NONMEM Users Network Archive

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Re: Code to avoid flip-flop kinetics

From: Nick Holford <n.holford>
Date: Sat, 08 Aug 2009 09:03:14 +1200

Hi,

I agree with Leonid -- especially this:
> If population K and KA are close, then it is unclear why individual K
> and KA should be consistently ordered as K < KA and not vice versa for
> some subjects. If so, why not to allow the model to decide whether to
> have flip flop or not?
I do not understand what the concern is with flip-flop kinetics and why
people want to force K<KA. If you have a good reason then various
methods are available (as reviewed again by Paulo).

I wonder if someone would like to describe why it is of interest to
force K<KA?

Nick

Leonid Gibiansky wrote:
> Paolo,
> Option 1 is very helpful. Option 2 is not attractive for the reason
> that you stated, especially, extra correlation introduced by this
> trick. If used, it should be used with the full OMEGA block (CL-V-KA).
> I used it once but only as the last resort when nothing else worked. I
> have not tried option 3 but this option artificially restricts
> distributions, so I am not sure whether it is good or not even when it
> is working.
>
> On the other hand, if population K and KA are sufficiently far apart,
> you are unlikely to get individual K and KA flip-flopped.
>
> If population K and KA are close, then it is unclear why individual K
> and KA should be consistently ordered as K < KA and not vice versa for
> some subjects. If so, why not to allow the model to decide whether to
> have flip flop or not?
>
> I would try to use option (1), and if you like the model, diagnostic
> plots, etc, I would not worry about individual K and KA relation. One
> of the diagnostics could be the fraction of patients with the
> flip-flop. If it is small, this would justify the approach. Another
> possible diagnostic is ETA_KA - ETA_K differences, If it is close to
> normal you are OK, if it has two mirror-symmetric (relative to the
> y-axis) peaks, then flip flop is interfering with the model.
>
> Thanks
> Leonid
>
> --------------------------------------
> Leonid Gibiansky, Ph.D.
> President, QuantPharm LLC
> web: www.quantpharm.com
> e-mail: LGibiansky at quantpharm.com
> tel: (301) 767 5566
>
>
>
>
> Paolo Denti wrote:
>> Dear NMUsers,
>> having to deal with the flip-flop kinetics phenomenon, I had a look
>> at previous posts on the NMusers list.
>> I found this post particularly enlightening:
>> http://www.cognigencorp.com/nonmem/nm/99aug072003.html
>>
>> Some code was proposed to avoid the flip-flop at population and
>> individual level. Here's a not-so-brief summary.
>>
>> This parameterization solves the issue at population level:
>> CL=THETA(1)*EXP(ETA(1))
>> V=THETA(2)*EXP(ETA(2))
>> TVKE=THETA(1)/THETA(2)
>> TVKA=TVKE+THETA(3)
>> KA=TVKA*EXP(ETA(3))
>>
>> However, it does not prevent the phenomenon occurring at individual
>> level. Vlamidir Piotrovsky proposed the code below, which does solve
>> the problem at individual level, but makes the interpretation of the
>> results a bit awkward and introduces correlation among the model
>> parameters. In particular, variance of ETA3 was greatly increased.
>> CL=THETA(1)*EXP(ETA(1))
>> V=THETA(2)*EXP(ETA(2))
>> KE=CL/V
>> KA=KE+THETA(3)*EXP(ETA(3))
>>
>> Another approach, suggested by Nick Holford, implements error
>> recovery using EXIT 1. The code is reported below:
>> CL=THETA(cl)*EXP(ETA(cl))
>> V=THETA(v)*EXP(ETA(v))
>> KA=THETA(ka)*EXP(ETA(ka))
>> K=CL/V
>> IF (KA.LE.K) EXIT 1 101 ; try again (PREDERR message error code 101)
>>
>> As far as I understand, this interrupts the computation whenever the
>> flip-flop occurs and lets NONMEM restart. However, if such an error
>> arises at initialization, NONMEM does not recover and the run goes no
>> further. Nick probably experienced something similar, but apparently
>> received no answer
>> http://www.cognigencorp.com/nonmem/nm/99oct072004.html
>>
>> Does anyone know of a way around this drawback? Or have other code to
>> deal with flip-flop kinetics?
>>
>> Thank you in advance,
>> Paolo
>>
>>
>> --
>> ------------------------------------------------
>> Paolo Denti, Post-Doctoral Fellow
>> 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
>> ------------------------------------------------

--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
n.holford
mobile: +64 21 46 23 53
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
Received on Fri Aug 07 2009 - 17:03:14 EDT

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