Re: How to account for M-M in the presence of Ka>Ke constraint in PopPK model

On 9/07/2015 7:57 a.m., Paolo Denti wrote: > Dear Lei, > I feel your pain, cuz I have also battled with models with stubborn > flip-flop and I started concocting all sort of codes similar to yours > to prevent it - you can probably find some desperate posts of mine > about this on NMUSERS :). > > In my experience, the only code that sort of works without causing too > many side-effects is the one that prevents flip-flop of the typical > values (the THETAs). Unfortunately, this does not work every time, but > all the other codes accounting for individual parameters (such as the > one you propose) introduce funny correlations between the parameters > and the ETAs, they reshape the between-subject variability, and they > may end up causing more trouble than they solve. > In your case with nonlinear clearance, it may be even more complicated > than usual. > > In my experience, the best option is to use priors on ka and volume, > even weakly informative. These should help stabilising your model. > Adding priors may seem "artificial", but if you think about it, it is > doing exactly what you are trying to achieve with all these tricky > codes. One cannot solve the flip-flop problem only with data from oral > administration, the only way is to add external information, like the > fact that you expect ka to be larger than ke, or include IV data that > helps you identify the correct value of volume. With the priors you do > just that, and in a more natural way than "cheating" NONMEM with funny > codes. > > Good luck! > Paolo > > > On 2015/07/08 22:41, Lei Diao wrote: >> >> Dear NONMEM Users, >> >> I have a popPK model for which the Ka is constrained to be larger >> than Ke at the individual level to avoid flip-flop. The question is >> that if there is an additional nonlinear clearance component (M-M), >> how should I constrain between the absorption rate (KA) and terminal >> phase elimination rate (KE) since nonlinear clearance causes the KE >> to change with time? Is there any reference on this topic? >> >> >> KA and KE constraining in the absence of nonlinear clearance in NM code: >> >> KE=((K+K23+K32)-SQRT((K+K23+K32)*(K+K23+K32)-4*K*K32))/2 >> >> KA=KE+THETA(5)*EXP(ETA(3)) >> >> Thanks a lot for your input! >> >> Lei Diao >> >> Biogen >> > > -- > ------------------------------------------------ > Paolo Denti, PhD > Pharmacometrics Group > Division of Clinical Pharmacology > Department of Medicine > University of Cape Town > > K45 Old Main Building > Groote Schuur Hospital > Observatory, Cape Town > 7925 South Africa > phone: +27 21 404 7719 > fax: +27 21 448 1989 > email:paolo.denti_at_uct.ac.za > ------------------------------------------------ > ------------------------------------------------------------------------ > UNIVERSITY OF CAPE TOWN > > This e-mail is subject to the UCT ICT policies and e-mail disclaimer > published on our website at > http://www.uct.ac.za/about/policies/emaildisclaimer/ or obtainable > from +27 21 650 9111. This e-mail is intended only for the person(s) > to whom it is addressed. If the e-mail has reached you in error, > please notify the author. If you are not the intended recipient of the > e-mail you may not use, disclose, copy, redirect or print the content. > If this e-mail is not related to the business of UCT it is sent by the > sender in the sender's individual capacity. -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand office:+64(9)923-6730 mobile:NZ+64(21)46 23 53 FR+33(7)80 48 55 50 email: n.holford_at_auckland.ac.nz http://holford.fmhs.auckland.ac.nz/ Holford SD, Allegaert K, Anderson BJ, Kukanich B, Sousa AB, Steinman A, Pypendop, B., Mehvar, R., Giorgi, M., Holford,N.H.G. Parent-metabolite pharmacokinetic models - tests of assumptions and predictions. Journal of Pharmacology & Clinical Toxicology. 2014;2(2):1023-34. Holford N. Clinical pharmacology = disease progression + drug action. Br J Clin Pharmacol. 2015;79(1):18-27.