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Re: time-dependent residual error models

From: Nick Holford <n.holford>
Date: Fri, 09 Oct 2009 19:44:26 -0400

Barry,

Thanks for this information. It is good to know that one can ignore this
limitation. I never understood why it was there - especially in NONMEM 7
which was supposed to be a complete rewrite with more flexible structure.

The inability to write out a label for THETA and ETA after 70 is just
one of those odd things about this program...

Nick

Barry Weatherley wrote:
> Nick, only occasionally it is worth while to forget to read the manual!
> In this instance (using NONMEM V, not tried for NONMEM 6), I needed
> more than the allotted ration of THETAs and ETAs. I had to increase
> the variables within *SIZES to allocate bigger LTH, LVR etc. Bill
> Bachman gave me a spreadsheet to get the exact sizes of all the array
> variables.
>
> The only problem was that the output file could not count the THETAs
> and ETAs beyond 70 for labelling them. So above this number the
> labels for THETAs and ETAs were hieroglyphics but the values were fine.
>
> Barry
>
>
> In message <4AC65A15.5050901
> <n.holford
>> Phylinda,
>>
>> Thanks for the explanation about the impracticability of using the
>> 'complex flexible input' model. However, I would have thought the
>> problem was not the run time but the upper limit on number of THETAs
>> of 70 and on OMEGA+SIGMA of 70 in NONMEM (still there in NONMEM 7!).
>>
>> "/III.2.9.1. Changing the Number of Theta’s, Eta’s, and Epsilon’s
>> LTH gives the maximum number of theta’s allowable. It must be between
>> 1 and 70.
>> LVR gives the maximum number of eta’s plus epsilon’s allowable. It
>> must be between 1 and 70/" NONMEM VI User Guide III
>>
>> Where would you get the ultra-big NONMEM version with 97 THETAs and
>> 87 OMEGAs?
>>
>> Nick
>>
>> Chan, Phylinda wrote:
>>> Hi Nick,
>>>
>>> There are 97 thetas and 87 omegas in the complex flexible input model.
>>> Despite of the run time, it is impractical to apply such model for
>>> covariates searching in the meta-analysis.
>>>
>>> Phylinda.
>>>
>>>
>>> -----Original Message-----
>>> From: owner-nmusers
>>> [mailto:owner-nmusers
>>> On Behalf Of Nick Holford
>>> Sent: 30 September 2009 04:31
>>> To: nmusers
>>> Subject: Re: [NMusers] time-dependent residual error models
>>>
>>> Phylinda,
>>>
>>> Thanks for the explanation -- it seems that the more usual approach
>>> of complex structure+simple residual error model had already been
>>> done by Barry Weatherley.
>>> Your simple structure+complex residual error is an interesting
>>> alternative but apart from your feelings ("We felt ...") was there
>>> any reason not to use Barry's structural model?
>>>
>>> Nick
>>>
>>> Chan, Phylinda wrote:
>>>
>>>> Hi Nick,
>>>>
>>>> Being a substrate of P-gp and CYP3A4, the compound itself has a very
>>>> complex absorption profile including dose non-linearity, double peaks,
>>>> food effects as well as high between individual and within individual
>>>> variability. Barry Weatherley has spent a substantial amount of time
>>>> and effort in understanding the dose non-linearity and some covariate
>>>> effects on the PK of this compound, including development of a very
>>>> complex flexible input model which was presented at PKUK in 2004.
>>>>
>>> More
>>>
>>>> details of some of this modelling work can be found in a recent
>>>> publication.
>>>> http://www3.interscience.wiley.com/journal/122386172/abstract
>>>>
>>>>
>>>> The main objective of the meta-analysis was to develop a compartmental
>>>> model which would be useful in identifying significant covariates
>>>> explaining inter-individual variability and was simple enough to be
>>>>
>>> used
>>>
>>>> in the later modelling of sparsely sampled PK in phase 2b/3 studies
>>>> where a full time profile and samples were likely to be clustered in
>>>>
>>> the
>>>
>>>> elimination phase of the PK. We felt the first-order input with dose
>>>> and food effects on Ka in addition to the time-dependent residual
>>>>
>>> error
>>>
>>>> model was adequate for this purpose.
>>>>
>>>>
>>>> For those who interested in the coding of the time-dependent residual
>>>> error model: $ERROR
>>>> IPRED = F+.00001
>>>> LPRED = 0
>>>> IF(IPRED.GT.0) LPRED = LOG(IPRED)
>>>>
>>>> PMAX=THETA(7) TMAX=THETA(8) K=THETA(9)
>>>> BASE=THETA(10)
>>>>
>>>> P=K*TMAX A=EXP(P)/TMAX**P
>>>>
>>>> W= PMAX*A*(TAD+.01)**P*EXP(-K*(TAD+.01))+BASE
>>>> IRES= DV-LPRED
