Are there any measurements that are not BQLs and that are more than 24
hrs from the last dose? What is the residual error ? Combined error
(rather than proportional or exponential) may help. Random effect on
residual error is very helpful to identify aberrant
subjects/observations. $ABBREV PROTECT helps sometimes. NOHABORT (with
H) can help but it is dangerous, so it can be used for debugging, but
not for the final models.
I would look on the data with large WRES (after the FO run) to see
whether any of the observations are so far off that Nonmem cannot fit
them and crashes.
Thank you
Leonid
On 12/5/2024 2:33 PM, Dennis Fisher wrote:
Colleagues
I have encountered a problem during NONMEM execution.
Most subjects are dosed daily but a small number of subjects have large
intervals (> 30 days) between successive doses.
For subjects dosed daily, concentrations 24 hours after a dose are BQL
and there is no evidence of accumulation.
For the problem subjects, NONMEM either:
1. aborts (despite a NOABORT option) with an error message at the first
dose after the lengthy gap
2. or sends the following error message:
0PRED EXIT CODE = 1
0INDIVIDUAL NO. 103 ID= 3.11040000000000E+04 (WITHIN-INDIVIDUAL)
DATA REC NO. 56
THETA=
1.66E+02 1.15E-01 2.95E+01 1.81E+01 4.33E+01 3.01E+02
8.26E+00 0.00E+00 1.00E+00 0.00E+00
0.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00
1.00E+00
OCCURS DURING SEARCH FOR ETA AT INITIAL VALUE, ETA=0
NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
MAXIMUM NO. OF EVALUATIONS OF DIFFERENTIAL EQUATIONS, 1000000,
EXCEEDED.
The error occurs with METHOD=1 but NOT with METHOD=0.
For one subject in whom doses were administered on Days 1, 30, and 60
(followed by daily dosing), I deleted the first two dosing records and
the error no longer occurs with METHOD=1. I speculate that the error
might relate to the predicted concentration becoming Infinitesimally
small after a lengthy interval between doses, However, I have no idea
if this is the explanation. And I am reluctant to change the dataset so
I seek other solutions.
Any ideas as to an explanation or a work-around?
Dennis
Dennis Fisher MD
P < (The "P Less Than" Company)
Phone / Fax: 1-866-PLessThan (1-866-753-7784)
www.PLessThan.com
