Re: time-dependent residual error models

> > From: [email protected] [mailto:[email protected]] > > 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: [email protected] > > > > [mailto:[email protected]] > > > > > 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: [email protected] > > > > > > [mailto:[email protected]] On > > > > > > > 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