Exploration of sexual dimorphism and inter-individual variability in multivariate parameter spaces for a...

Pharmacokinetic models are particularly useful to study the underlying and complex physiological mechanisms contributing to clinical differences across patient subgroups or special populations. Unfortunately, the inherent variability of biological systems and knowledge gaps in physiological data limit confidence in model predictions for special populations. Sourcing data to reflect the desired physiologies can be resource intensive, particularly for a larger model. Thus, a critical step in model development for special populations involves an in-depth analysis of model inputs, which can be guided by Monte Carlo simulations. Such an approach enables the generation of parameter values by stochastic sampling that are subsequently restricted to the combinations that describe biologically plausible or target model output. Our approach utilized a published pharmacokinetic compartmental model to demonstrate how sampling in conjunction with global sensitivity analysis can be used to explore sexual dimorphism and inter-individual variability in multivariate parameter spaces for differentiation of model input and behavior across phenotypes. Despite limiting the model output to relatively narrow ranges, male and female phenotypes were associated with wide variability in both individual parameter values and combinations of parameters. Through an integrated approach using a support vector machine, principal component analysis and global sensitivity analysis, our approach revealed that specific combinations of parameters gave rise to a certain phenotype, while individual parameters influenced the shape of plasma concentration profile. Augmenting analysis of the model input with global sensitivity analysis enabled an understanding of both sexual dimorphism and inter-individual variability in pharmacokinetics. While the current study revealed how model input could be separated by sex for a simple compartment model, the approach could be extended to other patient factors, such as age or disease, and to a more complex physiologically-based model that describes absorption, distribution, metabolism, and elimination with more detail.