Placebo in indirect PD models

From: "INTV (Ivan Nestorov)" nestorvi@zgi.com Subject: [NMusers] Placebo in indirect PD models Date: Wed, 26 Apr 2006 16:36:39 -0700 Dear All, I would be interested if anybody from the list can share ideas and experiences with ways to include placebo in indirect PD models. Considering (one type of such) model - with inhibition of synthesys, I have seen this done by: DADT(n) = SYN*(ACTIVE+PLACEBO) - LOSS*A(n), where the term for placebo may range from nothing (leaving all the placebo observations at the mercy of the residual error), all the way to a complex periodic function, adding at least three more thetas to estimate and thus almost always overparametrizing your model. In addition to this, it is a pain, if at all possible, estimating IIV on both SYN, components of ACTIVE and of PLACEBO because of the interaction between them in the equation above. Kind Regards. Ivan Nestorov Zymogenetics 1201 Eastlake Avenue East Seattle, Washington 98102 Tel: 206 442 6613 Fax: 206 442 6608 Cell: 425 442 9303 Email: intv@zgi.com

From: Mark Sale - Next Level Solutions mark@nextlevelsolns.com Subject: Re: [NMusers] Placebo in indirect PD models Date: 26-Apr-2006 21:33 Ivan, General thoughts: Placebo effect is (IMHO) not generally part of the pharmacology. This, it occurs to me is the case in pain. It is something else, expectations (on the part of the patient or the observer), other behavioral/dietary/lifestyle changes etc. So, (also IMHO) it wouldn't be my first choice to model it is part of the drug-related biology. Rather, it is something separate. My favorite placebo model is something that I just simply add to the response plac = Pmax*Time/(TC50+TIME) Y = (F+plac)*exp(eps(1)) where Pmax is the maximum possible placebo effect, and TC50 is the time at which half the maximum is acheived. I really can't think of a case where I would consider the placebo effect to be part of the pharmacology. If you would like something to go up and then down (as, I beleive occurs in pain placebo models), you might consider just a one-compartment, first order absorption model. Mark Sale MD Next Level Solutions, LLC www.NextLevelSolns.com

From: Nick Holford n.holford@auckland.ac.nz Subject: Re: [NMusers] Placebo in indirect PD models Date: Thu, 27 Apr 2006 17:16:19 +1200 Ivan, Mark, I broadly agree with Mark's suggestion for a placebo response based on the 'Bateman' function as an empirical description. But there is a related class of models which describe disease progression that can be intepreted as having a biological basis e.g. the rate of bone resorption changes with time; growth of tumour cells (see Holford et al 2001). These models are extensions to the turnover (aka indirect effect) model family which incorporate time varying changes in either input or loss which are independent of drug. Whether or not one can estimates the model parameters is a question of the design of the study but with suitable designs the structural and randome effects parameters should be estimable. Best wishes, Nick Holford NHG, Mould DR, Peck CC. Disease Progress Models. In: Atkinson A, editor. Principles of Clinical Pharmacology. San Diego: Academic Press; 2001. p. 253-62. -- Nick Holford, Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand email:n.holford@auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556 http://www.health.auckland.ac.nz/pharmacology/staff/nholford/

From: "Piotrovskij, Vladimir [PRDBE]" VPIOTROV@PRDBE.jnj.com Subject: RE: [NMusers] Placebo in indirect PD models Date: Thu, 27 Apr 2006 09:27:39 +0200 Dear Ivan, There may be no general rule how to implement a placebo effect. It depends very much on what is your dependent variable. In case it is a score you may try the method presented at the PAGE meeting in Pamplona last year: http://www.page-meeting.org/?abstract=773 Best regards, Vladimir -------------------------------------------------------------------- Vladimir Piotrovsky, PhD Research Fellow Clinical Pharmacology & Experimental Medicine J&J Pharmaceutical Research and Development Beerse Belgium

From: jeffrey.a.wald@gsk.com Subject: RE: [NMusers] Placebo in indirect PD models Date: Mon, 1 May 2006 08:30:07 -0400 Mark - Thanks for your general thoughts, but in the case of Ivan's original posting I do not think they are relevant. In the case of drug effects that can be described by a semi-physiological model such as an indirect response model the placebo response is typically inextricably linked to the pharmacology and the underlying physiology. One of the advantages in physiologically-based models is that you basically "borrow" degrees of freedom from your knowledge of the system. So for example, if inter-individual variability in drug response relates to the measurements under baseline or placebo conditions then you can perhaps share an ETA for these 2 components that would otherwise be considered separate in a phenomenological model. Furthermore, pain is not a good example for the separability of drug/placebo effects. How could naloxone be a "placebo antagonist" if this were the case? For example: Benedetti, F., C. Arduino, and M. Amanzio. 1999. Somatotopic activation of opioid systems by target-directed expectations of analgesia. Journal of Neuroscience 19(May 1):3639. is one example from a large set of work addressing this for pain in particular. Meta analyses in pain and other diseases (depression is one that springs to mind) have shown that the magnitude of placebo response correlates with the magnitude of pharmacological response. Unfortunately, these have primarily been for parallel group trials and thus look at population averages confounded by other factors. Moreover, I do not yet know of examples that explore this on an individual basis in crossover trials, but it nevertheless suggests to us that placebo response is much more closely linked to drug response than the conventional wisdom of many decades of drug development has allowed for. Getting back to the original question.... If a placebo response model can do any of the following: credibly borrow from the pharmacological part of the model, if it can be implemented in such a way as to make the model simpler than the use of an empirical placebo response model, or if it provides for an improved understanding of the system (either in the presence or absence of drug) then I think it is worth pursuing the physiologically based approach. Now, with all that said I'll expose my mercurial nature and suggest that for an empirical placebo model the 'bateman' function in which k10=k01 is parsimonious and has proven to be very flexible and useful in my own experience. Regards, Jeff Jeff Wald, PhD jeffrey.a.wald@gsk.com Director, Clinical Pharmacokinetics/Modeling and Simulation RTP, North Carolina They always say time changes things, but you actually have to change them yourself. - Andy Warhol

From: Mark Sale - Next Level Solutions mark@nextlevelsolns.com Subject: RE: [NMusers] Placebo in indirect PD models Date: Mon, 01 May 2006 06:37:33 -0700 Jeff, If the placebo model is inextricably linked to the biology/pharmacology, then it is easy. I'm not sure the citation is about a physiologic link. As you point out, pain may be a very poor example of seperation of placebo and drug effect - but I'm searching for another example where they might actually be a physiologic link between placebo effect and drug effect (I'm imagining endorphins, but I'm way out of my depth here). But, I'm not sure that the placebo response being proportional to the drug response demonstrates that the same mechanism/pathway is involved. Does the placebo effect result in greater receptor occupany? The discussion uses words like "correlate" and "metaanalysis" and "confounding", not pharmacologic terms. I assume that "closely linked" means statistically. Not sure what data they might have that could demonstrate a physiologic link. And I can think of a number of mechanisms resulting in a statistical link - including but not limited to being mediated by the same biochemical pathways. Mark Mark Sale MD Next Level Solutions, LLC www.NextLevelSolns.com _______________________________________________________