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Re: time-dependent residual error models

From: Barry Weatherley <barry_weatherley>
Date: Fri, 9 Oct 2009 14:39:26 +0100

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 Ep=
silon’s
>LTH gives the maximum number of theta’s allowable. It must be betw=
een
>1 and 70.
>LVR gives the maximum number of eta’s plus epsilon’s allow=
able. 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
>> 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
>>>>>
>>>>>
>>>>
>>>
>>
>>
>
Received on Fri Oct 09 2009 - 09:39:26 EDT

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