From: Rebecca Wrishko <wrishko@unixg.ubc.ca>
Subject: Error (72) - Overflow
Date: Mon, 15 Nov 1999 17:23:29 -0800
Fellow NONMEM Users,
Recently, when altering the initial theta estimates I received the following error message: forrt1: error (72): error overflow. The error resulted when the initial theta estimates were set to:
$THETA (0,0.5) (0,0.5) (0,1) (0,3)
with the implementation of the following pk block;
$PK
TVCL=THETA(1)*WT
CL=TVCL*(1+ETA(1))
TVV=THETA(2)*WT
V=TVV*(1+ETA(2))
TVVSS=V+THETA(3)*WT
VSS=TVVSS*(1+ETA(3))
However, when the initial theta estimates were set to $THETA (0,3) (0,5)(0,10) (0,3), no error message was given. Any suggestions to the cause and possible remedy would be greatly appreciated.
Also, how does NONMEM generate the predicted serum concentrations at the times for which there is a corresponding event record? I have attempted using the final parameter one- and two-compartment estimates of CL and Vss, obtained from individual and population modeling routines, to calculate expected drug concentrations and do not derive the same values as those generated from the NONMEM execution.
Thank you for your assistance.
Rebecca Wrishko
Division of Clinical Pharmacy
Faculty of Pharmaceutical Sciences
University of British Columbia
Vancouver, British Columbia, Canada
Email: wrishko@unixg.ubc.ca
Error (72) - Overflow
From: "Piotrovskij, Vladimir [JanBe]" <VPIOTROV@janbe.jnj.com>
Subject: RE: Error (72)
Date: Tue, 16 Nov 1999 11:24:31 +0100
Dear Rebecca,
You should be more specific when posting your questions. The convergence behaviour of NONMEM depends very much on the METHOD you select for $EST. It can be totally different for METHOD=0 (the default first order linearization method) and for METHOD=1 (first-order conditional method). It would be better if you attach the entire NM-TRAN control.
The way you implement the fixed effect of WT is not optimal. Firstly, it is preferable to center it using median WT (say, 70) as offset. Then, it worth to include an intercept in the fixed effect model, e.g.: TVCL=THETA(1)+THETA(2)*(WT-70). THETA(1) corresponds to the typical clearance at median WT. Lastly, I would strongly recommend to avoid using TRANS3. You will have much less troubles with TRANS4.
Hope this helps,
Vladimir
----------------------------------------------------------------------
Vladimir Piotrovsky, Ph.D.
Janssen Research Foundation
Clinical Pharmacokinetics
B-2340 Beerse
Belgium
Email: vpiotrov@janbe.jnj.com
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These postings lead to a quite lengthy thread of messages under the subject heading of "Covariate Models Using Weight". Reading through the entirity of this thread revealed that the discussion progressed across four subtopics and was therefore archived as four inter-linked threads. Messages that served to transition the discussion from one subtopic to the next will appear in both subtopics.
Centering Covariates
Covariate Models Using Weight (Allometric Scaling)
Covariate Models Using CrCL
Predefined Models vs. "Context-Sensitive" Emperical Models