Re: [NMusers] NONMEM code verification

From: Ana Miranda Bastos <ana.bastos_at_uclouvain.be>
Date: Mon, 25 Jan 2016 22:26:04 +0000

Hi,


Thank you all for your input.


Nick - I'll follow your approach, but I'll try to use the R package suggest=
ed by Kyle, as I don't have Berckeley Madonna.


Suruchi - The weird behaviour is that the model simulation is suggesting th=
at for a given Probability of treatment target, a lower dose is needed as t=
he weight goes up and dosing interval goes up. Weight is incorporated in th=
e model using allometric scaling for different parameters. The drug is a pe=
nicillin.


The model diagnostics, including VPCs, look OK, but this result seems to be=
 counter-intuitive...Has anyone seen a behaviour like that before?



Ana

________________________________
From: owner-nmusers_at_globomaxnm.com <owner-nmusers_at_globomaxnm.com> on behalf=
 of Denney, William S. <William.S.Denney_at_pfizer.com>
Sent: 22 January 2016 15:03
To: Bakshi, S.D.
Cc: nmusers_at_globomaxnm.com
Subject: Re: [NMusers] NONMEM code verification

Hi,

Adding to Suruchi, one issue I have encountered in the past when working wi=
th complex or mathematically stiff models is that different integrators occ=
asionally give different results.

This will usually show up as instability of one of the integrators (big jum=
ps up and down on a percent basis from one point to the next). In the past=
 several years, this is getting rarer, but it can never be eliminated while=
 using computers and numerical methods.

Thanks,

Bill

On Jan 22, 2016, at 5:21, "Bakshi, S.D." <s.d.bakshi_at_lacdr.leidenuniv.nl<ma=
ilto:s.d.bakshi_at_lacdr.leidenuniv.nl>> wrote:

Hi Ana,
What kind of weird behavior do you get?
If your model is complex in that it is nonlinear, it is likely that it show=
s multistationarity or oscillations or other emergent behavior which you ma=
y not expect. Some mathematical analysis of the structural model itself may=
 be useful in that case.

Suruchi.

From: owner-nmusers_at_globomaxnm.com<mailto:owner-nmusers_at_globomaxnm.com> [ma=
ilto:owner-nmusers_at_globomaxnm.com] On Behalf Of Kyle Baron
Sent: donderdag 21 januari 2016 22:42
To: Bauer, Robert
Cc: Nick Holford; nmusers_at_globomaxnm.com<mailto:nmusers_at_globomaxnm.com>
Subject: Re: [NMusers] NONMEM code verification

If working in R, you can use mrgsolve:
http://metrumrg.com/opensourcetools.html<https://urldefense.proofpoint.com/=
v2/url?u=http-3A__metrumrg.com_opensourcetools.html&d=CwMGaQ&c=UE1eNs=
edaKncO0Yl_u8bfw&r=4WqjVFXRfAkMXd6y3wiAtxtNlICJwFMiogoD6jkpUkg&m=ppRE3m=
LmLwEUK40XIVKCcYhDBPg6Ut8daFHz3--izi4&s=xZxJx4fKx0tHuBPX2jrymatHCBV3ia4MD=
ZXvDqjP_qw&e=>

It is open-source, validated R package interfacing with DLSODA solver in OD=
EPACK.

It should be able to directly utilize your NONMEM data set:
http://metrumrg.com/mrgsolve-howdoi.html#implement-events-via-data-set<http=
s://urldefense.proofpoint.com/v2/url?u=http-3A__metrumrg.com_mrgsolve-2Dh=
owdoi.html-23implement-2Devents-2Dvia-2Ddata-2Dset&d=CwMGaQ&c=UE1eNseda=
KncO0Yl_u8bfw&r=4WqjVFXRfAkMXd6y3wiAtxtNlICJwFMiogoD6jkpUkg&m=ppRE3mLmL=
wEUK40XIVKCcYhDBPg6Ut8daFHz3--izi4&s=1jnINFT9t3Y9xLxm6u7WDT-q0RoQgWvx7vkw=
AnMgp5Q&e=>
(you might need to rename some columns ... use tolower() or mrgsolve has a =
function to do it).

If you're really making a really close comparison, pay attention to the sol=
ver tolerances and the number of digits in the answer (you can control them=
 in both NONMEM and mrgsolve). Caution: mrgsolve advances with the covaria=
te at T1 (in Bob's example). But I guess I'd tend to take that factor out =
of play and just look at predictions from some parameters constant over tim=
e where possible (assuming you're really wanting to diagnose what is happen=
ing with the ODEs; that's how I understood Nick's post).

