Inter-compound and Intra-compound Global Sensitivity Analysis of a Physiological Model for Pulmonary Absorption of Inhaled Compounds

Abstract

In recent years, global sensitivity analysis (GSA) has gained interest in physiologically based pharmacokinetics (PBPK) modelling and simulation from pharmaceutical industry, regulatory authorities, and academia. With the case study of an in-house PBPK model for inhaled compounds in rats, the aim of this work is to show how GSA can contribute in PBPK model development and daily use. We identified two types of GSA that differ in the aims and, thus, in the parameter variability: inter-compound and intra-compound GSA. The inter-compound GSA aims to understand which are the parameters that mostly influence the variability of the metrics of interest in the whole space of the drugs’ properties, and thus, it is useful during the model development. On the other hand, the intra-compound GSA aims to highlight how much the uncertainty associated with the parameters of a given drug impacts the uncertainty in the model prediction and so, it is useful during routine PBPK use. In this work, inter-compound GSA highlighted that dissolution- and formulation-related parameters were mostly important for the prediction of the fraction absorbed, while the permeability is the most important parameter for lung AUC and MRT. Intra-compound GSA highlighted that, for all the considered compounds, the permeability was one of the most important parameters for lung AUC, MRT and plasma MRT, while the extraction ratio and the dose for the plasma AUC. GSA is a crucial instrument for the quality assessment of model-based inference; for this reason, we suggest its use during both PBPK model development and use.

Physiologically Based Pharmacokinetic Modeling of Transporter-Mediated Hepatic Disposition of Imaging Biomarker Gadoxetate in Rats

“…An uncertainty analysis was performed to account for the in vitro data uncertainty within the bottom-up transporter clearance IVIVE. 46 Briefly, in this analysis, all the uncertain or unknown parameters were considered as random variables with a given probability distribution function (pdf) and then a Monte Carlo simulation was performed. In the Monte Carlo simulations, the samples were extracted from the parameters’ joint pdf and, for each sample, the model was evaluated.…”

A latent variable approach to account for correlated inputs in global sensitivity analysis

“…In this work, we focused on the variance-based GSA (also referred to as Sobol's method) [36,38]. This choice was made as variance-based GSA is able to handle nonlinear and nonmonotonic relationships between the input factors and the model outputs [49][50][51].…”

“…Sensitivity analysis (SA) and global SA (GSA) are essential instruments for the quality assessment of model-based inference [ 43 ] and their use has gained interest from pharmaceutical industry and academia in recent years [ 10 , 26 , 34 , 36 – 38 , 58 , 60 ]. Moreover, both the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have highlighted the importance of SA and GSA as best practice in PBPK to inform model development and refinement [ 6 , 7 ].…”

“…For example, GSA can be a valuable method for testing if the model behaves as expected and, if not, it can provide useful information that helps in identifying the reasons and possible errors in the model assumptions or implementation. Moreover, GSA can help identify what parameters may need to be more precisely characterised to allow reliable model predictions [ 36 , 38 , 50 ]. Therefore, by extension, the method is relevant for decision-making informed by modelling in drug development and clinical practice [ 17 , 36 , 37 , 47 , 58 ].…”

“…Moreover, with this method it is possible to quantify the effect of each factor taken singularly and the extent of its interaction effects. As we have reported in our previous work, understanding the extent of the interaction effects can be particularly important for an informed use of PBPK models during drug development [ 38 ].…”