Date Published: August 30, 2020
Publisher: Springer International Publishing
Author(s): Nicola Melillo, Silvia Grandoni, Nicola Cesari, Giandomenico Brogin, Paola Puccini, Paolo Magni.
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.
Due to the opportunity of directly targeting the biophase of interest, the inhalation route has been considered a convenient way of drug administration for local treatment of lung-specific diseases, such as asthma and chronic obstructive pulmonary disease (COPD). This route allows the administration of drugs at lower dosages, minimizing potential side effects driven by high systemic exposures. Topically active compounds for lung diseases have normally an adequate, and generally sustained, lung residence time (1–3). However, efforts have to be placed in the optimization of drug lung disposition looking for an optimal lung retention. In fact, an increased residence time in the airways could potentially translate into the risk of drug removal from the lung due to mucociliary clearance or into the risk of unsafe drug accumulation in pulmonary tissues. For this reason, it is necessary to maintain an appropriate balance between lung retention and absorption by the modulation of the interplay of some key properties, such as solubility, permeability and lung tissue binding (1,3).
In this manuscript, we showed how GSA techniques were used to assess model behaviours and support the development of a mechanistic model describing pulmonary absorption for inhaled compounds. We identified two ways of performing GSA that differ in the aims and, thus, in the considered parameter variability: inter-compounds and intra-compound. Both the approaches helped in understanding different model aspects.
In this work, we showed how GSA can be used within PBPK modelling and simulation. Performing GSA during both the model development and routine use increases the knowledge of the model; it helps in finding errors and in identifying the parameters that must be known with higher confidence, if one is interested in reducing the model prediction uncertainties. 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.