not be worth the effort to go for one of the advanced
absorption models. If predicting Cmax is of interest, then
describing the absorption kinetics well is more critical.

I have not systematically studied the following. However, my guess
is that programs that calculate gradients (like NONMEM) might
have more difficulties with estimating variability in lag-time and
duration of infusion. My prediction is that MC-PEM, SAEM,
MCMC and NPAG are more robust in estimating BSV on such
discontinuous processes. (Of course, more hard data are
needed on the latter prediction).

Kind regards

Juergen Bulitta, PhD
Pharmacometrics, University at Buffalo, NY, USA
Phone: +1 716 645 2855 ext. 281, j

-----Ursprüngliche Nachricht-----
Von: <nidal.alhuniti
Gesendet: 12.12.08 22:56:01
An: nmusers
Betreff: Re: [NMusers] ETA on ALAG1

As Nick said you could have a negative objective function that is not
an error. Usually estimating an ETA on lag time could be problematic;
however you could use the hybrid method in NM. Please see the NM help
files for more details.

Nidal AL-Huniti, PhD
Associate Director, Modeling and Simulations
ICON Development Solutions

On 12/12/08, *Nick Holford* <n.holford

It is not an error to have a negative objective function value.

It is an error not to describe the problem accurately.
If you want to get help from nmusers then please quote the EXACT
wording of the error message and describe what you did that caused
the error to appear.



Dear All,

It is an old topic, but definetely not completely resolved. Can
anybody provide tips on estimating variability on ALAG1 in a 2 comp,
oral absorption model (I am using NONMEM V). I am getting an error
message OBJFUN is negative. I have searched in usernet archive but
could not solve the problem. I appreciate your help.

Ayyappa Chaturvedula
1500 Littleton Road,
Parsippany, NJ 07054

Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New

Received on Sat Dec 13 2008 - 02:02:44 EST

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