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

From: Paolo Denti <paolo.denti_at_uct.ac.za>
Date: Fri, 4 May 2018 18:03:12 +0200

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 ste=
ps 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 rememb=
er - but I am happy to stand corrected - that some DES work in such a way t=
hat 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 retr=
y with a small step size. So I was thinking that maybe the difference in Cm=
ax could be from one of those "faux pas" when NONMEM has overshot the solut=
ion and then it would take a step back?

Just an idea on something to check. But I guess the NONMEM developers may h=
ave 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 m=
odel 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 nec=
k. The various ODE routines are also remarkably sensitive to how the grid i=
s 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 Behal=
f 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 proba=
bly other stats) in the DES block. We used to use this way:
>
> http://cognigencorp.com/nonmem/current/2007-December/4125.html<https://pr=
otect-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(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 i=
nfusion. Unexpectedly, Tmax was estimated at times > 1 hr, and Cmax was hig=
her than 1-hr concentration (true Cmax is at 1 hr).
>
> After some experiments, the explanation was that Nonmem computes concentr=
ation-time course (with infusion ON) for longer than 1 hr, and resulting Cm=
ax/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 devi=
ation (still small, 1-3 percents) was for ADVAN8, ADVAN9, and ADVAN13. ADVA=
N15 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 ou=
tput). So, the discrepancy is small but if 1-2% difference is important, on=
e 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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Received on Fri May 04 2018 - 12:03:12 EDT

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