Pharmacokinetic-pharmacodynamic model sensitivity analyses

Nestorov, I. A. Sensitivity analysis of pharmacokinetic and pharmacodynamic models in clinical trial simulation and design. In Kimko, H. C., Duffull, S. B eds. Simulation for designing clinical trials. A pharmacokinetic-pharmacodynamic modeling perspective. (Drugs and the pharmaceutical sciences, volume 127) Marcel Dekker, New York, 2003. 

With the complexity of modern pharmacokinetic-pharmacodynamic models, analytical derivation of sensitivity indexes is rarely possible because rarely can these models be expressed as an equation. More often these models are written as a matrix of derivatives and the solution to finding the sensitivity index for these models requires a software package that can do symbolic differentiation of the Jacobian matrix. Hence, the current methodology for sensitivity analysis of complex models is empirical and done by systematically varying the model parameters one at a time and observing how the model outputs change. While easy to do, this approach cannot handle the case where there are interactions between model parameters. For example, two... 

Nestorov, I. A. (1999). Sensitivity analysis of [4iarmacokinetic and pharmacodynamic systems 1. A structural approach to sensitivity analysis of physiologically based pharmacokinetic models. J Pharmacokinet Biopharm 27, 577-596. 

Documentation on assumptions should address those assumptions implicit in the pharmacokinetic or pharmacodynamic model and the statistical methodology chosen to evaluate the data. It should also state the assumed sensitivity of the parameters required to define the model relative to the data space being evaluated as well as any preconceived notions regarding biomarkers or surrogate markers evaluated as responses or covariates in the analysis. Hypotheses should be defined based on what was held a priori as true before the study or analysis, what was developed from preliminary or exploratory data analysis, and what would constitute a difference or equivalence in an effect or outcome, hi some instances the criteria for difference as opposed to equivalence can be defined from a statistical viewpoint independent of the actual study design. This approach does not always confer regulatory acceptance, however. 

Chen, K., Teo, S., Seng, K.Y., 2009. Sensitivity analysis on a physiologically-based pharmacokinetic and pharmacodynamic model for diisopropylfluorophos-phate-induced toxicity in mice and rats. Toxicol. Mech. Methods 19 (8), 486-497. 

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