>>>> IWRES= IRES/W
>>>> Y= LPRED+EPS(1) * W
>>>>
>>>> Note:
>>>> i) $SIGMA (1 FIX)
>>>> ii) TAD=time after dose
>>>>
>>>> Phylinda.
>>>>
>>>>
>>>> -----Original Message-----
>>>> From: owner-nmusers
>>>>
>>> [mailto:owner-nmusers
>>>
>>>> On Behalf Of Nick Holford
>>>> Sent: 24 September 2009 08:42
>>>> To: nmusers
>>>> Subject: Re: [NMusers] time-dependent residual error models
>>>>
>>>> Mats,
>>>>
>>>> I agree with your general idea but in this particular case there is no
>>>>
>>>
>>>
>>>> description in the paper of efforts made to test structural models for
>>>>
>>>
>>>
>>>> absorption apart from first order input with dose and food effects
>>>> on Ka. There seems to be quite a lot of time related structure in
>>>> the residual error model function that Phylinda reported and I
>>>> would have thought that at least some of this could have been
>>>> explored via
>>>>
>>> another
>>>> structural model e.g. involving parallel or sequential zero-order
>>>> inputs. It struck me as a rather unusual approach and I wondered
>>>> what reasons for it were.
>>>>
>>>> It does not really bother me which approach is used when describing
>>>> absorption (fancy structure+vanilla residual or vanilla
>>>>
>>> structure+fancy
>>>> residual) because the details of the rate of absorption rarely have
>>>>
>>> any
>>>> clinical relevance (Justin Wilkins may want to disagree <grin>). Of
>>>> course, as you point out the errors may often arise from poorly
>>>> reproducible fixed effects such as timing errors etc. and thus the
>>>>
>>> goal
>>>> may be to describe the error adequately and not the structure
>>>> because the structure is not really fixed or of any interest.
>>>>
>>>> Nick
>>>>
>>>>
>>>> Mats Karlsson wrote:
>>>>
>>>>> Hi Nick,
>>>>>
>>>>> I can't answer for Phylinda, but the general idea is to build the
>>>>>
>>> most
>>>
>>>>> appropriate structural model that is supported by data. However,
>>>>>
>>> after
>>>
>>>>>
>>>> that
>>>>
>>>>> is done, if there still is variation in residual error magnitude
>>>>>
>>>> should
>>>>
>>>>> take that into account and not ignore it. All models are wrong, and
>>>>>
>>>> would
>>>>
>>>>> say that in general our models for absorption are more wrong than
>>>>>
>>>> models
>>>>
>>>>> for disposition. That is not just because we have focused more on
>>>>> latter, but because the underlying processes governing absorption are
>>>>>
>>>> of a
>>>>
>>>>> different nature (e.g. with discrete events like food intake, gastric
>>>>> emptying, bile release and formulation disintegration and movement).
>>>>>
>>>> Further
>>>>
>>>>> often part of the error magnitude is from timing errors. Such errors
>>>>>
>>>> are
>>>>
>>>>> more pronounced when concentrations are changing fast (normally
>>>>>
>>>> fastest
>>>>
>>>>> changes in absorption phase). We wrote on time-varying residual
>>>>>
>>> errors
>>>
>>>>>
>>>> (and
>>>>
>>>>> alternatives such as residual error magnitude related to rate of
>>>>>
>>>> change) in
>>>>
>>>>> these publications: J Pharmacokinet Biopharm. 1995 Dec;23(6):651-72.
>>>>> J Pharmacokinet Biopharm. 1998 Apr;26(2):207-46
>>>>>
>>>>> Best regards,
>>>>> Mats
>>>>>
>>>>> Mats Karlsson, PhD
>>>>> Professor of Pharmacometrics
>>>>> Dept of Pharmaceutical Biosciences
>>>>> Uppsala University
>>>>> Box 591
>>>>> 751 24 Uppsala Sweden
>>>>> phone: +46 18 4714105
>>>>> fax: +46 18 471 4003
>>>>>
>>>>>
>>>>> -----Original Message-----
>>>>> From: owner-nmusers
>>>>>
>>>> [mailto:owner-nmusers
>>>>
>>>>> Behalf Of Nick Holford
>>>>> Sent: Thursday, September 24, 2009 7:46 AM
>>>>> To: nmusers
>>>>> Subject: Re: [NMusers] time-dependent residual error models
>>>>>
>>>>> Hi,
>>>>>
>>>>> If Phylinda reads this I'd be interested to hear why she choose to
>>>>>
>>> use
>>>
>>>>>
>>>> a
>>>>> plain vanilla first-order absorption model and a fancy time-dependent
>>>>>
>>>
>>>
>>>>> residual error model rather than trying to model a fancy
>>>>> absorption process with a plain vanilla residual error model?
>>>>>
>>>>> Nick
>>>>>
>>>>> Joseph Standing wrote:
>>>>>
>>>>>> Xiang,
>>>>>>
>>>>>>
>>>>>> There is a rather elegant time-dependent residual error model
>>>>>> described by Phylinda Chan et al in:
>>>>>>
>>>>>> BJCP, 2008;65(S1):76-85.
>>>>>>
>>>>>>
>>>>>> BW,
>>>>>>
>>>>>> Joe
>>>>>>
>>>>>>
>>>>>
>>>>
>>>
>>>
>>
>

--
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 Oct 09 2009 - 19:44:26 EDT

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