Re: time-dependent residual error models

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. Best Justin Justin Wilkins, PhD Senior Modeler Modeling & Simulation (Pharmacology) CHBS, WSJ-027.6.076 Novartis Pharma AG Lichtstrasse 35 CH-4056 Basel Switzerland Phone: +41 61 324 6549 Fax: +41 61 324 1246 Cell: +41 76 561 0949 Email : [email protected] Nick Holford <[email protected]> Sent by: [email protected] 24/09/2009 10:07 To nmusers <[email protected]> cc 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 > >