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Re: [NMusers] Cmax/Tmax in the DES block

From: Kyle Baron <kyleb_at_metrumrg.com>
Date: Fri, 4 May 2018 12:20:38 -0500

Here is some code to reproduce / demonstrate the observation in R:
https://github.com/metrumresearchgroup/mrgsolve/issues/369

I think it captures the essence of what you were doing, Leonid. The
comparison against the analytical solution just shows that the ODEs are
still giving the right answer (the overshoot isn't wrong; just a feature of
the solver).

Kyle




On Fri, May 4, 2018 at 12:15 PM, Leonid Gibiansky <lgibiansky_at_quantpharm.com
> wrote:

> Interesting links.
>
> So looks like one can provide tcrit=TIME (where TIME is the next EVENT
> time) to LSODA, and this will fix the over-shoot problem (as in ITASK=4). I
> wonder whether ADVAN13 and ADVAN6 use different settings for tcrit (or the
> difference in the results is just the difference in the amount of
> over-shooting)
>
> Leonid
>
>
>
> On 5/4/2018 12:58 PM, Kyle Baron wrote:
>
>> I agree with Paolo's explanation, but I suspect it isn't something
>> specific to NONMEM. When LSODA integrates up to the time of the
>> end of the infusion, there is no guarantee that it will never go
>> past that time. Rather, it's likely that it will "overshoot" that
>> time and interpolate back to the place where it was supposed to
>> stop (the end of the infusion). That might be why Leonid is seeing the
>> bias.
>>
>> I couldn't find the docs that specifically discuss this, but maybe
>> NONMEM uses ITASK 1 when it advances the system?
>>
>> https://github.com/metrumresearchgroup/mrgsolve/blob/master/
>> src/opk_dlsoda_mrg.f#L378-L381
>>
>> You can also see the overshoot discussed in the deSolve docs:
>>
>> https://www.rdocumentation.org/packages/deSolve/versions/1.
>> 20/topics/lsoda
>>
>> (see the tcrit argument)
>>
>> Kyle
>>
>> On Fri, May 4, 2018 at 11:03 AM, Paolo Denti <paolo.denti_at_uct.ac.za
>> <mailto:paolo.denti_at_uct.ac.za>> wrote:
>>
>> 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).
>>
>> Paolo
>>
>>
>> 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).
>>>
>>> Leonid
>>>
>>>
>>> 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_at_globomaxnm.com
>>> <mailto:owner-nmusers_at_globomaxnm.com>
>>> <owner-nmusers_at_globomaxnm.com>
>>> <mailto:owner-nmusers_at_globomaxnm.com> On Behalf Of Leonid Gibiansky
>>> > Sent: Thursday, May 3, 2018 7:59 PM
>>> > To: nmusers_at_globomaxnm.com <mailto:nmusers_at_globomaxnm.com>
>>> > 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:
>>> >
>>> > http://cognigencorp.com/nonmem/current/2007-December/4125.html
>>> <https://protect-za.mimecast.com/s/L8T-CAnX51ilA2ops83Si8>
>>> >
>>> > Specifically, reserved the place in the memory:
>>> >
>>> > $ABB COMRES=2
>>> >
>>> > Set these values to zero for each new subject:
>>> > $PK
>>> > IF(NEWIND.LE.1) THEN
>>> > COM(1)=0
>>> > COM(2)=0
>>> > ENDIF
>>> >
>>> > and computed Cmax/TMAX as
>>> > $DES
>>> > IF(CONC.GT.COM <http://CONC.GT.COM>(1)) THEN
>>>
>>> > COM(1)=CONC
>>> > COM(2)=T
>>> > ENDIF
>>> >
>>> > $ERROR
>>> > CMAX=COM(1)
>>> > TMAX=COM(2)
>>> >
>>> > 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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>>>
>>
>> -- ------------------------------------------------
>> Paolo Denti, PhD
>> Pharmacometrics Group
>> Division of Clinical Pharmacology
>> Department of Medicine
>> University of Cape Town
>>
>> K45 Old Main Building
>> Groote Schuur Hospital
>> Observatory, Cape Town
>> 7925 South Africa
>> phone: +27 21 404 7719
>> fax: +27 21 448 1989
>> email:paolo.denti_at_uct.ac.za <mailto:paolo.denti_at_uct.ac.za>
>> ------------------------------------------------
>>
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>>
>>
>>
>> --
>> Kyle Baron, PharmD, PhD
>> Senior Scientist
>> Metrum Research Group
>>
>>


--
Kyle Baron, PharmD, PhD
Senior Scientist
Metrum Research Group


Received on Fri May 04 2018 - 13:20:38 EDT

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