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Re: FO vs FOCE, sequential vs simultaneous

From: Nick Holford <n.holford>
Date: Wed, 10 Dec 2008 09:46:50 +1300


Thanks very much for this experimental data support confirming again the
wisdom of using FOCE rather than FO and not worrying about convergence.


Leonid Gibiansky wrote:
> Hi Alan,
> Here:
> I used all datasets that I had, and I was not able to find any problem
> where FO was superior to FOCE.
> Not-converged FOCE is better, in my opinion, than converged FO
> (although you can always check using diagnostic plots).
> If you cannot use FOCE due to time restrictions, it is better to use
> FO than just abandon modeling. Still, I would try to run the final
> model with FOCEI.
> Concerning sequential vs simultaneous: there are several points to
> consider, and this is usually relates to the PK-PD case. For PK-PD,
> the main question is the comparison of PK and PD variabilities.
> Usually, PK variability is smaller, and PK data are more reliable.
> Then, sequential modeling can be more warranted. If PK and PD
> variabilities are similar (both residual and inter-subject) you can
> use joint fit. I usually do PK first, then PK-PD, and then try to fit
> combined model at the very last stage.
> For parent-metabolite case, both sets of data are equally reliable (or
> not reliable), and variability is usually similar. Then the question
> boils down to time and convenience. Again, I usually do parent fist,
> then fix parameters and do metabolite, and then, if possible, do
> simultaneous fit. This often saves time: parent model is more simple,
> it can be done in standard ANDANs for 1-2 compartment models that are
> much quicker. You can experiment freely with random effect,
> covariates, residual error, etc. Joint model often needs to be solved
> using ADVAN5, 7 or even $DES which are more CPU-consuming. You want to
> do minimum number of runs here. Thus, you want to start with good
> parent model, and study metabolite part only. The final joint run fits
> all parts together.
> Thanks
> Leonid
> --------------------------------------
> Leonid Gibiansky, Ph.D.
> President, QuantPharm LLC
> web:
> e-mail: LGibiansky at
> tel: (301) 767 5566
> Xiao, Alan wrote:
>> Dear All,
>> I know this is an old topic, too, but would like to see the statistics.
>> When you have a dataset with about 10% of dense Phase II data
>> (predose, 2, 4, 8, and 12 hrs post dose on day 1 and at steady state,
>> twice-daily dose regimen) and about 90% of very sparse Phase III data
>> (1-2 samples/patient), which method do you prefer: FO or FOCE? or FO
>> for model development but FOCE for model refinement/finalization? If
>> FOCE is not practical because of long run-time or numerical
>> difficulties in converge, do you stop here or would you use FO?
>> Thanks,
>> Alan

Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
Received on Tue Dec 09 2008 - 15:46:50 EST

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