RE: Placebo in indirect PD models

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