Challenging the dose-response-time data approach: Analysis of a complex system

R. Andersson, M. Jirstrand, J. Almquist, J. Gabrielsson. Eur J Pharm Sci. 2019 Feb 1;128:250-269. Online 17 November, 2018.


This study presents an extensive dose-response-time (DRT) meta-analysis of the nicotinic acid-induced inhibition of free fatty acids and insulin release. The purpose was to quantify the implications of lacking exposure data when analysing complex pharmacodynamic systems. The DRT model successfully characterised various response behaviours — including time-delays, rebound, feedback mechanisms, and adaptation — on both the individual and the population level. Comparing the fitted DRT model to an exposure-driven reference analysis showed that bias and uncertainty were introduced in the parameter estimates. However, most estimates were within one standard error from the reference. In both approaches, a few parameters suffered from practical identifiability issues, likely due to large differences in half-lives of the different rate processes. Moreover, the optimal dosing strategies predicted by the DRT model differed slightly from those of the exposure-driven analysis, having a lower optimal steady-state reduction of free fatty acids exposure.

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