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Re: time-dependent residual error models

From: justin.wilkins
Date: Thu, 24 Sep 2009 15:03:28 +0200

Hi Nick (and all),

A challenge has been issued and I must respond <grin>. I agree rate of
absorption is often not particularly important (we're usually more
interested in extent) - unless, of course, you're looking to maintain a
concentration above a certain threshold for a period of time, as is the
case with minimum inhibitory concentrations for tuberculosis chemotherapy,
for example. Here, rate of absorption can mean the difference between
killing an infectious organism or merely making it mildly uncomfortable.
The same would apply to any kind of irreversible dose-response.


Justin Wilkins, PhD
Senior Modeler
Modeling & Simulation (Pharmacology)
CHBS, WSJ-027.6.076
Novartis Pharma AG
Lichtstrasse 35
CH-4056 Basel
Phone: +41 61 324 6549
Fax: +41 61 324 1246
Cell: +41 76 561 0949
Email : justin.wilkins

Nick Holford <n.holford
Sent by: owner-nmusers
24/09/2009 10:07

nmusers <nmusers

Re: [NMusers] time-dependent residual error models


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
the 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.


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
> is done, if there still is variation in residual error magnitude one
> take that into account and not ignore it. All models are wrong, and I
> say that in general our models for absorption are more wrong than our
> for disposition. That is not just because we have focused more on the
> latter, but because the underlying processes governing absorption are of
> different nature (e.g. with discrete events like food intake, gastric
> emptying, bile release and formulation disintegration and movement).
> 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
> alternatives such as residual error magnitude related to rate of change)
> 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
> 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
mobile: +64 21 46 23 53

Received on Thu Sep 24 2009 - 09:03:28 EDT

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