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RE: Cmax/Tmax in the DES block

From: Bauer, Robert <Robert.Bauer>
Date: Fri, 4 May 2018 17:23:39 +0000

Paolo and Kyle are correct on this point. ODE solving can be complicated, and each algorithm has its own method, calling the DES routine at will at various times T (which varies to a finer degree than TIME from the data set), sometimes carrying out an iterative process, until it has the satisfied precision for the grid times that it was asked to evaluate (in NONMEM’s case, values at TIME from the data set, or MTIME positions). Hence, the need sometimes for fine grid points in a data set that may be embellished by the finedata utility, if you want to find a position near when a peak occurs, or some other event. This process is not a function of NONMEM, but of the particular ODE solver used.

In Leonid’s case, things are a little easier in that an exact evaluation at the end of infusion is desired. The finedata utility can calculate the specific time at end of infusion and add the record, if it is a hard-coded position that can be determined from the data set, and not one that might be evaluated from a model parameter. This will make the results at a particular position available as a record in a $TABLE file.

Robert J. Bauer, Ph.D.
Senior Director
Pharmacometrics R&D
ICON Early Phase
820 W. Diamond Avenue
Suite 100
Gaithersburg, MD 20878
Office: (215) 616-6428
Mobile: (925) 286-0769
Robert.Bauer uer<>

From: owner-nmusers ers
Sent: Friday, May 04, 2018 9:03 AM
To: Leonid Gibiansky; Bob Leary; nmusers .com<mailto:nmusers
Subject: Re: [NMusers] Cmax/Tmax in the DES block

Dear all,
Very interesting, just adding my two cents, but not sure it's 100% relevant.

When I played with ADVAN13 before and asked NONMEM to print out all the steps in a file, I could see that the time (T) was not always going forward, but sometimes NONMEM was taking some steps back in time and then proceeding again.

Not sure if this is because of how LSODA is implemented in NONMEM. I remember - but I am happy to stand corrected - that some DES work in such a way that they rework the size of the time steps dynamically when they solve the ODEs and if the TOL (precision) criterion is not met, they go back and retry with a small step size. So I was thinking that maybe the difference in Cmax could be from one of those "faux pas" when NONMEM has overshot the solution and then it would take a step back?

Just an idea on something to check. But I guess the NONMEM developers may have a quick answer to this one (hint hint).

On 2018/05/04 17:32, Leonid Gibiansky wrote:
The procedure described in the original post is working without extra
points. It is working fine, just have a small bias, and the bias seems
to be zero with ADVAN6. For all the practical purposes it can be used
without extra points. I was just surprised that it is not exact in some
cases, so extra check is warranted each time when it is used (may be we
can switch to ADVAN6 rather than ADVAN13 when computing Cmax/Cmin in the
DES block).

Latest NONMEM versions have "finedata" Utility Program that can be used
to add extra points to the dataset (nm741.pdf, page 237).


On 5/4/2018 11:01 AM, Bob Leary wrote:
> One of the problems with all of this is that the user must manually enter artificial time points (or at least in 2007 had to do this - I don't know if this has been fixed in
> The latest NM versions) in the data set in order to evaluate the fitted model over more grid points than are in the original data.
> To get a fine grid and good resolution on Cmax and Tmax
> You have to enter a lot of extra time points., which is a pain in the neck. The various ODE routines are also remarkably sensitive to how the grid is set up.
> Much better would be to have a grid generator within NMTRAN that lets you just specify beginning and end points and number of points in the grid.
> I would point out that Phoenix NLME PML has always had this capability.
> Bob Leary
> -----Original Message-----
> From: owner-nmusers to:owner-nmusers
> Sent: Thursday, May 3, 2018 7:59 PM
> To: nmusers m>
> Subject: [NMusers] Cmax/Tmax in the DES block
> Interesting experience concerning computation of Cmax and Tmax (and probably other stats) in the DES block. We used to use this way:
> Specifically, reserved the place in the memory:
> Set these values to zero for each new subject:
> $PK
> COM(1)=0
> COM(2)=0
> and computed Cmax/TMAX as
> $DES
> COM(2)=T
> Recently I applied the same procedure to compute Cmax following 1 hr IV infusion. Unexpectedly, Tmax was estimated at times > 1 hr, and Cmax was higher than 1-hr concentration (true Cmax is at 1 hr).
> After some experiments, the explanation was that Nonmem computes concentration-time course (with infusion ON) for longer than 1 hr, and resulting Cmax/Tmax are at the end of the "computation window" rather than at 1 hr.
> Turns out that the results also depend on ADVAN routine. The largest deviation (still small, 1-3 percents) was for ADVAN8, ADVAN9, and ADVAN13. ADVAN15 was better but still off. ADVAN14 was almost perfect but still slightly (0.01%) off. ADVAN6 provided correct answer (up to the precision of the output). So, the discrepancy is small but if 1-2% difference is important, one has to be careful when using DES block computations.
> Thanks
> Leonid
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Received on Fri May 04 2018 - 13:23:39 EDT

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