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RE: [NMusers] NONMEM code verification

From: Bakshi, S.D. <>
Date: Fri, 22 Jan 2016 09:35:10 +0000

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 shows multistationarity or oscillations or other emergent behavior which you may not expect. Some mathematical analysis of the structural model itself may be useful in that case.


From: [] On Behalf Of Kyle Baron
Sent: donderdag 21 januari 2016 22:42
To: Bauer, Robert
Cc: Nick Holford;
Subject: Re: [NMusers] NONMEM code verification

If working in R, you can use mrgsolve:

It is open-source, validated R package interfacing with DLSODA solver in ODEPACK.

It should be able to directly utilize your NONMEM data set:
(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 solver tolerances and the number of digits in the answer (you can control them in both NONMEM and mrgsolve). Caution: mrgsolve advances with the covariate 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 time where possible (assuming you're really wanting to diagnose what is happening with the ODEs; that's how I understood Nick's post).


On Thu, Jan 21, 2016 at 2:02 PM, Bauer, Robert <<>> wrote:
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 changes with each record, the default action of NONMEM is for an interval covering T1>Time<=T2, it uses the covariate at record TIME=T2. This behavior 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><><>

From:<> [<>] On Behalf Of Nick Holford
Sent: Thursday, January 21, 2016 11:33 AM
Subject: Re: [NMusers] NONMEM code verification


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,


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

"Declarative languages are a form of dementia -- they have no memory of events"

Holford SD, Allegaert K, Anderson BJ, Kukanich B, Sousa AB, Steinman A, Pypendop, B., Mehvar, R., Giorgi, M., Holford,N.H.G. Parent-metabolite pharmacokinetic models - tests of assumptions and predictions. Journal of Pharmacology & 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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Received on Fri Jan 22 2016 - 04:35:10 EST

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