Kyle


On Thu, Jan 21, 2016 at 2:02 PM, Bauer, Robert <Robert.Bauer_at_iconplc.com<ma=
ilto:Robert.Bauer_at_iconplc.com>> wrote:
Ana:
The most common reason NONMEM may produce a different result than expected =
is if the evaluation depends on covariates listed in the data set that chan=
ges with each record, the default action of NONMEM is for an interval cover=
ing T1>Time<=T2, it uses the covariate at record TIME=T2. This behavio=
r can be changed with $BIND. Also, if you program in discontinuities that =
vary with model parameters, like changing a rate constant suddenly, you may=
 want to use the MTIME() system. Both of these items are discussed in viii=
.pdf.



Robert J. Bauer, Ph.D.
Vice President, Pharmacometrics R&D
ICON Early Phase
Office: (215) 616-6428<tel:%28215%29%20616-6428>
Mobile: (925) 286-0769<tel:%28925%29%20286-0769>
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conplc.com&d=CwMGaQ&c=UE1eNsedaKncO0Yl_u8bfw&r=4WqjVFXRfAkMXd6y3wiAtx=
tNlICJwFMiogoD6jkpUkg&m=ppRE3mLmLwEUK40XIVKCcYhDBPg6Ut8daFHz3--izi4&s=Y=
_rKfgK60QKPvt-a1cR51zCfjhe03CecdbU1RGJHEmk&e=>

From: owner-nmusers_at_globomaxnm.com<mailto:owner-nmusers_at_globomaxnm.com> [ma=
ilto:owner-nmusers_at_globomaxnm.com<mailto:owner-nmusers_at_globomaxnm.com>] On =
Behalf Of Nick Holford
Sent: Thursday, January 21, 2016 11:33 AM
To: nmusers_at_globomaxnm.com<mailto:nmusers_at_globomaxnm.com>
Subject: Re: [NMusers] NONMEM code verification

Ana,


I call this process fixed effect (or deterministic) model qualification.

I code complex models using Berkeley Madonna then run NONMEM without any
$EST or $SIM records. The NONMEM PRED values should agree with the
Berkeley Madonna predictions if your structural model is coded the same
way in both systems.

Best wishes,

Nick

On 20-Jan-16 11:14, Ana Miranda Bastos wrote:
>
> Hi,
>
>
> I have a complex model with manually coded ODEs and multiple
> compartments. VPC etc seem ok but simulation results are getting a bit
> weird.
>
>
> I'd like to find out what people use to ensure that the NONMEM code
> written really represents the set of ODEs written on paper. Just to
> clarify, this is just to make sure the NONMEM instructions are
> actually a correct representation of the mathematical description of
> the model, not if the model is a correct representation of the biology
> at this stage.
>
>
> This problem is not so obvious when you use the built-in macros but
> once the model grows complex, and has a lot manual inputs, it is more
> likely that a bug creeps in.
>
>
> I'm looking for something more stringent than a code review by a peer.
>
>
> Thank you advance for your time and attention,
>
>
> Ana
>
>
> ------------------------------------------
> Ana Bastos, Pharm, MSc, PhD student
> Pharmacologie cellulaire et moléculaire
> (Cellular and Molecular Pharmacology Unit)
> Louvain Drug Research Institute
> Université catholique de Louvain (Catholic University of Louvain)
> UCL 7370 avenue E. Mounier 73
> 1200 Bruxelles, Belgique
>

--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
office:+64(9)923-6730<tel:%2B64%289%29923-6730> mobile:NZ+64(21)46 23 53
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IVKCcYhDBPg6Ut8daFHz3--izi4&s=n_lm1CsMIyouNC38ssmFpdHdQGI1_0IDXFKGjy0C-iE=
&e=>

"Declarative languages are a form of dementia -- they have no memory of eve=
nts"

Holford SD, Allegaert K, Anderson BJ, Kukanich B, Sousa AB, Steinman A, Pyp=
endop, B., Mehvar, R., Giorgi, M., Holford,N.H.G. Parent-metabolite pharmac=
okinetic models - tests of assumptions and predictions. Journal of Pharmaco=
logy & Clinical Toxicology. 2014;2(2):1023-34.
Holford N. Clinical pharmacology = disease progression + drug action. Br =
J Clin Pharmacol. 2015;79(1):18-27.


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--
Kyle Baron
Metrum Research Group
860-735-7043, Ext. 202
kyleb_at_metrumrg.com<mailto:kyleb_at_metrumrg.com>


Received on Mon Jan 25 2016 - 17:26:04 EST

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