Re: time-dependent residual error models

> -----Original Message----- > From: 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 > 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. > > 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 one >> > should > >> take that into account and not ignore it. All models are wrong, and I >> > would > >> say that in general our models for absorption are more wrong than our >> > models > >> for disposition. That is not just because we have focused more on the >> 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