Re: time-dependent residual error models

>>> From: owner-nmusers >>> [mailto: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 >>>>>> >>>>>> >>>>> >>>> >>> >>> >> > -- 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